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Doctoral Thesis

Identification of therapeutic targets for 19q12 amplified ovarian cancers by a kinome-scale loss of function screen

Author(s): Stark, Rebekka

Publication Date: 2017

Permanent Link: https://doi.org/10.3929/ethz-b-000161378

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ETH Library DISS. ETH NO. 24344

Identification of therapeutic targets for 19q12 amplified ovarian cancers by a kinome-scale loss of function screen

A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (Dr. sc. ETH Zurich)

presented by REBEKKA STARK M.sc. in Biology, University of Tuebingen

born on 21.07.1987 citizen of Germany

accepted on the recommendation of Prof. Dr. Wilhelm Krek Prof. Dr. Josef Jiricny Dr. Matthias Gstaiger

2017

Für Thomas

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«Wenn man auf ein Ziel zugeht, ist es äusserst wichtig, auf den Weg zu achten. Denn der Weg lehrt uns am besten, ans Ziel zu gelangen, und er bereichert uns, während wir ihn zurücklegen» Paulo Coelho

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4 Danksagung

Danksagung

Die Zeit als Doktorand an der ETH Zürich in Prof. Wilhelm Kreks Labor war mit Sicherheit eine der lehr- und erfahrungsreichsten, sowohl auf wissenschaftlicher als auch auf persönlicher Ebene; eine Zeit mit vielen Höhen und Tiefen, Herausforderungen und schmerzhaften Erfahrungen, aber auch eine Zeit vieler schöner Momente voller Freude, Hoffnung und Erfolg. Ich möchte mich herzlich bei allen Personen bedanken, die mich ihn dieser Zeit unterstützt, gefördert und gefordert haben, vor allem bei:

- Prof Dr. Wilhelm Krek für die Betreuung meiner Doktorarbeit sowie für die exzellenten Forschungsmöglichkeiten, die mir zur Verfügung standen und die ich immer sehr zu schätzen wusste. Weiterhin möchte ich mich für den erheblichen Beitrag zu meiner persönlichen Entwicklung als Wissenschaftler bedanken. Durch die stetigen Herausforderungen konnte ich über meine bisherigen Grenzen hinauswachsen. - Prof. Dr. Josef Jiricny und Dr. Matthias Gstaiger, den Korreferenten und Mitgliedern meines Doktoratskomitees - Dr. Werner Kovacs, Dr. Stefanie Flückiger-Mangual und Dr. Andrea Aloia für die Korrektur und Verbesserungsvorschläge dieser Arbeit - Dr. Christian Stirnimann und Miquel Busquet Lopez von Nexus Personalized Health Technologies, ETHZ für die Erstellung der shRNA Kinome Library - Dr. Weihong Qi und Lennart Opiz vom Functional Genomics Center Zürich für den Sequencing Service und die Datenauswertung des shRNA Screens - Dr. Ana Vukolic für die Assistenz bei den Mouse Xenograft Experimenten - Dr. Jonathan Ward und Birte Appelt und dem gesamten ETH Phenomics Center Team für den exzellenten Tierhaltungsservice - Allen momentanen und ehemaligen Krek Lab Members, die für mich mehr Freunde als Kollegen waren und aufgrund vieler schöner gemeinsamer Momente und Erlebnisse erheblich dazu beigetragen haben, dass mir die Zeit an der ETH sehr positiv in Erinnerung bleiben wird - Meinen Eltern und Geschwistern für ihre stetige Unterstützung, den Glauben an mich und meine Stärken, sowie ihre Liebe - Meinem Thomas, dem diese Arbeit gewidmet ist, weil sie ohne ihn schlichtweg nicht existieren würde. Ich bin dir so unglaublich dankbar für deine enorme Unterstützung und den Rückhalt, den du mir v.a. während meiner PhD Zeit aber auch zuvor immer gegeben hast. Vielen Dank für deine Liebe, Kraft und Stärke, die ich nicht nur in schwierigen Zeiten zu schätzen wusste, für das gemeinsame Durchhaltevermögen und nicht zuletzt für das Ertragen meines ungebremsten Temperaments. Vielleicht waren die letzten 4.5 Jahre bisher unsere härtesten, aber auch unsere bisher schönsten, aufregendsten und glücklichsten gemeinsamen.

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6 Zusammenfassung

Zusammenfassung

Epitheliale Ovarialkarzinome sind die fünft häufigste Todesursache bei Frauen (Jemal, Siegel et al. 2010). Bei den meisten Patientinnen treten Therapieresistenzen nach cryo-reductiver Entfernung des Primärtumors und anschliessender Chemotherapie auf. Dies führt zum Wiederauftreten der Krankheit und damit verbundener schlechter Langzeitprognose und Überlebenschance. Insbesondere Patientinnen mit epithelialen High Grade Serous (HGS) Ovarialkarzinomen, welche die bösartigste Untergruppe von Eierstocktumoren darstellt, sind davon betroffen (Bowtell 2010, Sun, Su et al. 2016). Um neue Therapieansätze für Patientinnen mit HGS Ovarialkarzinomen zu finden, beschäftigt sich die Wissenschaft aktuell mit der Entwicklung von spezifischen Angriffsstrategien, indem spezifische molekularen Zielobjekte dieser Tumore therapeutisch inhibitert werden, welche Zellwachstum und – überleben fördern. Der chromosomale Locus 19q12 repräsentiert ein vielversprechendes therpeutisches Zielobjekt, da die Amplifizierung dieses Loci mit erfolgloser Platinum-basierter chemotherapeutischer Behandlung, kürzerer progressionsfreier Zeit und schlechteren Langzeitüberlebenschance in Zusammenhang gebracht wird (Etemadmoghadam, deFazio et al. 2009, Theurillat, Metzler et al. 2011, Yang, Gu et al. 2011, Tummala, Gomes et al. 2014, Gu, Liang et al. 2015, Patch, Christie et al. 2015, Wang, Garabedian et al. 2015). Aus diesem Grund war das Ziel der vorliegenden Arbeit, spezifische Eigenschaften und Signalwegabhängigkeiten von 19q12 amplifizierten HGS Ovarialkarzinomen zu identifizieren. Um dieses Ziel zu erreichen wurde nach essentiellen Genen gesucht, die dazu beitragen, dass 19q12 amplifizierte Tumorzellen überleben und sich weitervermehren. Wir fokussierten uns auf die Identifizierung von Kinasen, da diese Proteine und deren Signalwegskomponenten in Krebszellen häufig dereguliert sind und somit zu abnormalem Tumorwachstum beitragen (Cohen 2002, Zhang, Yang et al. 2009). Durch die Herunterregulierung aller Kinasen des menschlichen Genoms mit Hilfe von «short hairpin RNAs», konnten wir Casein Kinase 1 ε (CSNK1E) und Cyclin-dependent kinase 13 (CDK13) als essentielle Gene für 19q12 amplifizierte HGS Ovarialkarzinomzellen entdecken und validieren. Für CDK13 konnte weiterhin in in vivo Xenograft Modellen gezeigt werden, dass die Herunterregulierung von CDK13 das Fortschreiten des Tumorwachstums von Tumoren vermindert, welche von 19q12 amplifizierten Ovarialkarzinomzellen abstammen. Die Entdeckung von CSNK1E und CDK13 könnte ein neuer potentieller Therapieansatz für HGS Ovarialkarzinome, aber auch für andere Krebsarten, welche die molekulare Eigenschaft der 19q12 Amplifizierung aufweisen. Weiterführende Studien, die sich mit der Entwicklung von selektiven kleinmolekularen Inhibitoren gegen Casein kinase 1 ε und CDK13 beschäftigen würden, welche die Aktivität der jeweiligen Kinasen und somit Tumorwachstum unterbinden, könnten ein weiterer Meilenstein in der personalisierten Medizin gegen 19q12 amplifizierte Tumore darstellen.

7 Abstract

Abstract

Epithelial ovarian cancer is the fifth leading cause of cancer death in women (Jemal, Siegel et al. 2010). The emergence of drug resistance after cryo-reductive surgery followed by chemotherapy and the recurrence of the disease results for most patients in a poor long-term prognosis and survival. This applies especially to patients with high-grade serous epithelial ovarian cancer (HGSOC), which is the most malignant subtype of epithelial ovarian cancer (Bowtell 2010, Sun, Su et al. 2016). In order to find new therapy options for HGSOC patients, the current focus in research is set on the identification of strategies which target vulnerabilities of HGSOC by therapeutic intervention of molecular targets, which promote cell growth and survival. The chromosomal locus 19q12 represents a promising therapeutic target since amplification of this locus is considered as a major genomic feature of HGSOC and has been associated with primary treatment failure of platinum based chemotherapy, shorter progression free survival and poor survival outcome (Etemadmoghadam, deFazio et al. 2009, Theurillat, Metzler et al. 2011, Yang, Gu et al. 2011, Tummala, Gomes et al. 2014, Gu, Liang et al. 2015, Patch, Christie et al. 2015, Wang, Garabedian et al. 2015). Therefore, we aimed to focus on properties and pathway dependencies of 19q12 amplified HGSOC cells by screening for essential genes which contribute to the survival and progression of 19q12 amplified cells and tumors. In particular, we focused on the identification of kinases since kinases and their signaling pathway components are often aberrantly regulated in cancer cells contributing to survival advantages and tumor progression (Cohen 2002, Zhang, Yang et al. 2009). In a pooled shRNA screen targeting all kinases of the human genome, we identified and validated Casein Kinase 1 ε (CSNK1E) and Cyclin dependent kinase 13 (CDK13) as hits being essential for 19q12 amplified HGSOC. CDK13 was also validated in in vivo mouse xenograft models as 19q12 essential hit, since downregulation of CDK13 diminished tumor growth progression in tumors deriving from 19q12 amplified HGSOC cells. The identification of CSNK1E and CDK13 represents a novel approach for a potential targeted therapy for HGSOC and most likely for other types of cancer exhibiting the molecular feature of 19q12 amplification. In further studies, the development of selective small molecule inhibitors targeting and therefore preventing Casein kinase 1 ε and CDK13 activity, which convey tumor cell growth and survival respectively, could set a further milestone in the development of personalized medicine against 19q12 amplified tumors.

8 Table of contents

Table of contents

Danksagung ...... 5

Zusammenfassung ...... 7

Abstract ...... 8

Table of contents ...... 9

List of figures ...... 13

Abbreviations ...... 16

1. Introduction ...... 21

1.1 The genetic origin and properties of cancer ...... 21

1.1.1 Mutations ...... 21

1.1.2 Gene amplifications ...... 22

1.1.3 Hallmarks of cancer ...... 23

1.1.4 Cancer stress phenotypes ...... 24

1.2 Cancer statistics ...... 25

1.2.1 Global cancer incidence and mortality rates ...... 25

1.2.2 Expected new cancer cases and cancer related deaths for 2017 (USA) ...... 25

1.3 Ovarian Cancer ...... 27

1.3.1 Ovarian Cancer Statistics ...... 27

1.3.2 Ovarian Tumor Types and Origins ...... 27

1.3.3 Epithelial Ovarian Cancer ...... 28

1.3.3.1 Type I and II classification of epithelial ovarian cancer ...... 28

1.3.3.2 High Grade Serous Ovarian Cancer (HGSOC) ...... 30

1.3.3.2.1 Genomic features of HGSOC ...... 30

1.3.3.2.2 19q12 amplification as major genomic feature of HGSOC ...... 33

1.3.3.2.3 Features and functions of 19q12 genes ...... 35

1.3.3.2.4 URI1 and CCNE1 as major oncogenic driver genes of the chromosomal locus 19q12 ...... 37

1.3.4 Treatment of ovarian cancer ...... 40

9 Table of contents

1.3.4.1 General treatment and recent precision targeted therapy options ...... 40

1.3.4.2 Challenges in the treatment of ovarian cancer ...... 43

1.3.4.3 Diagnosis and therapy options for HGSOC with 19q12 amplification ...... 44

2. Aims of the study ...... 46

3. Results ...... 47

3.1 Characterization of cell lines ...... 47

3.2. Dependency of ovarian cancer cell lines on URI1 and CCNE1 ...... 51

3.3 Identification of genes essential for 19q12 amplified ovarian cancer cells by a pooled shRNA screen ...... 54

3.4 Hit validation of top hits ULK3, INSR, CSNK1E and CDK13 ...... 61

3.5 Hit validation of CSNK1E and CDK13 in an extended panel of 19q12 non-amplified ovarian cancer cell lines ...... 65

3.6 CK1ε inhibition with small molecule inhibitors ...... 70

3.7 CDK13 phenotype rescue experiments ...... 74

3.7.1 Testing the specificity of antibodies against CDK13 ...... 74

3.7.2 Test of CDK13 rescue constructs ...... 74

3.7.3 Phenotypic rescue of CDK13 depleted 19q12 amplified cell lines ...... 75

3.8 In vivo tumor growth of CDK13 depleted subcutaneous tumors of mouse xenograft models ...... 79

3.8.1 Preparation and test of cell lines with tetracycline-inducible CDK13 knockdown...... 79

3.8.2 Mouse xenograft pilot experiment ...... 82

3.8.3 Mouse xenograft main experiment ...... 91

4. Discussion ...... 96

4.1 Gene amplification as characteristic feature of HGSOC ...... 96

4.2 19q12 specific survival dependencies ...... 97

4.2.1 19q12 specific dependency on the oncogenic driver genes URI1 and CCNE1 ...... 97

4.2.2 19q12 specific gene cluster and pathway dependencies ...... 98

4.2.3 Identification of kinases essential for 19q12 amplified HGSOC ...... 99

4.2.3.1 Identification of CSNK1E as 19q12 essential gene ...... 100

10 Table of contents

4.2.3.2 Identification of CDK13 as 19q12 essential gene ...... 102

4.2.3.3 Connection between 19q12 and CDK13...... 106

5. Materials and Methods ...... 110

5.1. Cell culture techniques ...... 110

5.1.1 Cell maintenance/passaging ...... 110

5.1.2 Freezing cells ...... 110

5.1.3 Thawing cells ...... 110

5.1.4 Mycoplasm test ...... 111

5.2 Transfection of cell lines ...... 113

5.2.1 Transient DNA plasmid transfection of 293T cells for lentiviral production ...... 113

5.2.2 Viral infection/transduction of host cells ...... 113

5.3 Cloning ...... 114

5.3.1 Cloning of CDK13 overexpression constructs ...... 114

5.3.2 Cloning of CDK13 rescue constructs ...... 115

5.3.3 Cloning of tetracycline-inducible shRNA constructs ...... 116

5.4 Transcription Analyses...... 116

5.4.1 Quantitative PCR (qPCR) ...... 116

5.4.2 Western Blotting ...... 117

5.5 Bioinformatical analysis ...... 118

5.5.1 Copy number variation determination ...... 118

5.5.2 mRNA expression determination ...... 118

5.6 RNAi screen ...... 119

5.6.1 Preparation of pooled kinome shRNA library ...... 119

5.6.2 Production of lentiviral particles containing plasmids of 2688 constructs ...... 120

5.6.3 Multiplicity of infection (MOI) determination by lentiviral titering ...... 120

5.6.4 Infection of cell lines...... 123

5.6.5 Isolation of genomic DNA (gDNA) ...... 123

5.6.6 Amplification of hairpins sequences with barcode specific primers ...... 124

11 Table of contents

5.6.7 Illumina Sequencing ...... 125

5.6.8 Bioinformatic analysis ...... 125

5.6.9 Hit validation ...... 127

5.6.9.1 Cell viability assays ...... 127

5.6.9.1.1 Colony Formation Assay ...... 127

5.6.9.1.2 Annexin V Assay...... 128

5.6.9.1.3 PrestoBlue assay ...... 129

5.7 Mouse xenografts models ...... 129

5.7.1 Husbandry of BALB/cAnNRj-Foxn1nu/nu ...... 129

5.7.2 Establishment of human tumor xenografts in BALB/cAnNRj-Foxn1nu/nu mice ...... 129

5.7.3 Animal monitoring/ Tumor measurement ...... 130

5.7.4 Test of CDK13 knockdown efficiency in tumor samples ...... 131

References ...... 132

Supplement ...... 151

Supplemental figures ...... 151

Supplemental Tables ...... 155

Curriculum Vitae ...... 203

12 List of figures

List of figures

Figure 1: Median number of non-synonymous somatic mutations per tumor in representative human cancers ...... 21 Figure 2: Hallmarks of cancer ...... 23 Figure 3: Ten leading cancer types of estimated new cancer cases and deaths by sex in the United States, 2017 ...... 26 Figure 4: Expanded dualistic model of carcinogenesis of epithelial ovarian cancers ...... 29 Figure 5: Incidence and amplification frequency of genes of the chromosomal locus 19q12 ...... 34 Figure 6: Frequency of 19q12 amplifications in CCLE cell lines...... 35 Figure 7: Composition of the Prefoldin and the Prefoldin-like/URI1 complex and the RT2P module39 Figure 8: Ranking of ovarian cancer cell lines by suitability as HGSSOC models for in vitro studies. 47 Figure 9: Number of pubmed citations for the 47 ovarian cancer cell lines being ranked as suitable HGSOC models...... 48 Figure 10: Amplification status of 19q12 genes of in ovarian cancer cell lines used for the pooled shRNA screen ...... 49 Figure 11: mRNA and protein expression levels of 19q12 genes in 19q12 amplified and non-amplified cell lines...... 50 Figure 12: 19q12 amplified ovarian cancer cells are more dependent on URI1 than 19q12 non- amplified cells ...... 52 Figure 13: 19q12 amplified ovarian cancer cells are more dependent on CCNE1/Cyclin E than 19q12 non-amplified cells ...... 53 Figure 14: Statistical analysis of pooled shRNA screen in 7 different cell lines ...... 56 Figure 15: Identification of “gene solutions” by ATARiS analysis approach ...... 58 Figure 16: Dependency pattern of the 143 genes for which “gene solutions” could be found according ATARiS ...... 59 Figure 17: Knockdown efficiency of shRNAs targeting genes identified as being essential for 19q12 amplified cells tested in OVCAR8 cells ...... 61 Figure 18: Hit validation of top hits identified as being essential for 19q12 amplified cells ...... 64 Figure 19: Hit validation of top hits CSNK1E and CDK13 identified as being essential for 19q12 amplified cells in an extended panel of 19q12 non-amplified cell lines ...... 65 Figure 20: Validation of CSNK1E as being essential for 19q12 amplified ovarian cancer cells ...... 67 Figure 21: Validation of CDK13 as being essential for 19q12 amplified ovarian cancer cells ...... 68 Figure 22: CK1ε inhibitor IC261 decreases cell viability of both 19q12 amplified and 19q12 non- amplified cells...... 71

13 List of figures

Figure 23: CK1ε inhibitor PF4800567 decreases cell viability of both 19q12 amplified and 19q12 non- amplified cells ...... 72 Figure 24: Test of knockdown efficiency of CDK13 on protein level ...... 74 Figure 25: Test of CDK13 overexpression constructs...... 75 Figure 26: Overexpression of CDK13 promotes increased cell proliferation and rescues apoptosis induced by depletion of CDK13 ...... 77 Figure 27: CDK13 knockdown efficiency of tet-inducible induction of CDK13 k.d. in OVCAR3, OVCAR8, SKOV, TYKNU cells...... 79 Figure 28: Tetraycyline-inducible k.d. of CDK13 ...... 81 Figure 29: Scheme of pilot experiment of in vivo xenograft mouse models ...... 83 Figure 30: CDK13 depletion in 19q12 amplified tumors derived from OVCAR8 cells reduces tumor growth xenograft models ...... 85 Figure 31: Xenograft experiment with the 19q12 amplified cell line OVCAR3 ...... 86 Figure 32: Xenograft Models of 19q12 non-amplified cell line SKOV3...... 88 Figure 33: CDK13 depletion in 19q12 non- amplified tumors does not affect tumor growth in xenograft models ...... 90 Figure 34: Scheme of main experiment of in vivo xenograft mouse models ...... 91 Figure 35: CDK13 depletion in 19q12 amplified tumors derived from OVCAR8 cells reduced tumor growth in xenograft models ...... 93 Figure 36: CDK13 depletion in 19q12 non- amplified tumors does not affect tumor growth in xenograft models ...... 95 Figure 37: Hypothesized model of the prefoldin-like/URI1 complex interacting with snoRNP complexes via the R2TP module ...... 108 Figure 38: Lentiviral titer estimation assay ...... 122 Figure 39: Scheme of TRC-pLKO vectors of TRC 1.0/1.5 library carrying short hairpin sequences between EcoRI and AgeI restriction sites ...... 124 Supplementary Figure 1: Mouse Xenograft Main experiment TYKNU mice of CTRL feed group ...... 151 Supplementary Figure 2: Mouse Xenograft Main experiment TYKNU mice of Doxycycline feed group ...... 152 Supplementary Figure 3: Mouse Xenograft Main experiment OVCAR8 mice of CTRL feed group .... 153 Supplementary Figure 4: Mouse Xenograft Main experiment OVCAR8 mice of Doxycycline feed group ...... 154

14 List of tables

List of tables

Table 1: Summary of key molecular features of HGSOC and alteration frequency…………...... …32 Table 2: Top hits of genes essential for 19q12 amplified cell lines identified by own analysis approach……………………………………………………………………………………………………………………...... 57 Table 3: Top hits of genes essential for 19q12 amplified cell lines identified by ATARiS analysis approach……………………………………………………………………………………………………………………………60 Table 4: Cell line information………………………………………………………………………………………………………..111 Table 5: Antibody information………………………………………………………………………………………………………117 Table 6: Missing bacterial cultures of TRC clones………………………………………………………………………….118 Table 7: Amount of virus being used for infection of 5386000 cells of according cell line……………..122 Table 8: Cell numbers seeded for cell viability assays (CFA and Annexin V) for hit validation………..126

15 Abbreviations

Abbreviations

µL Microliter µm Micrometer µM Micromolar a Ampere Ab Antibody ACVRL1 Activin receptor like type 1 ANT2 Adenine nucleotide translocase 2 approx. Approximately ATARiS Analytic Technique for Assessment of RNAi by Similarity ATCC American Type Culture Collection ATM Ataxia-Telangiectasia ATP Adenosine triphosphate BCR Breakpoint cluster region BIR Break induced replication bp Basepair BRCA Breast cancer C19orf12 Chromosome 19 open reading frame 12

CaCl2 Calcium chloride CCLE Cancer Cell Line Encyclopedia CCNE1 Cyclin E (gene) CDK12 Cyclin-dependent kinase 12 CDK13 Cyclin-dependent kinase 13 CDK2 Cyclin-dependent kinase 2 cDNA Complementary DNA CFA Colony formation assay CK1 δ Casein kinase I isoform delta (protein) CK1 ε Casein kinase I isoform epsilon (protein) CNV Copy number variation

CO2 Carbon dioxide CSNK1E Casein kinase I isoform epsilon (gene) CT Cycle threshold CTRL Control DDR DNA damage response DMEM Dulbecco’s modified eagle’s medium DMSO Dimethyl sulfoxide DNA Deoxyribonucleic acid doxy Doxycycline DSB Double strand break DTT Dithiothreitol ECL Enhanced chemiluminescence EDTA Ethylenediaminetetraacetic acid EMA European Medicines Agency EOC Epithelial ovarian cancer

16 Abbreviations

EPIC ETH Phenomics Center ESA Esophageal adenocarcinoma ESCC Esophageal squamous cell carcinoma EtOH Ethanol FA Fanconi anemia FACS Fluorescence-activated cell sorting FBXW7 F-box/WD repeat-containing protein 7 FCS Fetal calf serum FRα Folate receptor α fw Forward GAPDH Glyceraldehyde 3-phosphate dehydrogenase gDNA Genomic DNA GFP Green fluorescent protein HCl Hydrochloride HGSC High grade serous carcinoma HGSOC High grade serous ovarian cancer HOSE Human ovarian surface epithelium HPRT Hypoxanthine phosphoribosyltransferase 1 HR Homologous recombination HRP Horseradish peroxidase HSP90 Heat shock protein 90 IARC International Agency for Research on Cancer

IC50 Half maximal inhibitory concentration IL17 Interleucin 17 incl. Including INDEL Insertion or deletion mutation INSR Insulin receptor ISH In situ hybridisation JCRB Japanese Collection of Research Bioresources Cell Bank k.d. Knockdown kDa Kilo dalton LB Lysogeny broth LGSOC Low grade serous ovarian cancer MAPK Mitogen-activated protein kinase ml Milliliter mm Millimeter MOI Multiplicity of infection MSI Microsatelite instability mRNA Messenger ribonucleic acid mTOR Mammalian target of rapamycin MW Molecular weight NaCl Sodium chloride NaF Sodium fluoride NASH Non-alcoholic steatohepatitis NCBI National Center for Biotechnology Information NGS Next generation sequening

17 Abbreviations nM Nano meter nM Nano molar NSCLC Non-small cell lung cancer nt Nucleotide OE Overexpression OGT O-linked N-acetylglucosamine transferase OVGP1 Oviductal glycoprotein 1 PARP Poly-ADP ribose polymerase PBS Phosphate buffered saline PDRG1 P53 and DNA damage-regulated protein 1 PEI Polyethylenimine PEI Polyethylenimine PFA Paraformaldehyde PFD Prefoldin Pih1 Protein interacting with Hsp90 1 PLEKHF Pleckstrin homology domain-containing family F member 1 POLR2E RNA polymerase II DNA-directed polypeptide E POP4 Ribonuclease P protein subunit p29 PP1 γ Protein phosphatase 1 γ PVDF Polyvinylidene fluoride qPCR Quantitative PCR RAS Rat sarcoma rev Reverse RLU Relative light units RMP Rounds per minute RNAi RNA interference RPB1 RNA polymerase II subunit B1 RPB5 RNA polymerase II binding protein 5 RPMI Roswell Park Memorial Institute rRNA Ribosomal RNA RT Room temperature S6K1 Ribosomal protein S6 kinase beta-1 SCLC Small cell lung cancer SD Standard deviation SDS Sodium dodecyl sulfate SEM Standard error of the mean SET Solid, pseudoendometrial, transitional shRNA Short hairpin ribonucleic acid snoRNA Small nucleolar ribonucleic acid snRNA Small nuclear ribonucleic acid

SRSF1 Serine/arginine-rich splicing factor 1 SSB Single strand break STAP1 SKP2-associated α- PFD 1 STIC Serous intraepithelial tubal carcinoma Tah1 TPR (tetratricopeptide repeat)-containing protein associated with HSP 90 TB Terrific broth

18 Abbreviations

TBP TATA-box binding protein TCEP Tris(2-carboxyethyl)phosphine hydrochloride solution TCGA The Cancer Genome Atlas tet Tetracycline TH17 T helper 17 cells THEG5 Testis highly expressed protein 5 TRC The RNAi Consortium Tris Tris(hydroxymethyl)aminomethane TSHZ3 Teashirt zinc finger homeobox 3 UBC Ubiquitin C ULK3 Unc-51 like kinase 3 UQCRFS1 Ubiquinol-cytochrome C reductase, rieske iron-sulfur polypeptide 1 URI1 Unconventional prefoldin RPB5 interactor 1 v Volt vs. versus VSTM2B V-set and transmembrane domain containing 2B WAT White adipose tissue ZNF563 Zink finger protein 563

19 Abbreviations

20 1. Introduction

1. Introduction

1.1 The genetic origin and properties of cancer

1.1.1 Mutations

Cancer is an evolutionary driven genetic disease which results from the accumulation of somatic mutations in the progeny of a single cell, leading to selective growth advantages and uncontrolled proliferation of the mutated cells (Nowell 1976, Vogelstein and Kinzler 1993). According to this sequential multistep model of carcinogenesis a sufficient number of mutations is required in order to drive the development from a clone of neoplastic cells to a malignant tumor. The number of mutations in a common solid tumor can vary from less than ten to thousands of non-synonymous clonal mutations (Figure 1), which specifically affect genes and alter the amino acid sequence of their encoded proteins.

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0 Breast Gastric Prostate Colorectal Pancreatic Melanoma Lung (SCLC)Lung Endometrial Glioblastoma Glioblastoma Hepatocellular Head and Neck Neuroblastoma Colorectal(MSI) Ovarian(HGSOC) Esophageal (EAC) RhabdoidCancers Medulloblastoma Esophageal(ESCC) Acute Lymphoblastic… Chronic Lymphocytic…Chronic Endometrial(serous) AcuteLeukemia Myeloid Non-HodgkinLymphoma LungCancer(NSCLC - non… Lung CancerLung (NSCLC- smokers) mutagens

Adult solid tumors liquid pediatric

Figure 1: Median number of non-synonymous somatic mutations per tumor in representative human cancers. Results are based on 29 different sequencing studies. Horizontal bars indicate the 25 and 75% quartiles. Adapted from (Vogelstein, Papadopoulos et al. 2013).

21 1. Introduction

Tissues with a higher susceptibility for mutations are self-renewing tissues (e.g. intestinal epithelium) and tissues with higher exposure to potent mutagens (e.g. lung, skin) (Vogelstein, Papadopoulos et al. 2013). A large number of these mutations arise even before tumor initiation and positively correlate with the age (Tomasetti, Vogelstein et al. 2013). However, the great majority (>99.9%) of these non- synonymous mutations do not provide a selective growth advantage and have no obvious effect on the neoplastic process (Vogelstein, Papadopoulos et al. 2013). Mutations providing no selective growth advantage are referred to as “passenger” mutations, whereas positively selected mutations during the evolution of the cancer conferring a growth advantage are called “driver” mutations (Bishop, Weinberg 1996). Driver mutations often contribute to the generation of oncogenes with a dominant gain of function and/or trigger a loss of function in tumor suppressor genes (Stratton, Campbell et al. 2009). However, the strict differentiation between consequential driver mutations and inconsequential passenger remains still challenging. Supek, Minana et al. 2014 postulated that even mutations, which do not generate changes in the amino acid sequence, called synonymous mutations, represent 6%–8% of all driver mutations due to single- nucleotide changes in these genes. Moreover, synonymous drivers are associated with changes in splicing and altered protein folding (Kimchi-Sarfaty, Oh et al. 2007, Zhang, Baran et al. 2011, Zhou, Guo et al. 2013, Supek, Minana et al. 2014).

1.1.2 Gene amplifications

About 95% of all non-synonymous mutations are single-base substitutions and 5% are other genomic alterations affecting several bases to large DNA sequences which include small insertions and deletions (INDELs), translocations, infections and copy number variations (CNV) encompassing deletions and amplifications (Futreal, Coin et al. 2004, Vogelstein, Papadopoulos et al. 2013). Gene amplification is a copy number increase of a restricted region of a chromosome which is prevalent in some tumors and can be associated with overexpression of the amplified gene(s) (Albertson, Collins et al. 2003). Amplification can provide positive selection of neoplastic clones due to enhanced expression of oncogenes and genes enabling pathway addictions in order to promote growth of the tumor. Amplified DNA sequences can be organized as extrachromosomal elements, as repeated units at a single locus or scattered throughout the genome (Albertson 2006). Many prominent cancer- associated genes as ERBB2, EGFR, MDM2, C-myc, CCND etc. are known to contribute to cancer progression due to amplification. Common chromosomal fragile sites, defects in DNA replication or telomere function are assumed to promote amplification, however the mechanisms of amplicon generation remain largely unknown. Four hypotheses have been proposed for the generation of amplifications, which are either homologous based or non-homologous based: 1. extrareplication and recombination. This type is triggered by aberrant replication in a replication fork, resulting from a

22 1. Introduction single additional initiation of replication within the replication fork (Schimke 1984, Stark, Debatisse et al. 1989, Schwab and Amler 1990, Matsui, Ihara et al. 2013). 2. Breakage-fusion bridge cycle. In this type, chromatids with missing telomeres due to DNA double strand breaks (DSB) replicate over cycles and produce amplifications with inverted repeats (Maser, dePinho, 2002, (Maser and DePinho 2002, Tanaka and Yao 2009, Matsui, Ihara et al. 2013). 3. Double rolling circle replication. This model follows the first (aberrant replication in replication fork) or second model (breakage fusion bridge cycle) by a subsequent DBS and break induced replications (BIR) between sequences with homology in both broken ends. As consequences two replication forks chase each other, facilitating gene amplifications (Kraus, Leung et al. 2001, Watanabe, Tanabe et al. 2011). 4. Replication fork stalling and template switching. In this model replication fork stalls, a single-stranded lagging strand is exposed and anneals to the lagging strand template of another replication fork, forming a microhomology junction by polymerase I and ligase. Two products are generated by RuvC-mediated resolution of the Holliday junction. (Lee, Carvalho et al. 2007, Zhang, Khajavi et al. 2009).

1.1.3 Hallmarks of cancer

Capabilities gained by genomic alterations of neoplastic cells that are essential for the development of malignancy can be defined as hallmarks of cancer. The original 6 hallmarks formulated by Hanahan and Weinberg comprise (1) Limitless replicative potential; (2) sustained angiogenesis; (3) evading apoptosis; (4) self-sufficiency in growth signals; (5) insensitivity to anti-growth signals and (6) tissue invasion and metastasis (Hanahan and Weinberg 2000) (Figure 2A).

Figure 2: Hallmarks of cancer. A. Original six biologicals capabilities acquired during the multistep development of human carcinogenesis (Hanahan and Weinberg 2000) B. Addition of 2 emerging hallmarks and 2 consequential characteristics, which enable acquisition of all 8 hallmarks (Hanahan and Weinberg 2011).

Due to conceptual progress, the original hallmarks were extended by following two emerging hallmarks being involved in the pathogenesis of cancer: (1) deregulating cellular energetics in order to

23 1. Introduction most efficiently support neoplastic proliferation (2) evading immune destruction. Furthermore, two consequential characteristics of neoplasia were postulated which facilitate acquisition of both core and emerging hallmarks: (1) Genomic instability which provide genetic alterations that drive tumor progression; (2) Tumor promoting inflammation which contributes to multiple hallmark capabilities by supporting the tumor microenvironment (Hanahan and Weinberg 2011) (Figure 2 B).

1.1.4 Cancer stress phenotypes

The six original hallmarks of cancer were extended by five additional hallmarks that depict the stress phenotypes of cancer cells (Luo, Solimini et al. 2009). DNA damage stress, oxidative stress, mitotic stress, proteotoxic stress and metabolic stress have been postulated to functionally interplay with the classical hallmarks to promote tumorigenesis. These hallmarks are not responsible for initiating tumorigenesis, they are common characteristics of many tumor types which comprise oncogene and non-oncogene addictions. The term non-oncogene addiction was created by Solimini et al, 2007 describing the phenomenon that cancer cells display an increased dependency on the normal cellular function of certain genes that act in oncogenic pathways but are not themselves classical oncogenes (Solimini, Luo et al. 2007). Non-oncogene addiction genes fall into two general categories, tumor intrinsic, which support oncogenic state of the tumor cell in a cell autonomous manner, and tumor extrinsic which function in stromal and vascular cells that provide heterotypic support for the tumor (Luo, Solimini et al. 2009). Furthermore, Luo et al, 2009 elaborated on how these stress phenotypes of cancer can be exploited through stress sensitization and stress overload to selectively kill cancer cells due to targeting pathways which are vulnerable to therapeutic interference.

24 1. Introduction

1.2 Cancer statistics

1.2.1 Global cancer incidence and mortality rates

The latest assessment on global cancer statistics was published in 2012. According to estimates from the International Agency for Research on Cancer (IARC), there were 14.1 million new cancer cases in 2012 worldwide. 8 million occurred in economically developing countries, in which about 82% of the world’s population live. The corresponding estimates for total cancer deaths in 2012 were 8.2 million – 2.9 million in economically developed countries, and 5.3 million in economically developing countries. In both economically developed and developing countries, the three most common cancer types for females in 2012 were breast, colon/rectum, and lung/ bronchus; for males the most common cancer types were lung, prostate, colon, liver and stomach. It is expected that by 2030, the global rates of new cancer cases and cancer deaths will grow to 21.7 million and 13 million, respectively, due to the growth and aging of the population. It is also assumed that rates will rise due to the adoption of lifestyles of developed countries that are known to increase cancer risk, such as smoking, poor diet, physical inactivity, etc.

1.2.2 Expected new cancer cases and cancer related deaths for 2017 (USA)

The most current cancer statistics for developed countries is represented by the yearly update of the American Cancer Society, which publishes the estimated numbers of new cancer cases and deaths at the beginning of each year that will occur in the United States in the current year. In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are estimated to arise. The overall cancer incidence rate was stable in women since 2004 and declined by approximately 2% annually in men, however the incidence rate is still 20% higher in men than in women. The cancer death rate declined since 2005 by about 1.5% annually in both men and women, however it is 40% higher in men than in women (Siegel, Miller et al. 2017). Figure 3 shows a ranking of the most common cancer types expected to occur in men and women in 2017. Prostate, lung/bronchus, and colorectal are the most common cancers in men, whereas breast, lung/bronchus, and colorectal are the most common cancer types in women in the USA. This sexual distribution of cancer types is in accordance with the global IARC statistics of 2012.

25 1. Introduction

Figure 3: Ten leading cancer types of estimated new cancer cases and deaths by sex in the United States, 2017.Estimates are rounded to the nearest 10 and cases exclude basal cell and squamous cell skin cancers and in situ carcinoma except urinary bladder. (Siegel, Miller et al. 2017)

The number of estimated new cancers does not necessarily correlate with the number of estimated cancer deaths. This is due to the fact that for some cancers diagnostic methods and therapy options are more advanced than for others. Furthermore, the stage of the disease at the diagnosis time point plays also a tremendous role in terms of curability of the disease. For examples breast cancer accounts for 30% of all estimated new cancer cases, but accounts only for 14% of all estimated deaths. Also prostate cancer patients benefit from early diagnostic methods and successful treatment options reflected by the percentage of 19% of all estimated new cancer deaths, however only a percentage of 8% of estimated cancer deaths among males. However, there are also cancer types for which the cancer death rate is higher than occurance rate, as for ovarian cancer, which is the fifth most common cancer type in females, but number 12 of the most common occurring cancer types (Siegel, Miller et al. 2017).

26 1. Introduction

1.3 Ovarian Cancer

1.3.1 Ovarian Cancer Statistics

About 240000 new cases of ovarian cancer are diagnosed and over 150000 ovarian cancer related deaths are registered worldwide each year (Ferlay, Soerjomataram et al. 2015). Even though ovarian cancer represents only 1.3% of all cancer incidences, it is the fifth most common cause of cancer- related death in women (Siegel, Miller et al. 2017, National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available online: https://seer.cancer.gov/statfacts/html/ovary.html. Accessed on 10th February 2017), and the most lethal of all gynecologic malignancies (Brucks 1992). Ovarian cancer mainly develops in older women since approx. 50% of patients diagnosed with ovarian cancer are 63 years or older (American Cancer Society. What Is Ovarian Cancer? Available online: https://www.cancer.org/cancer/ovarian- cancer/about/what-is-ovarian-cancer.html. Accessed on 11th February 2017). The high mortality rates are ascribed to the diagnosis of up to 80% of cases only at advanced stage disease due to unspecific abdominal symptoms and limited early detection methods (Bast et al., 2009). At this stage effective treatment options are very limited leading to an overall ovarian cancer 5-year survival rate of around 45% (Kim et al., 2012b) which has not improved over the past three decades (National Cancer Institute). However, cure options for patients with early stage ovarian cancer are much more promising and the 5-year survival rate is 94% (American Cancer Society).

1.3.2 Ovarian Tumor Types and Origins

The conventional classification differentiates between three main types of ovarian tumors based on the tissue of origin, called germ, stromal and epithelial cell tumors. Ovarian germ cell tumors are derived from primordial germ cells of the ovary that produce the ova (Talerman 1994). Ovarian stromal tumors evolve from mature ovarian stroma and undergo common non-neoplastic transformations such as stromal changes associated with follicle development and nodular stromal hyperplasia (Sternberg and Dhurandhar 1977). Epithelial ovarian tumors were originally assumed to arise from the ovarian surface epithelium (mesothelium) originating in metaplastic changes which lead to the development of the different subtypes. However, several lines of evidence exist now that ovarian epithelial tumors develop independently along different molecular pathways and the primary tumors or precursor lesions originate in other pelvic organs and involve the ovary secondary (Dubeau 1999, Dubeau 2008, Kurman and Shih Ie 2010). Most ovarian tumors are benign (non-cancerous) and do not spread. These tumors can be removed by surgery, whereas for malignant (cancerous) tumors therapy options are limited due to the high

27 1. Introduction metastasizing potential. Malignant germ cell and stromal tumors combined account for 5–10% of all ovarian cancers, whereas malignant epithelial ovarian tumors, also called carcinomas, account for 85- 90% of all ovarian cancers (Algeciras-Schimnich 2013).

1.3.3 Epithelial Ovarian Cancer

1.3.3.1 Type I and II classification of epithelial ovarian cancer

Epithelial ovarian cancer (EOC) has originally been classified into four histological subtypes called mucinous, clear cell, endometrioid and serous (Prat 2004, Seidman, Horkayne-Szakaly et al. 2004). All subtypes are considered as heterogeneous and inherently different diseases, as indicated by differences in tissues of origin, epidemiological and genetic risk factors, molecular events during oncogenesis, precursor lesions, patterns of spread, response to chemotherapy and prognosis (D'Angelo and Prat 2010). In the past 10 years, a substantial re-evaluation of the conventional classification has taken place due to new molecular, genetic and pathological findings. Therefore a dualistic model was proposed that categorizes various types of ovarian cancer into two groups designated type I and type II (Shih Ie and Kurman 2004). Type I tumors account for 25% of all EOC and include endometrioid, clear cell, seromucinous, low grade serous and mucinous carcinomas and malignant Brenner tumors (Guth, Huang et al. 2007, Kurman and Shih Ie 2016) (Figure 4). Based on epidemiological and genetic features, carcinomas of the subtype endometroid, clear cell and seromucinous, which represent a mixture of epithelial cell types including endometroid, squamous cells and endocervical type mucinous cells, are assumed to originate from Müllerian ducts. Müllerian ducts are the precursor tissue of the internal female sex organs. These carcinomas are known to develop from endometriosis as a result of retrograde menstruation (Martin 1997, Bulun 2009, Kurman and Shih Ie 2010, Kurman and Shih Ie 2016). Furthermore, precursor lesions of clear cell carcinomas might also originate in other pelvic organs since they have similar expression profiles to renal clear cell and uterine clear cell carcinomas (Zorn, Bonome et al. 2005). Low grade serous ovarian cancer (LGSOC) evolve from atypical proliferative serous tumors in a stepwise manner indicated by hyperplastic lesions in the fallopian tube (Kurman, Vang et al. 2011). Mucinous tumors represent a spectrum of neoplastic disorders with no-Müllerian origin. They are assumed to be of either germ cell origin or from benign transitional (Brenner) tumors which in turn derive from the transitional-type epithelium located at the tubal-peritoneal junction (Seidman and Khedmati 2008, Kurman and Shih Ie 2010). Type I tumors exhibit a shared lineage between benign cystic neoplasms and the corresponding carcinomas often through an intermediate borderline tumor (Shih Ie and Kurman 2004, Kurman and Shih Ie 2010). In terms of molecular features, type I tumors exhibit a low genomic alteration frequency

28 1. Introduction and are therefore genetically relatively stable. In addition, Type I tumors display a variety of somatic mutations that include KRAS, BRAF, ERBB2, PTEN, PIK3CA, CTNNB1, ARID1A, and PPP2R1A (Shih Ie and Kurman 2004, Kuo, Guan et al. 2009, Jones, Wang et al. 2010, Kurman and Shih Ie 2011). However, TP53 mutations are very rare (Kuo, Guan et al. 2009). In terms of pathology, type I tumors are low grade (well-differentiated and similar to original tissue), show an indolent, slow growing behavior. Furthermore, they are usually confined only to the ovary and spread late in their development (Kurman and Shih Ie 2010). The surgical removal of a fallopian tube and the affected ovary is generally curative for type I tumors, explaining the fact that only 10% of all EOC deaths are based on type I tumors (Guth, Huang et al. 2007, Kurman and Shih Ie 2016).

Figure 4: Expanded dualistic model of carcinogenesis of epithelial ovarian cancers. Four histological types of epithelial ovarian cancers (endometrioid, clear cell, serous, mucinous) are classified according to their origin tissue deriving from endometrial tissue, fallopian tube tissue, germ cells and transitional epithelium. LG, low grade; HG, high grade; SET, solid pseudoendometrioid transitional (Kurman and Shih Ie 2016).

Type II account for 75% of all EOC and comprise high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcoma), and undifferentiated carcinoma (Shih Ie and Kurman 2004, Kurman and Shih Ie 2016) (Figure 4). High grade serous carcinomas (HGSC) are subdivided into two morphological subsets, the usual type (solid, glandular, often accompanied by necrosis) and the SET variant (solid, pseudoendometrial, transitional). In contrast to the usual HGSC type, the SET type histologically and morphologically simulates endometrioid and transitional cell carcinomas, however exhibits an identical molecular profile to HGSC (Soslow, Han et al. 2012, Kobel, Kalloger et al. 2013). In addition to the two different morphological subtypes, type II EOC are divided into four molecular subtypes based on their expression profiles called immunoreactive, differentiated, proliferative, mesenchymal (Cancer Genome Atlas Research 2011). These subtypes have been originally defined by Tothill, Tinker et al. 2008 as high stromal (C1), high immune signature (C2), low stromal response (C4) and low immune signature, mesenchymal (C5) (Tothill, Tinker et al. 2008). By adding significant prognostic values in terms of survival and potential subtype specific treatment strategies, these

29 1. Introduction subtypes were validated (Verhaak, Tamayo et al. 2013, Konecny, Wang et al. 2014) and therefore renamed as immunoreactive, differentiated, proliferative, mesenchymal (Cancer Genome Atlas Research 2011). Several lines of evidence indicate that type II high grade serous carcinoma develop from intraepithelial carcinomas in the fallopian tube (Piek, van Diest et al. 2001, Shaw, Rouzbahman et al. 2009, Przybycin, Kurman et al. 2010). Serous intraepithelial tubal carcinoma (STIC) have been identified as putative precursor lesion in the fallopian tube that morphologically and molecularly resembles high grade serous ovarian carcinomas (Gagner and Mittal 2005, Kindelberger, Lee et al. 2007, Kurman and Shih Ie 2010). Furthermore, gene expression profiles of HGSC are more closely related to the fallopian tube than to the ovarian surface epithelium (Marquez, Baggerly et al. 2005). In terms of molecular features, Type II tumors exhibit a low frequency of somatic mutations, which are characteristic for type I tumors. However, TP53 mutations occur in 95% and genomic alterations in Homologous Recombination (HR) pathway genes in 50% of all HGSOC and carcinosarcomas (Shih Ie and Kurman 2004, Ahmed, Etemadmoghadam et al. 2010). Furthermore, Type II tumors are characterized by a high frequency of genomic alterations in particular copy number variations and therefore a high genomic instability (Shih Ie and Kurman 2004, Kuo, Guan et al. 2009). In terms of pathology, type II tumors are high-grade neoplasms, presenting stages II-IV (moderately well differentiated (II) undifferentiated, anaplastic) in >75% of all cases. They evolve rapidly, are highly aggressive and metastasize early in their course and are characterized by a poor survival outcome (Guth, Huang et al. 2007, Kurman and Shih Ie 2016).

1.3.3.2 High Grade Serous Ovarian Cancer (HGSOC)

1.3.3.2.1 Genomic features of HGSOC

In 2011, The Cancer Genome Atlas Research Network set a milestone in the molecular characterization of HGSOC by employing a variety of high-throughput technologies to systematically catalogue genomic and epigenomic aberrations in approx. 500 HGSOC samples. By analyzing mRNA and miRNA expression, promoter methylation and copy number variations, a new large-scale integrative view on HGSOC was provided. Based on this analysis, subtypes of HGSOC were re-defined and subtype- stratified therapy options were suggested which might improve outcomes for HGSOC patients (Cancer Genome Atlas Research 2011). Since TP53 mutations occur in >95% of all HGSOC they can be considered as early key driver events of tumorigenesis (Ahmed, Etemadmoghadam et al. 2010, Cancer Genome Atlas Research 2011). Approx. 50% of HGSOC exhibit genetic or epigenetic alterations affecting DNA damage repair via HR comprising germline mutations of BRCA1/2 (17-22%), somatic mutations of BRCA1/2 (6-7%), BRCA1 promoter methylation (10%), mutations in several Fanconi Anemia pathway genes (2%), in core HR Rad genes (1.5%) and other HR damage response genes (2%), additionally genomic alterations in genes indirectly

30 1. Introduction causing HR deficiency (PTEN loss, 8%, CDK12 mutation 3%, EMSY amplification, 17%) (Baldwin, Nemeth et al. 2000, Esteller, Silva et al. 2000, Hughes-Davies, Huntsman et al. 2003, Pal, Permuth-Wey et al. 2005, Hennessy, Timms et al. 2010, Cancer Genome Atlas Research 2011, Alsop, Fereday et al. 2012). Furthermore, other independent genes were identified to be statistically recurrently mutated at lower rates (<6%) including RB1, NF1, CSMD3 and GABRA6 (Cancer Genome Atlas Research 2011, Patch, Christie et al. 2015). In addition to frequent alterations affecting HR repair genes, HGSOC exhibit a large burden of copy number gains and losses, both contributing to high chromosomal instability. Genomic instability promotes the acquisition of further DNA alterations leading to genetic diversity within a tumor and creating the possibility of coexistence of genetically distinct subclones contributing to a selective advantage during ongoing oncogenesis (Salomon-Perzynski, Salomon-Perzynska et al. 2017). Most commonly amplified genes include CCNE1, MYC and MECOM which were identified to be amplified in ≥20% of HGSOC cases (Cancer Genome Atlas Research 2011). Furthermore, EMSY (17%), PAX8 (16%), NOTCH3 (21%), AKT2 (27%) (Hughes-Davies, Huntsman et al. 2003, Nakayama, Nakayama et al. 2007, Cheung, Cowley et al. 2011). Homozygous deletions most frequently affected the genes PTEN (7%), RB1 (2%) and NF1 (2%). Notably, RB1 and NF1 were among the significantly mutated genes (Cancer Genome Atlas Research 2011).

31 1. Introduction

Table 1: Summary of key molecular features of HGSOC and alteration frequency Molecular Alteration Sub-feature Affected gene(s) Literature feature frequency Gene mutations TP53 >95% Ahmed, et al. 2010 Bowtell, et al. 2010 Cancer Genome Atlas Research, 2011 germline BRCA1/2 17-22% Alsop, Fereday et al. 2012 Cancer Genome Atlas Research, 2011 Hennessy, Timms et al. 2010 somatic BRCA 1/2 6-7% Alsop, Fereday et al. 2012 Cancer Genome Atlas Research, 2011 CDK12 3% Cancer Genome Atlas Research, 2011 RB1, NF1, CSMD3, GABRA6 ≥ 6% Cancer Genome Atlas Research, 2011 Patch, Christie et al. 2015 FA genes 2% Cancer Genome Atlas Research, 2011 HR DNA damage response genes 2% Cancer Genome Atlas Research, 2011 RAD genes 1.5% Cancer Genome Atlas Research, 2011 Epigenetic BRCA1 promoter methylations 10% Baldwin, Nemeth et al. 2000 changes Cancer Genome Atlas Research, 2011 Hughes-Davies, 2003 Copy number amplification CCNE1, MYC, MECOM ≥20% Cancer Genome Atlas Research, 2011 alterations EMSY 17% Cancer Genome Atlas Research, 2011 PAX8 16% Cancer Genome Atlas Research, 2011 Cheung, Cowley et al. 2010 Notch3 21% Nakayama, Nakayama et al. 2007 AKT2 27% Nakayama, Nakayama et al. 2007 deletion PTEN 8% Cancer Genome Atlas Research, 2011 deletion NF1 2% Cancer Genome Atlas Research, 2011 RB1 2% Cancer Genome Atlas Research, 2011 Gene proliferative High expression: MCM2, PCNA, HMGA2, SOX11 30% Tothill,et al, 2008 expression Low expression: MUC1, MUC16 Cancer Genome Atlas Research, 2011 subtypes Immuno- High expression: CXCL11, CXCL10, CXCR3, CDK12 24% Tothill,et al, 2008 reactive Cancer Genome Atlas Research, 2011 differentiated High expression: MUC1, MUC16, CDK12, SLP1 20% Tothill,et al, 2008 Cancer Genome Atlas Research, 2011 mesenchymal High expression: WNT genes, HOX genes 26% Tothill,et al, 2008 Low expression: e-cadherin Cancer Genome Atlas Research, 2011 Altered RB signaling RB1 (deletion, mutation) 8%, 2% Cancer Genome Atlas Research, 2011 signaling CCNE1 (amplification) 20% pathways CCND1 (amplification) 4% CCND2 (upregulation) 15% CDKN2A (downregulation) 30% RAS/PI3K PTEN (deletion) 8% Cancer Genome Atlas Research, 2011 signaling PI3KCA (genomic alteration) 18% AKT1, AKT2 (amplification) 3%, 7% NF1 (deletion, mutation) 8%, 4% KRAS (genomic alteration) 11% BRAF (mutation) 0.5% NOTCH JAG1, JAG2 (amplification) 2%, 3% Cancer Genome Atlas Research, 2011 NOTCH3 (amplification) 11% MAML1, MAML2, MAML3 (mutation) 2%, 4%, 2% FOXM FOXM1, TP53, ATM, ATR, CHEK1, CHEK2, BRCA1, Cancer Genome Atlas Research, 2011 BRCA2, RAD51, BRCC, CCNB1, PLK1, AURBK, BIRC5, CDC25B

According to specific expression profiles HGSOC are further sub-classified as mentioned above. The proliferative/high stromal (C1) subtype exhibits high expression of proliferative markers (MCM2, PCNA) and transcription factors (HMGA2, SOX11) and low expression of ovarian tumor markers (MUC1 and MUC16). Molecular features of the immunoreactive subtype/high immune signature (C2) include high expression of T-cell chemokine ligands (CXCL11 and CXCL10) and the receptor CXCR3 and increased infiltration of intratumoral CD3+ cells, furthermore high expression of CDK12. The

32 1. Introduction differentiated/ low stromal response (C4) subtype displays high expression of ovarian tumor markers MUC1 and MUC16, furthermore CDK12 and the secretory fallopian tube marker SLP1. The low immune signature, mesenchymal (C5) subtype is associated with high expression of HOX-genes, WNT signaling genes, and developmental transcription factors, however reduced expression of E-cadherin, which are features of epithelial-mesenchymal transition (EMT) (Cancer Genome Atlas Research 2011). The best overall survival rate showed the immunoreactive subtype, whereas the proliferative and mesenchymal subtypes showed the worst outcome (Konecny, Wang et al. 2014). Multidimensional analyses integrating genomics and proteomics data including mutations, copy number changes, changes in gene expression, epigenetic changes, protein-protein interactions and differential network activities revealed cancer associated pathways significantly altered in HGSOC. Four commonly deregulated pathways in HGSOC included the RB, RAS/PI3K, FOXM1 and NOTCH pathways altered in 67%, 45%, 84% and 22%, respectively of all analyzed cases.

1.3.3.2.2 19q12 amplification as major genomic feature of HGSOC

HGSOC are characterized by a high frequency of copy number variations. According to literature amplification of CCNE1 is one of the most prevalent amplifications in HGSOC (Nakayama, Nakayama et al. 2010, Cancer Genome Atlas Research 2011, Patch, Christie et al. 2015). However, this region comprises other co-amplified genes and is not restricted to CCNE1 as a single amplified gene, but rather to the entire chromosomal locus 19q12 which may have an important function in tumor development in different types of cancer (Leung, Ho et al. 2006, Etemadmoghadam, George et al. 2010, Theurillat, Metzler et al. 2011, Natrajan, Mackay et al. 2012). Besides CCNE1 the chromosomal locus 19q12 harbors additional 9 genes (UQCRFS1, VSTM2B, POP4, PLEKHF1, C19orf12, CCNE1, URI1, ZNF536, TSHZ3, THEG5), 2 pseudogenes (LOC100420587, TAF9P3) and uncharacterized regions (NCBI map viewer. Available online: https://www.ncbi.nlm.nih.gov/projects/mapview/maps.cgi?TAXID=9606&CHR=19&MAPS=ideogr%2 Ccntg-r%2Cregions%2Cgenes&QUERY=19q12&BEG=28.00M&END=32M&oview=default (Figure 5 A). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal revealed that amplification of the chromosomal locus 19q12 occurs in multiple tumor types and the most common cancer type carrying 19q12 amplifications is ovarian cancer (Figure 5B). Analyses from two different studies, TCGA provisional, with 591 patient samples and TCGA, Nature 2011, with 557 patient samples showed that 19q12 genes are amplified in 24% (142 out of 591 samples) and 21% (117 out of 557 samples) of ovarian cancers (Cerami, Gao et al. 2012, Gao, Aksoy et al. 2013). Furthermore, a study of the Institute of Surgical Pathology, University hospital Zurich, revealed that 36,6% of epithelial ovarian

33 1. Introduction carcinomas (49 out of 134 samples) harbor 19q12 amplifications and even 44,8% of the HGSOC subtype (30 out of 67 samples) (Noske, Henricksen et al. 2015). Amplification of 19q12 genes can either comprise all genes of the whole chromosomal locus or only single genes varying between patients (Figure 5 C). Genes in the center of the amplicon seem to be more frequently amplified than genes in the border regions. This observation will be discussed in part 4.1. The incidence of co-amplifications and solitary amplifications of 19q12 genes has also been described in a study of the Institute of Surgical Pathology, University hospital Zurich including 150 primary epithelial ovarian carcinomas (n = 148) (Noske, Henricksen et al. 2015).

Figure 5: Incidence and amplification frequency of genes of the chromosomal locus 19q12 A. 19q12 includes 10 genes (UQCRFS1, VSTM2B, POP4, PLEKHF1, C19orf12, CCNE1, URI1, ZNF536, TSHZ3, THEG5), 2 pseudogenes (LOC100420587, TAF9P3) and several uncharacterized regions being mapped on NCBI map viewer (accessed 12.3.2015). B. Cross-cancer copy number alteration frequency of 19q12 genes (Cerami, Gao et al. 2012, Gao, Aksoy et al. 2013). Analysis include 59 TGCA studies with a sample size of at least 100 per study. Only 48 out of 59 studies are displayed for which copy number alterations

34 1. Introduction could be identified. First bar represents a study of 579 patients out of which 142 patients (25%) show alterations in 19q12 genes. Second bar represents another study of 489 patients out of which 11 patients (24%) show alterations in 19q12 genes. C. Copy number alterations frequency of individual 19q12 genes of first study with 579 patients (Cerami, Gao et al. 2012, Gao, Aksoy et al. 2013).

Analysis of 1019 cell lines registered in the Cancer cell line encyclopedia (CCLE) data base (https://portals.broadinstitute.org/ccle/data/browseData?conversationPropagation=begin File: CCLE_copynumber_byGene_2013-12-03) (Marum 2012) confirmed the observation taken from the TCGA data showing that 19q12 amplifications occur most frequently in ovarian cancer cell lines (Figure 6A). 35% of all epithelial ovarian cancer cell lines registered in the CCLE database carry an amplification of 19q12.

A B Incidence of 19q12 amplifications in CCLE cell lines CCLE epithelial ovarian cancer cell lines with 19q12 amplification ovary stomach 5.0% liver 5.0% biliary tract breast lung 20.0% oesophagus pancreas endometrium 70.0% thyroid central nervous system pleura haematopoietic & lymphoid tissue high grade serous clear cell soft tissue mucinous endometrioid 0% 5% 10% 15% 20% 25% 30% 35% mixednot known not known

Figure 6: Frequency of 19q12 amplifications in CCLE cell lines (Marum 2012). A. Distribution of 19q12 amplifications among different cancer type. 19q12 genes considered genes for analysis: UQCRFS1, VSTM2B, POP4, PLEKHF1, C19orf12, CCNE1, URI1, ZNF536, TSHZ3, THEG5. B. Frequency of 19q12 amplifications in CCLE ovarian cancer cell line subtypes high grade serous, clear cell, mucinous, endometrial. Amplification threshold of 0.04 (Nijhawan, Zack et al. 2012).

70% of epithelial ovarian cancer cell lines with 19q12 amplification are from the subtype HGSOC (Figure 6 B). 20% of the 19q12 amplified ovarian cancer cell lines are from the subtype clear cell and only a very small percentage are mucinous carcinomas. Cell lines of the endometrioid subtype were not represented in the CCLE. Therefore, amplification of 19q12 can be considered as a major genomic feature of high grade serous ovarian cancer cells. Sung et al even defined 19q12 amplified HGSOC as a new subtype of HGSOC (Sung, Song et al. 2014).

1.3.3.2.3 Features and functions of 19q12 genes

Functions of most 19q12 genes are mostly known only to a very limited extend or not at all. Ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1 (UQCRFS1) is a subunit of the cytochrome bc1 complex (complex III) of the mitochondrial respiratory chain which generates an

35 1. Introduction electrochemical potential coupled to Adenosine triphosphate (ATP) synthesis (Pennacchio, Bergmann et al. 1995). UQCRFS1 has been found to be amplified in particular in breast cancers correlating with higher aggressiveness of the cancers (Ohashi, Kaneko et al. 2004). Part of ribonuclease P 4 (POP4) represents the p29 subunit of the related ribonucleoproteins ribonuclease (RNase) P and RNase MRP (van Eenennaam, Pruijn et al. 1999). RNase P is a protein complex that generates mature tRNA molecules by cleaving their 5'-ends (Hartmann and Hartmann 2003). RNase MRP (mitochondrial RNA processing) is an ribosomal RNA (rRNA) processing enzyme that cleaves a specific site within precursor rRNA to generate the mature 5'-end of 5.8S rRNA (Walker, Aspinall et al. 2005). Plekstrin homolog domain containing family 1 (PLEKHF1) is assumed to induce apoptosis through the lysosomal-mitochondrial pathway. It was shown to translocate to the lysosome initiating the permeabilization of lysosomal membrane (LMP) resulting in the release of CTSD and CTSL to the cytoplasm. Furthermore, it triggers the caspase-independent apoptosis by altering mitochondrial membrane permeabilization (MMP) resulting in the release of PDCD8. (Chen, Li et al. 2005) C19orf12 is a small transmembrane protein predominantly localized to mitochondria involved mitochondrial membrane protein-associated neurodegeneration associated with brain iron accumulation (Hartig, Iuso et al. 2011, Gagliardi, Annesi et al. 2015). C19orf12 might play a role in lipid homeostasis since high C19orf12 expression levels are observed in adipose tissue, which is upregulated during adipocyte differentiation. Furthermore, C19orf12 coregulates genes predominately involved in fatty acid metabolism (Langwinska-Wosko, Skowronska et al. 2016). Zink finger protein 563 (ZNF536) is specifically expressed in the brain, negatively regulates neuron differentiation by repressing retinoic acid-induced gene transcription (Qin, Ren et al. 2009). Teashirt homolog 3 (TSHZ3) encodes a zinc-finger transcription factor that regulates smooth muscle cell differentiation in the developing urinary tract (Martin, Caubit et al. 2013). Furthermore, TSHZ3 comprises a gene silencing complex that inhibits caspase expression. Reduced expression of this gene and consequent caspase upregulation may be correlated with progression of Alzheimer's disease in human patients (Kajiwara, Akram et al. 2009). The TSHZ3 gene promoter was found to be methylated in all the breast/prostate cancer cell lines and some of the breast cancer clinical specimens analyzed. TATA-Box Binding Protein Associated Factor 9 Pseudogene 3 (TAF9P3) and LOC100420587 are pseudogenes. Pseudogenes were originally regarded as non-functional genomic fossils resulted from inactivating gene mutations during evolution. However, later studies revealed that they play a role in diverse physiological and pathological processes, especially in cancer. Pseudogenes can interact with parental genes or other gene loci, leading to alteration in their sequences and/or transcriptional activities. Pseudogene-derived RNAs play multifaceted roles in post-transcriptional regulation.

36 1. Introduction

Pseudogenic proteins can mirror, mimic or interfere with the functions of their parental counterparts (Xiao-Jie, Ai-Mei et al. 2015). For the genes Testis highly expressed gene 5 (THEG5) and V-set and transmembrane domain- containing protein 2B (VSTM2B) no functions are known so far.

1.3.3.2.4 URI1 and CCNE1 as major oncogenic driver genes of the chromosomal locus 19q12

The best studied genes of the chromosomal locus 19q12 are the Unconventional prefoldin RPB5- Interactor 1 (URI1) and CCNE1 coding for Cyclin E. Both genes URI1 and CCNE1 are involved in the regulation of crucial cellular processes and can therefore be considered as so called housekeeping genes. Aberrant regulation of housekeeping genes is a frequent mechanism exploited by cancer cells in order to drive tumorigenesis. Overexpression of URI1 and CCNE1 can drive tumorigenesis through different mechanisms in several cancer types. Furthermore, reduced expression of both genes respectively has been shown to significantly inhibit cell growth or to induce apoptosis (Schraml, Bucher et al. 2003, Etemadmoghadam, deFazio et al. 2009, Nakayama, Nakayama et al. 2010, Theurillat, Metzler et al. 2011, Natrajan, Mackay et al. 2012). High expression levels of both URI1 and CCNE1 on mRNA and protein levels are not necessarily a result of high copy number variations, but can also be a result of disordered transcription or posttranscriptional modifications (Karst, Jones et al. 2014, Noske, Henricksen et al. 2015). Furthermore, high copy number variations do not always correlate with high expression levels, however in the majority of cases (Sung, Song et al. 2014, Noske, Henricksen et al. 2015). Cyclin E plays a crucial role in the regulation of the cell cycle, since it promotes G1-S phase transition in complex with its partner kinase Cyclin-dependent kinase 2 (CDK2) by phosphorylating the tumor suppressor retinoblastoma (Rb) protein and other cell cycle regulators which function as CDK inhibitors like p27 or p21 (Koff, Giordano et al. 1992, Sheaff, Groudine et al. 1997). Hyper-phosphorylation and therefore inactivation of Rb leads to dissociation from the E2F transcriptional factor. Released and active E2F induces the expression of genes that drive cells to S phase through G1 phase and Cyclin E/CDK2 phosphorylated cell cycle inhibitors p27 and p21 are being tagged for proteosomal degradation (Hinds, Mittnacht et al. 1992). After G1-S phase transition Cyclin E is subsequently ubiquitinated and degraded by the proteasome ensuring a tightly regulated cell cycle quality control during G1-S phase. Apart from the function in cell cycle progression, the Cyclin E/CDK2 complex plays a role in the centrosome cycle. Nucleophosmin as well as CP110 have been demonstrated to be phosphorylation targets of Cyclin E/CDK2 in the initiation of centrosome duplication. Both proteins are released from binding to an unduplicated centrosome upon phosphorylation thereby triggering duplication and centrosome separation (Okuda, Horn et al. 2000, Chen, Indjeian et al. 2002).

37 1. Introduction

Aberrantly regulated Cyclin E/CDK2 activity due to high expression levels of Cyclin E causes lineage- specific abnormalities and has been associated with multiple tumor types (Donnellan and Chetty 1999, Akli and Keyomarsi 2003, Schraml, Bucher et al. 2003). Several mechanisms lead to deregulated expression of Cyclin E. In most cases, CCNE1 amplification causes overexpression and accumulation of Cyclin E (Akama, Yasui et al. 1995, Demetrick, Matsumoto et al. 1995, Kitahara, Yasui et al. 1995), but also defects in targeting cyclin E for proteosomal degradation can cause accumulation of Cyclin E. For example loss-of-function mutations of F-box/WD repeat-containing protein 7 F-box (FBXW7), a subunit of ubiquitin protein ligase complex SCFs, which target Cyclin E for ubiquitination were found in several cancer cells (Cassia, Moreno-Bueno et al. 2003, Ekholm-Reed, Spruck et al. 2004). Accumulation of Cyclin E results in a hyper-proliferative phenotype characterized by high genomic instability (Spruck, Won et al. 1999). Potential underlying mechanisms of Cyclin E driven genomic instability include defective S-phase progression, e.g. by stalled replication forks or impaired replication which may result in cells entering mitosis before their chromosomes are fully replicated or the occurrence of aneuploidy caused by aberrant centrosome amplification. Cyclin E driven hyperproliferation of tumor cells can also be explained by the presence of lower molecular isoforms of Cyclin E derived from proteolytic processing of the full-length form which have been discovered in breast cancer and other tumor samples. Lower molecular isoforms have be demonstrated to be biochemically hyperactive displaying a stronger activity toward their substrates and a stronger binding affinity to CDK2 resulting in overstimulated cell cycle progression (Harwell, Porter et al. 2000, Porter, Zhang et al. 2001). Another mechanism contributing to Cyclin E/CDK2 driven tumorigenesis includes the regulation of the apoptotic response to DNA damage via phosphorylation and therefore inhibition of the FOXO1 transcription factors which induces apoptosis by up-regulating a number of pro-apoptotic genes (Huang, Regan et al. 2006). In normal cells, aberrant regulation and subsequent deleterious effects of Cyclin E-CDK2 is guarded by p53 and p21 by inducing apoptosis. Counterintuitively, tumor cells with excessive Cyclin E-CDK2 activity are also dependent on p53 since additional p53 loss may be particularly genotoxic, due to the fact that cells cannot appropriately respond to the caused cell cycle anomalies (Minella, Swanger et al. 2002). A high burden of genotoxic stress as eliminating factor for cells with excessive Cyclin E-CDK2 activation cells goes in line with the finding that Cyclin E overexpression due to amplification of 19q12 require an intact DNA damage response. It has been shown that 19q12 amplified tumors are specifically dependent on BRCA1. Therefore BRCA1 mutations are mutually exclusive with 19q12 amplifications (Etemadmoghadam, deFazio et al. 2009). In addition, loss of members of the ubiquitin pathway and inhibition of the proteasome have also been shown to be deleterious for 19q12 amplified cells due to the excessive burden of genotoxic stress (Etemadmoghadam, deFazio et al. 2009).

38 1. Introduction

The second known oncogene of the 19q12 locus is URI1, which is a member of the prefoldin (PFD) family of chaperones. Molecular chaperones are required for essential cellular functions such as folding of newly translated polypeptides into three-dimensional conformations, inhibition of protein aggregation, and assembly of multiprotein complexes involved in transcriptional processes (Whitesell and Lindquist, 2005; Young et al., 2004). URI1 contains all features of an α-class PFD, with 2 α-helices and 4 β-strands, however it is unconventionally large due to its C-terminal extension harboring specific binding sites for RNA polymerase II subunit 5 (RPB5), also known as RNA polymerase II DNA-directed polypeptide E (POLR2E), a crucial subunit of all 3 RNA polymerases in eukaryotes (Cheong, Yi et al. 1995), and Protein Phosphatase 1 γ (PP1 γ), a regulator of the mitochondrial nutrient and growth factor dependent threshold for apoptosis (Siegert, Leroux et al. 2000, Gstaiger, Luke et al. 2003, Djouder, Metzler et al. 2007). URI1 assembles to a heterohexameric multiprotein complex called prefoldin- like/URI1 complex which contains another α-class prefoldin, STAP1 (SKP2-associated α- PFD 1) and the three β-class prefoldins containing 2 α- helices and 2 β-strands PFD2, PFD6, and PDRG1 (p53 and DNA damage-regulated protein 1) with one of the β-class PFDs present in two copies (Figure 7). The function of the prefoldin-like/URI1 complex is the folding and assembly of proteins in particular the assembly of RNA polymerases (Boulon, Pradet-Balade et al. 2010). PFD2 and PFD6 are shared subunits being part of another prefoldin complex called the prefoldin/GimC complex which is responsible for the folding of actin and tubulin monomers. Both prefoldin complexes, the prefoldin-like/URI1 and the prefoldin/GimC, are functionally dependent on the RT2P module which serves as “ATP engine” (Siegert, Leroux et al. 2000, Cloutier and Coulombe 2010).

Figure 7: Composition of the Prefoldin and the Prefoldin-like/URI1 complex and the RT2P module. Both prefoldin complexes consist of 2 α-class prefoldins (circled in yellow) and 4 β-class prefoldins displaying a heterohexameric structure. The R2TP module serves as “ATP engine” for both complexes (Lipinski and Britschgi, unpublished, according to Siegert, Leroux et al. 2000, Cloutier and Coulombe 2010, Gstaiger et al, 2003).

In cancer related context the prefoldin-like/URI1 chaperone complex was demonstrated to create “non-oncogene addictions” by developing cell survival dependencies in particular on both α-type prefoldins URI1 and STAP1 (Lipinski, Britschgi et al. 2016). α-type prefoldins are responsible for the stability of the whole prefoldin-like/URI1 complex since depletion of both URI1 and STAP1 was shown to introduce degradation of the whole complex (Mita, Savas et al. 2013, Lipinski, Britschgi et al. 2016).

39 1. Introduction

However, plenty of evidence suggests that URI1 can also function independently of the chaperone complex. URI1 was discovered to be a downstream target of mTOR-controlled pathway that modulates nutrient-sensitive gene expression since URI1 protein levels were down-regulated in response to various signals known to inhibit mTOR (mammalian Target of Rapamycin) activity, such as nitrogen starvation or rapamycin (Gstaiger, Luke et al. 2003) Furthermore, it was discovered that URI1 is directly phosphorylated by the mTOR downstream target S6K1 (Ribosomal protein S6 kinase beta-1) regulating a negative feedback loop protecting from constitutive S6K1 cell growth and survival signaling and keeping the balance between cell death and cell survival (Djouder, Metzler et al. 2007). This negative feedback was discovered to be disabled in particular in 19q12 amplified ovarian cancer. In those cells, URI1 is highly amplified and overexpressed and acts as an addictive oncogene leading to constant entrapping of PP1γ resulting in constitutive S6K1 signaling, which promotes cell survival (Theurillat, Metzler et al. 2011). Recently this model was extended by the fact that URI1 and PP1γ share and additional complex component called OGT (O- linked N-acetylglucosamine transferase) which catalyzes O-GlcNAcetylation, a post-translational modification competitive to phosphorylation. Upon glucose depletion phosphorylated URI1, released from the OGT-URI1-PP1γ complex, inhibits OGT resulting in reduced O-GlcNAcetylation, whereas upon glucose availability URI1 is dephosphorylated triggering increased O-GlcNAcetylation. Reduced O- GlcnNAcetylation promotes degradation of c-Myc and increased O-GlcnNAcetylation induces c-Myc stabilization promoting tumorigenesis. Therefore, URI1 can be considered as a rate limiting glucose- sensing factor protecting cancer cells from metabolic stress induced cell death by regulating OCT activity and therefore c-Myc expression (Buren, Gomes et al. 2016). URI1 was also brought in context with the induction of DNA damage by abolishing apoptosis and increasing genotoxic stress and p53 inactivation (Tummala, Gomes et al. 2014, Lipinski, Britschgi et al. 2016). Prior to DNA damage URI1 was shown to inhibit NAD synthesis by downregulating the L- tryptophan/kynurenine catabolism resulting in DNA damage URI1 induced DNA damage is assumed to be triggered by nutrient excess activating TH17 (T helper 17 cells) and IL17 (Interleucin 17) production. This induces neutrophil infiltration mediating insulin resistance in the WAT (white adipose tissue) and fatty acid released causing NASH (non-alcoholic steatohepatitis), a pre-stage of the majority of hepatocellular carcinomas (Tummala, Gomes et al. 2014)

1.3.4 Treatment of ovarian cancer

1.3.4.1 General treatment and recent precision targeted therapy options

The first-line standard therapy of ovarian cancer comprises debulking surgery of the primary tumor followed by chemotherapy and/or targeted therapy. The standard chemotherapy approach, which was

40 1. Introduction introduced more than 20 years ago, combines a platinum compound and a taxane administered every 3-4 weeks in 3 to 6 cycles depending on the stage of the disease (McGuire, Hoskins et al. 1996, Jelovac and Armstrong 2011). Platinum-based compounds induce DNA adducts that cause DNA damage and trigger cell death (Siddik 2003, Cepeda, Fuertes et al. 2007). Taxanes are mitotic inhibitors which stabilize GDP-bound tubulin in the microtubule preventing depolymerization, which results in the inhibition of the process of cell division (Abal, Andreu et al. 2003). 80% of all patients respond to first line treatment, however the majority develop recurrence of the disease and need second-line treatment (Rubin, Randall et al. 1999). Patients who progress or have stable disease during the primary treatment or who relapse within one moth are considered as “platinum-refractory”. Patients who respond to first-line treatment, however relapse within six months are considered as “platinum- resistant” and patients who relapse more than six months after completion of initial therapy are characterized as “platinum-sensitive” (Markman, Reichman et al. 1991). Second line treatment of platinum resistant ovarian cancers includes chemotherapeutic agents of classes with different mechanisms of action, for example anthracyclines (e.g. Doxorubicin), topoisomerase inhibitors (e.g. Etoposide), nucleoside analogues (Gemcitabine) (Jelovac and Armstrong 2011). However, response rates are to second line treatments are low, ranging between 10-30%. Furthermore, for 95% of all patients the time period of remission after second-line treatment is shorter than for the first-line treatment (Markman, Markman et al. 2004). Concurrent use of two or more chemotherapeutic drugs provides an efficient approach to minimizing drug resistance, improves outcomes and prolongs patients survival, presupposed that components of the drug combination exhibit different mechanisms of action by blocking unrelated pathways crucial for cancer cell survival (Pfisterer, Plante et al. 2006, Stordal, Pavlakis et al. 2007, Pignata, Scambia et al. 2014, Pujade-Lauraine, Hilpert et al. 2014). Besides chemotherapy, targeted therapy is gaining importance due to its specificity towards cancer cells while sparing toxicity to off-target cells (Padma 2015). The basis of molecular targeted therapy was set by the improved understanding of the underlying biology of ovarian tumor etiology and chemoresistance. The approach of molecular targeted therapy is to design a more efficacious plan for treating the disease by delivering drugs to particular genes or proteins that are specific to cancer cells or the tissue environment that promotes cancer growth (Sapiezynski, Taratula et al. 2016). In cancers driven by a dominant oncogene (e.g. chronic myeloid leukemia Her2 positive breast cancers), targeted therapies have led to remarkable improvements in response and survival, whereas in others (e.g. ovarian cancer) the outcome has been modest (Ellis and Hicklin 2009). Up-to-date following targeted therapies are approved and are clinically used to treat certain types of ovarian cancer:

1. Anti-angiogenic therapy

41 1. Introduction

Anti-angiogenic therapies have been one of the most successful classes of targeted therapeutics for ovarian cancer, which decelerate cancer growth and progression. Furthermore, by inhibiting angiogenesis certain subtypes become more susceptible to standard chemotherapy (Gavalas, Liontos et al. 2013). The authorized monoclonal antibody Bevacizumab (trade name: Avastin) inhibits the vascular endothelial growth factor, which is a major component in angiogenesis promoting tissue vascularization, from binding to its receptor VEGFR (Ferrara, Hillan et al. 2005, Schmid and Oehler 2014). An increase in progression free survival is observed for advanced stage patients being treated with bevacizumab combination with carboplatin and paclitaxel (Burger, Brady et al. 2011). Therefore, this combinatory treatment has already been approved as first-line therapeutic by the European Medicines Agency (EMA) (Schmid and Oehler 2014). Also angiokinase inhibitors like Panzopanib (trade name: Votrient), which targets VEGFR and PDGFR, are promising drugs aiming to inhibit angiogenesis, however still under investigations in difference clinical test trials (Eichbaum, Mayer et al. 2011).

2. Poly-ADP ribose polymerase (PARP) inhibitors PARP plays a key role in the base excision repair (BER) pathway fixing single strands breaks (SSB). In case of PARP inhibition SSBs collapse and result in double strand breaks (DSB) during replication (Schreiber, Dantzer et al. 2006, Mukhopadhyay, Curtin et al. 2011). DSBs are usually repaired by HR involving BRCA 1/2 or non-homologous end joining (NHEJ). In case of BRCA1/2 deficiencies, additional inhibition of PARP leads to cell death due to a high burden of DNA damage stress. Therefore, PARP inhibitors like Olaparib (trade name: Lynparza) has shown promising outcomes in the treatment of BRCA deficient cancers both as monotherapy and in combination with various chemotherapeutic drugs (Ashworth 2008).

3. Folate and folate receptor alpha antagonists Folate metabolism plays an important in DNA replication during mitosis. Inhibition of folate synthesis by targeting components like dihydrofolat reductase by methotrexate (different trade names) or thymidylate synthetase by 5-Fluorouracil or permetrexed (trade name: Alimta) causes cytotoxic effects resulting in reduction of tumor growth (Kamen 1997, Rajagopalan, Zhang et al. 2002, Longley, Harkin et al. 2003). It has been shown that 80% of all epithelial ovarian cancer overexpress the folate receptor α (FRα) and high expression levels correlate with the stage of the disease (Toffoli, Cernigoi et al. 1997, Chen, Chang et al. 2012, Crane, Arts et al. 2012, Kobel, Kalloger et al. 2013). The monoclonal antibody farletuzumab, directed against the FRα, promotes cell lysis of FRα expressing cancer cells by antibody dependent cellular cytotoxicity and complement-dependent cytotoxicity (Ledermann, Canevari et al. 2015). Phase II of clinical test trials showed promising results so far.

42 1. Introduction

4. Inhibitors of estrogen synthesis Estrogen has been shown to increase proliferation in a subset of ovarian cancers and 60% of ovarian cancer patients are ER-positive (Simpkins, Hevia-Paez et al. 2012, Simpkins, Garcia-Soto et al. 2013). Estrogene receptor inhibitors like Tamoxifen and estrogen synthase inhibitors like Letrozole or Exremestane have therefore been tested in ER-positive ovarian cancers (Lombardi 2002, Smyth, Gourley et al. 2007).

1.3.4.2 Challenges in the treatment of ovarian cancer

A major obstacle in the treatment of any type of cancer is the resistance towards chemotherapy either primary or acquired (Rohwer and Cramer 2011). The mechanisms of drug resistance are complex and multifactorial and can be classified broadly into 4 basic categories: 1. Pharmacokinetic resistance due to inadequate pharmacokinetic properties of the drug resulting in diminished drug concentration and distribution (Gottesman, Fojo et al. 2002, Gatti and Zunino 2005) 2. Tumor cell intrinsic resistance due to alterations in drug metabolism and drug transport, increased DNA damage repair and inhibition of apoptosis (Gottesman, Fojo et al. 2002, Gatti and Zunino 2005) 3. Resistance imposed by the tumor microenvironment triggered by conditions as hypoxia, acidosis, nutrient starvation and increased interstitial pressure (Morin 2003) 4. Acquired resistance through targeted therapies due to specific mutational or epigenetic mechanisms. For example, genetic mechanisms of resistance to kinase inhibitors include mutations in the target receptor and mutations or gene amplification of compensatory receptors or other signaling effectors (Lackner, Wilson et al. 2012) The major challenge in the treatment of ovarian cancer is that most ovarian tumors exhibit properties of several subtypes and therefore show high levels of intertumoral and intratumoral heterogeneity (Konecny, Wang et al. 2014). It is estimated that 95% of all ovarian cancer tumors display clonal heterogeneity with four or more subclones per tumor exhibiting distinct properties due to diverging clonal evolution (Lohr, Stojanov et al. 2014, Waldron, Riester et al. 2014). Dominant subclones may indeed suppress minor subclones, but they may also coexist or even promote their proliferation (Chesi, Robbiani et al. 2008). Clonal evolution is considered to occur independently at the level of mutational processes. Also genomic rearrangements and alterations in genomic rearrangements may, independently from mutations, affect the intratumoral diversity (Hoogstraat, de Pagter et al. 2014). A source of intratumoral heterogeneity and one of the most important driving forces of clonal evolution is genomic instability, a major characteristic of HGSOC (Salomon-Perzynski, Salomon-Perzynska et al. 2017). Genomic instability promotes the acquisition of further DNA alterations leading to genetic

43 1. Introduction diversity between cancer cells and creating the possibility of coexistence of genetically distinct subclones within the same tumor (Hanahan and Weinberg 2011). Clonal evolution in HGSOC is also driven by selective pressures imposed by the highly heterogenous tumor microenvironment (Junttila and de Sauvage 2013, Mumenthaler, Foo et al. 2015). Also chemotherapy constitutes a selection pressure widely affecting the patterns of tumor evolution (Burrell and Swanton 2014). Several studies demonstrated that elimination of sensitive subclones by surgery or chemotherapy forces treatment- related selection of subclones which are genetically and/or phenotypically best adapted to therapy- induced conditions (Ding, Ley et al. 2012, Melchardt, Hufnagl et al. 2016). Furthermore, the clonal architecture of recurrent tumors was more homogenous than their primary counterparty suggesting that during ongoing evolution the majority of somatic mutations were eliminated from cancer cell population by selection forces imposed by cancer therapy (Beltrame, Di Marino et al. 2015). Therefore, it is suggested that tumor relapse originates from drug-resistant subclones originally present in the primary tumors that expand under selective pressure of therapeutic intervention (Schwarz, Ng et al. 2015, Lambrechts, Smeets et al. 2016, Paracchini, Mannarino et al. 2016). Since clonal evolution can be claimed as major contributor to drug resistance and treatment failure, further studies should use more precise sequencing strategies such as single cell sequencing, able to identify low prevalent subclones and consequently providing a full insight into the spatial subclonal composition of HGSOC and its evolution over time (Burrell and Swanton 2014, Zhang, Marjani et al. 2016). The identification of early driver events but also subclone drivers could supplement prognostic and predictive models in order to develop patient tailored targeted multidrug combinatory treatments so successfully eliminated the whole heterogeneous tumor (Barretina, Caponigro et al. 2012). The envisioned goal is that ovarian cancer will not be treated as a single disease, but rather be individually treated by combinatorial targeted therapies according to the genomic profile of the heterogeneous tumor and on the basis of robust biomarkers and diagnostic tools.

1.3.4.3 Diagnosis and therapy options for HGSOC with 19q12 amplification

Amplifications of the major oncogenic driver genes of the chromosomal locus 19q12, URI1 and CCNE1, have been associated with primary treatment failure of platinum based chemotherapy, shorter progression free survival and poor survival outcome (Etemadmoghadam, deFazio et al. 2009, Theurillat, Metzler et al. 2011, Yang, Gu et al. 2011, Tummala, Gomes et al. 2014, Gu, Liang et al. 2015, Patch, Christie et al. 2015, Wang, Garabedian et al. 2015). However, the exact underlying mechanisms of resistance are mainly unknown. Also potential therapy options targeting 19q12 amplified HGSOC still need to be investigated. So far only one approach of inhibiting Cyclin E by targeting its partner kinase CDK2 has been demonstrated in ovarian and breast cancer (Natrajan, Mackay et al. 2012, Etemadmoghadam, Au-Yeung et al. 2013). However, in vitro resistance to CDK2 inhibitors was

44 1. Introduction associated with selection of a polyploid population in the CCNE1 amplified cells (Etemadmoghadam, Au-Yeung et al. 2013). Since rational drug combinations are a potential strategy to circumvent resistance (Yap, Omlin et al. 2013), Au-Yeung et al, 2016 performed a high throughput drug screen to identify drug combinations that synergize with the CDK2 inhibitor dinaciclib (Au-Yeung, Lang et al. 2016). They identified that pharmacologic inhibition of CDK2 in combination with AKT serves as selective targeted therapy for CCNE1 amplified HGSOC. Also therapeutic approaches for the inhibition of URI1 activity have been envisioned so far e.g. by the suggestion to disrupt the URI1-PP1γ complexes potentially with small molecule inhibitors (Theurillat, Metzler et al. 2011). Furthermore, inhibition of Ataxia-Telangiectasia (ATM), which has been shown to be upregulated upon URI1 overexpression in uterine carcinosarcoma, could also be a potential therapeutic approach (Wang, Garabedian et al. 2015). A more systemic approach of URI1 inhibition by targeting specific URI1 complex interactors and client proteins was suggested by Lipinski, Britschgi et al. 2016. Even though targeted therapy options for 19q12 amplified HGSOC still need to be further investigated, the clinical application of using the 19q12 as diagnostic biomarker has already been taken into consideration. Since the 19q12 amplification status serves as a critical chemotherapy determinant and therapeutic target, Noske et al, 2016 already developed an automated ISH (in situ hybridization) biomarker assay for identification of 19q12 amplifications applicable for routine diagnosis (Noske, Brandt et al. 2016).

45 2. Aims of the study

2. Aims of the study

Amplification of the chromosomal locus 19q12 can be considered as a major genomic feature of HGSOC (Marum, 2012, Ceami, Gao et al. 2012, Gao, Aksoy et al. 2013). In particular, amplification of the 2 major oncogenic driver genes within this locus, CCNE1 and URI1, have been associated with primary treatment failure of platinum based chemotherapy, shorter progression free survival and poor survival outcome (Etemadmoghadam, deFazio et al. 2009, Theurillat, Metzler et al. 2011, Yang, Gu et al. 2011, Tummala, Gomes et al. 2014, Gu, Liang et al. 2015, Patch, Christie et al. 2015, Wang, Garabedian et al. 2015). As mentioned in part 1.3.4.1, cryo-reductive surgery followed by chemotherapy is still the standard therapy of HGSOC since targeted therapy options are not well stablished so far. A crucial requirement for the development of effective targeted therapies for HGSOC is the proper understanding of the underlying molecular biological mechanisms, which initiate and contribute to the development of the disease. Therefore, the goal of this PhD project was to investigate genetic dependencies and molecular vulnerabilities of 19q12 amplified HGSOC cells, with the superordinate goal to identify new therapy options. The main focus was set on the discovery of genes and related signaling pathways which are essential for the survival and progression exclusively of 19q12 amplified cells and tumors. In particular, we focused on the identification of kinases due to the fact that kinases and their signaling pathway components are often aberrantly regulated in cancer cells contributing to survival advantages and tumor progression (Cohen 2002, Zhang, Yang et al. 2009). Furthermore, protein kinases have emerged as one of the most successful drug targets in recent years (Gross, Rahal et al. 2015). The identification of 19q12 essential kinases was experimentally approached by the performance of a pooled shRNA screen in 19q12 amplified vs. 19q12 non-amplified HGSOC targeting all kinases of the human genome, followed by an in vitro and in vivo hit validation. Identified and validated hits could serve as potential therapeutic targets for HGSOC but also other types of cancer with 19q12 amplification and future projects could focus on the identification of small molecule inhibitors targeting 19q12 essential kinases to further develop a 19q12 specific targeted therapy.

46 3. Results

3. Results

3.1 Characterization of cell lines

In order to investigate the potential dependency of high-grade serous ovarian cancer (HGSOC) cells with 19q12 amplification on specific kinases, we performed a pooled shRNA screen, for which cell lines had to be chosen first. Cell lines were selected from the ovarian cancer cell line panel of the study of Domcke, Sinha et al. 2013. In this study 47 ovarian cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) were ranked according to their copy-number changes, mutations and mRNA expression profiles, to have the highest genetic similarity to 316 ovarian tumors from The Cancer Genome Atlas (TCGA) and therefore serve as the most suitable HGSOC cell lines for in vitro models (Figure 8) (Domcke, Sinha et al. 2013).

Figure 8: Ranking of ovarian cancer cell lines by suitability as HGSSOC models for in vitro studies. Cell lines at the top of the list (green background) are considered as the most suitable HGSOC cell lines according to their genomic profile similar to human tissue samples from TGCA. Unsuitable cell lines at the bottom of the table (red background) are considered to be less suitable HGSOC cell line models according to their genetic profile. The order does not signify an exact ranking of cell line models (Domcke, Sinha et al. 2013)

47 3. Results

According to this study we chose the following three HGSOC cell lines: OVCAR8, OVCAR4, NIHOVCAR3 (further referred to as OVCAR3) all of which are 19q12 amplified according to copy number variation (CNV) data of the CCLE database (Figure 10). Furthermore, we intended to select 3 HGSOC cell lines without 19q12 amplification (further referred to as 19q12 non-amplified) as control cell lines. The first cell line, COV504, fulfilled both criteria (HGSOC and 19q12 non-amplified). The second cell line, SKOV3, was 19q12 non-amplified, however ranked as unlikely high grade serous according to Domcke, Sinha et al. 2013, even though it is the most cited HGSOC cell line on NCBI pubmed (Figure 9). The third cell line, TOV21G, also 19q12 non-amplified, was the only cell line classified as subtype clear cell instead of serous.

Figure 9: Number of pubmed citations for the 47 ovarian cancer cell lines being ranked as suitable HGSOC models. Number of citations is estimated to correlate with the frequency of use in laboratories. Data from 4th June 2012 (Domcke, Sinha et al. 2013)

The 19q12 amplification status of the above mentioned ovarian cancer cell line used for the screen was investigated by an analysis of copy number variation (CNV) data from the CCLE database (Figure 10). Furthermore, the 19q12 amplification status of three additional 19q12 non-amplified cell lines IGROV, TYKNU and CAOV3 was analyzed. These cell lines were used additionally for hit validation after the screen. CNV values of genes are displayed as log2 (CNV/2) values referring to a normalized ratio between tumor and normal samples, divided by 2 due to diploidy of the genome. log2 (CNV/2) values above the threshold of 0.04 were considered to be amplified (Nijhawan, Zack et al. 2012) referring to an absolute CNV value threshold above 2 (=one copy per allele). The analysis revealed that OVCAR4 is the only cell line with amplification of the whole chromosomal locus 19q12 since CNV values for all genes of the locus are identical and display a log2 (CNV/2) =1.0, referring to an absolute CNV value of 4 copies. The cell line OVCAR8 exhibits log2 (CNV/2) values for all genes between 0.6359 and 0.6745

48 3. Results referring to absolute CNV values of 3 copies for each gene, except for UQCRFS1, with a log2 (CNV/2) = - 0.22 referring to an absolute CNV value of 1.7. Furthermore, URI1 exhibits the highest log2 (CNV/2) = 1.22, referring to an absolute CNV value of 4.7 copies. The cell line OVCAR3 shows values of log2 (CNV/2) =2.33, referring to absolute CNV values =10 for most of the 19q12 genes except for the genes ZNF563, TSHZ3 and THEG5, with log2 (CNV/2) values = 0.8309 referring to absolute CNV values = 3.6. OVCAR3 is therefore the cell line exhibiting the highest number of copies for genes of the 19q12 locus. All other cell lines comprising SKOV, TOV21G, COV504, IGROV, TYKNU and CAOV exhibit log2 (CNV/2) values below the threshold 0.04 and can therefore be considered as 19q12 non-amplified. log2 (CNV/2) values vary between -0.69 and 0.11 referring to absolute CNV values between 1.24 and 2.16. COV504 with log2 (CNV/2) = -0.6886 /absolute CNV= 1.2409113 is assumed to have a monoallelic deletion of the 19q12 locus. OVCAR3 seems to have a monoallelic deletion as well, however only for UQCRFS1 due to log2 (CNV/2) = -0.7704, referring to an absolute CNV value of 1.2.

Figure 10: Amplification status of 19q12 genes of in ovarian cancer cell lines used for the pooled shRNA screen. The chromosomal locus 19q12 contains 11 genes listed on the right side of the graph. CNV values of genes are displayed as log2 (CNV/2) values referring to a normalized ratio between tumor and normal samples, divided by 2 due to diploidy of the genome. 0.04 is defined as threshold for the amplification of the respective genes (Nijhawan, Zack et al. 2012) referring to an absolute CNV value threshold above 2 (2 reflects one copy per allele). OVCAR8, OVCAR4 and OVCAR3 show log2 (CNV/2) values above the threshold 0.04 for all 19q12 genes, except for UQCRFS1 in case of OVCAR8 and OVCAR3, and are therefore considered as 19q12 amplified cell lines. SKOV, TOV21G, COV504, IGROV, TYKNU and CAOV3 are considered as 19q12 non-amplified cell lines due to log2 (CNV/2) values of <0.04 for each 19q12 gene.

Also mRNA and protein expression levels of all 19q12 genes were compared between 19q12 amplified and 19q12 non-amplified genes in order to check if amplification status of 19q12 genes correlates with high mRNA and protein expression levels. mRNA expression data was available on CCLE for all 19q12 genes except for UQCRFS1, VSTM2B and THEG5. Only 3 genes (URI1, CCNE1 and POP4) of the 19q12 locus showed significant higher mRNA expression levels in 19q12 amplified compared to non-amplified

49 3. Results cell lines (Figure 11A). Mean mRNA expression levels of 19q12 genes were slightly higher in 19q12 amplified than in 19q12 non-amplified cells however, without any significant difference (Figure 11B). Protein levels for URI1 and Cyclin E (encoded by CCNE1) were determined in different cell lines by western blotting (Figure 11C) and showed similar to the mRNA expression data, upregulated protein levels in the 19q12 amplified cell lines but not in the 19q12 non-amplified control cell lines. POP4 was not included in the western blot analysis since POP4-specific antibodies were not available in our lab.

Figure 11: mRNA and protein expression levels of 19q12 genes in 19q12 amplified and non-amplified cell lines. A. Relative mRNA expression levels of 19q12 genes in 19q12 amplified cell lines vs. non-amplified cell lines (CCLE data). Error bars represent n=3 19q12 amplified lines (OVCAR8, OVCAR3, OVCAR4) and n=6 19q12 non-amplified cell lines (SKOV, TOV21G, COV504, IGROV, CAOV3) ±SD, p*<0.05, p**<0.01 B. Mean mRNA expression of 19q12 genes in 19q12 amplified cell lines vs. 19q12 non-amplified cell lines. C. Protein expression levels were determined by western blotting of the 2 oncogenic driver genes URI1 and CCNE1, residing within the 19q12 locus.

50 3. Results

3.2. Dependency of ovarian cancer cell lines on URI1 and CCNE1

Since both URI1 and CCNE1 are known to be oncogenic driver genes within the 19q12 amplicon (Nakayama, Nakayama et al. 2010, Theurillat, Metzler et al. 2011), it was investigated if 19q12 amplified cell lines have developed specific dependencies on URI1 and CCNE1 in terms of cell survival and if 19q12 amplified cells are more affected by the loss of URI1 and CCNE1 than 19q12 non-amplified cells. For this, stable knockdowns of URI1 and CCNE1 were established separately by lentiviral delivery of short hairpin RNAs (shRNAs). Afterwards two cell viability assays, the Annexin V assay and the Colony Formation Assay (CFA) were performed in order to investigate the short and long term effect respectively of URI1 and CCNE1 depletion in 19q12 amplified and 19q12 non-amplified cells. For both assays cells were selected with puromycin containing medium 24h after lentiviral transduction and seeded for experiments 48 h after selection. 24 h after seeding and 5 days after the establishment of the respective knockdown the samples of the Annexin V time course were harvested and treated with Annexin V – FITC conjugate dye. Cell viability was quantitatively measure by Fluorescence Activated Cell Sorting (FACS). Knockdown cells were normalized to shCTRL cells at each time point. shCTRL cells contained the same TRC-pLKO vector with a non-targeting stuffer region instead of shRNA constructs. The Annexin V assay revealed that 19q12 amplified cells (OVCAR8, OVCAR4, OVCAR3) in contrast to 19q12 non-amplified cells (SKOV, TOV21G and COV504) are more dependent on URI1 and CCNE1. This was reflected by the cell viability rate of 19q12 amplified cells which was decreasing faster over time than the cell viability rate of 19q12 non-amplified cells (Figure 12 A and Figure 13 A). 19q12 amplified cell lines started to suffer from the URI1 and CCNE1 loss from day 5 on, whereas 19q12 non-amplified cells could compensate better for the loss of the genes until day 8. URI1 depleted OVCAR4 and also COV504 did not show a clear dependency pattern according to their amplification status. Another exception was given by CCNE1 depleted TOV21G cells, which showed a tremendous decrease in cell viability and therefore the same dependency pattern as 19q12 amplified cells. The long term effects of URI1 and CCNE1 knockdown were investigated by CFA for which cells were cultivated for 14 days after the establishment of the respective knockdown and 10 days after seeding. Cells were stained with crystal violet and colonies were scanned and quantified using Image J. Colonies of knockdown samples were normalized to shCTRL samples. Both 19q12 amplified and 19q12 non- amplified cells were suffering from URI1 and CCNE1 depletion respectively and could not compensated for the loss of both genes over a time period of 14 days since the survival rate of both URI1 and CCNE1 knockdown cells dropped down to 20 – 0% (Figures 12B, 12C, Figures 13B, 13C). Downregulation of URI1 and CCNE1 on mRNA and protein levels was confirmed by qPCR and western blotting (Figures 12D, 12E, Figure 13D, 13E).

51 3. Results

Figure 12: 19q12 amplified ovarian cancer cells are more dependent on URI1 than 19q12 non-amplified cells. A. Cell viability (%) of URI1 depleted cells measured by FACS after Annexin V –FITC conjugate staining, 5 to 11 days after the establishment of the stable shRNA mediated URI1 knockdown. Each data point represents the mean of n=3 independent experiments, error bars represent ±SD. B. Long term effect of URI1 depletion assessed by CFAs 14 days after the application of the stable shRNA mediated URI1 knockdown. C. Relative quantification of CFAs of n=3 independent experiments, error bars represent ±SD. D. Relative mRNA expression levels of URI1 normalized to TBP. n=3 independent replicates, ±SD. E. Protein expression levels of URI1.

52 3. Results

Figure 13: 19q12 amplified ovarian cancer cells are more dependent on CCNE1/Cyclin E than 19q12 non-amplified cells. A. Cell viability (%) of CCNE1 depleted cells measured by FACS after Annexin V-FITC conjugate staining, 5 to 11 days after the establishment of the stable shRNA mediated CCNE1 knockdown. Each data point represents the mean of n=3 independent experiments, error bars represent ±SD. B. Long term effect of CCNE1 depletion assessed by CFA 14 days after the application of stable shRNA mediated CCNE1 knockdown. C. Relative quantification of CFA of n=3 independent experiments, error bars represent ±SD. D. Relative mRNA expression levels of CCNE1 normalized to TBP. n=3 independent replicates, ±SD. E. Protein expression levels of Cyclin E.

53 3. Results

3.3 Identification of genes essential for 19q12 amplified ovarian cancer cells by a pooled shRNA screen

In order to identify genes, in particular kinases that are essential for 19q12 amplified ovarian cancer cells, we performed a pooled shRNA screen with the 6 ovarian cancer cell lines that have been characterized in terms of 19q12 amplification status and URI1 and CCNE1 dependency in part 3.1. In addition to the 3 cell lines 19q12 amplified cell lines (OVCAR8, OVCAR4, OVCAR3) and the 3 19q12 non- amplified cell lines (SKOV, TOV21G and COV504), one cell line, not derived from cancerous tissue, but instead from ovarian surface epithelium ovarian surface epithelium cell line (HOSE6-3), was added to the panel. The shRNA screen was performed in these 7 cell lines by targeting 537 kinase-encoding genes with approximately 5 lentivirally delivered shRNAs per gene. For this, a shRNA kinome library was established on an automated platform in cooperation with NEXUS Personalized Health Technologies ETHZ, by picking clones from the full genome TRC 1.0/1.5. library (Sigma Aldrich). Bacterial cultures were pooled and plasmid purification was performed in a pooled manner. The purified kinome library containing copies of 2688 shRNAs targeting 518 kinases was used for the production of lentiviruses. All 7 cell lines were lentivirally transduced by a Multiplicity of Infection (MOI) of 0.7 statistically ensuring 1 infection per cell. After subsequent puromycin selection each cell line was divided into 2 pools, 1 initial and 1 end pool. The initial pools were harvested directly after selection, whereas the end pools of each cell line were cultivated and passaged over 12 population doublings in order to ensure the selection pressure of enriched or depleted shRNAs due to proliferation or cell death of the host cells. Genomic DNA was isolated and hairpin sequences were amplified with forward primers containing individual barcodes for each of the 14 samples (7 initial pool and 7 end pool samples). The reverse primer was the same for each sample. The enrichment or depletion rate of each shRNA due to proliferation or cell death of the respective cells carrying 1 specific shRNA was determined by sequencing the shRNAs using Next Generation Sequencing performed at the Functional Genomics Center Zurich. All 14 different samples were pooled for sequencing since they could be demultiplexed after the run due to their specific barcodes. After quality analysis with FASTQC, count normalization and differential representation analysis (Robinson, McCarthy et al. 2010, Dai, Sheridan et al. 2014), sequencing raw reads were mapped to reference hairpins and log2 ratios (=log (raw read number of end pool/raw read number initial pool; 2)) were calculated. Log2 ratios revealed if hairpins were either depleted (negative log2 ratio) or enriched/unchanged (positive log2 ratio) in the end pool. All files of the quality analysis and differential expression analysis are accessible under http://fgcz- gstore.uzh.ch/projects/p1707/. All files with normalized read count numbers aligned to reference hairpins combined of 2 Hiseq runs for each cell line and each pool (end and initial) are accessible under http://fgcz-gstore.uzh.ch/projects/p1707/HiSeq_combined/.

54 3. Results

The number of raw reads which could be mapped to the reference hairpins multiple times (red), 1 time (blue) and not at all (grey) strongly differed between samples (Figure 14A and http://fgcz- gstore.uzh.ch/projects/p1707/Count_20150821/ file Count.stat.txt for exact numbers). This was due to the fact that the quality of the samples after 2 gel purification steps varied between the samples (Figure 14C), and due to the technical issue that exact equimolar concentrations of 8pM for each sample were not feasible to be loaded on a single sequencing lane. However, the shRNA coverage statistics (Figure 14B and http://fgcz-gstore.uzh.ch/projects/p1707/Count_20150821/ file shRNA.stat.txt for exact numbers) showed less variation between the samples and revealed that for all samples in average more than 50% of all expected reference hairpins could be detected by sequencing more than 10 times (red bars), additional 20-30% could be detected at least one and up to ten times (blue bars) and only approx. 20-30% of all reference hairpins could not be detected by sequencing and therefore covered at all (grey bars). In a further step, we investigated how the not- covered hairpins were distributed within the different cell lines (Figure 14D). A total number of 697 hairpins could not be detected in 1 up to 6 cell lines, but could be detected in at least 1 cell line. In detail this means that 162 hairpins could not be detected by sequencing in 1 cell line out of 7 cell lines, however those hairpins were represented in all other 6 cell lines; 85 hairpins could not be detected in 2 cell lines, however were represented in 5 other cell lines, etc. For all hairpins being present in at least 1 cell line, it can be assumed that they did not get lost during the library preparation or lentiviral production. However, for 369 hairpins which could not be detected in all 7 cell lines, it must be assumed that they got lost due to technical procedures. In a next step it was investigated how many genes were affected by the loss of those 369 missing hairpins throughout all cell lines due to the fact that all 5 hairpins targeting 1 gene got lost. Only 2 genes were affected for which all 5 hairpins got lost due to the technical procedure. For all other genes affected by non-detectable hairpins, at least 1 other hairpins targeting the same gene was present. Most of the non-detectable hairpins, at least 1 other hairpin targeting the same gene was present (Figure 14E). However, it needs to be considered that for some genes only 4 hairpins were present in the pool, estimating a number of approximately 10 genes which got lost due to technical procedures.

55 3. Results

Figure 14: Statistical analysis of pooled shRNA screen in 7 different cell lines. A. Statistics on total read count number of raw reads for each initial and end pool sample of each cell line which could be multiple mapped (red), single mapped (blue) or not mapped (grey) to the 2684 reference hairpins. B. shRNA coverage of raw reads which could be mapped to expected reference hairpin sequences that have been identified by sequencing more than 10 times (red), up to ten times (blue), not mapped to any reference hairpin (grey) C. Gel electrophoresis of amplified hairpins sequences for each initial and end sample of each cell lines with the expected size of 300bp before gel purification and sequencing. D. Statistics on the number of non-detectable hairpins by sequencing and therefore not covered hairpins within the cell lines. E. Statistics on the number of affected genes, which were not represented due to 5 missing hairpins (2 genes), only represented by 1 hairpin (6 genes), by 3 hairpins (18 genes), by 3 hairpins (65 genes), by 4 hairpins (151 genes)

2 analysis approaches with the tables of normalized read count numbers aligned to reference hairpins combined of 2 Hiseq runs for each cell line and each pool accessible under http://fgcz- gstore.uzh.ch/projects/p1707/HiSeq_combined/ were used to create top hit lists of genes which are essential for 19q12 amplified ovarian cancer cells. For the first method only genes were considered which showed an average depletion rate (depletion  normalized read count numbers initial pool > end pool) of all hairpins for the respective gene in 19q12 amplified cells, however an average enrichment rate (enrichment  normalized read count

56 3. Results numbers initial pool

ULK3 coding for UNC-51 like kinase 3 was assigned to be the first top hit. The knockdown of ULK3 was represented in each cell line by 3 distinct hairpins and the average depletion rate within all 19q12 amplified cells was -25%, whereas in 19q12 non-amplified cells knockdown of ULK3 did not lead to cell death but rather to a slight growth advantage and therefore to an enrichment rate of 13%. CSNK1E coding for Casein kinase 1 ε (CK1ε) was assigned to be the second tops hit even though the average depletion rate in 19q12 amplified cells was lower than for ULK3 and the average enrichment rate for 19q12 non-amplified cells was much higher. However, knockdown of CSNK1E was represented in each cell line only by 1 hairpin representing a lower reliability compared to ULK3. Top 3-5 hits showed an average enrichment rate between 28% and 76%, however a very low depletion rate (>10%) for 19q12 amplified cells and were therefore not considered for a follow up hit validation.

As second method we applied the Analytic Technique for Assessment of RNAi by Similarity (ATARiS) (Shao, Tsherniak et al. 2013). In order to create a top hit list of 19q12 essential genes, only genes for which so-called “gene solutions” could be found were considered. “Gene solutions” were assigned if significantly similar phenotypic patterns across all screened hairpins targeting one gene were identified (Figure 15). 3 distinct phenotypic patters could be distinguished in this screen: 1. depletion  normalized read count numbers initial pool > end pool 2. enrichment  normalized read count numbers initial pool

Figure 15: Identification of “gene solutions” by ATARiS analysis approach. According to 3 distinct phenotypic patterns (depletion, enrichment, no change) “gene solution” were identified depending on the number of represented shRNAs per gene. Summary of all bars represents the number of 516 genes. For 373 genes no gene solution could be found, due to the fact that all hairpins targeting one gene showed different phenotypic patterns and therefore no statistical significant tendency. For 143 genes a “gene solution” could be found due to the same tendency of the majority of the hairpins representing statistical significance.

58 3. Results

Figure 16: Dependency pattern of the 143 genes for which “gene solutions” could be found according ATARiS. All 143 showed a clear tendency pattern of enriched, depleted or not changed hairpins. Red= essential genes for according cell line, green= non-essential gene for according cell line.

59 3. Results

For a total number of 143 genes “gene solutions” were found, the dependency pattern on each gene and each cell line was represented in a heat map (Figure 16). The two 19q12 amplified cell lines OVCAR3 and OVCAR4 showed a very similar dependency pattern. However, this pattern was opposite to the dependency pattern of the other 19q12 amplified cell line OVCAR8. Unexpectedly OVCAR8 showed a dependency pattern similar to the two 19q12 non-amplified cell lines SKOV3 and TOV21G. The third 19q12 non-amplified cell line COV504 also made an exception by exhibiting a dependency pattern opposite to the other 2 non-amplified cell lines SKOV and TOV21G, however similar to the 2 19q12 amplified cell lines OVCAR3 and OVCAR4. The 143 genes for which a “gene solution” could be found were further considered for the identification of genes being exclusively essential only for 19q12 amplified cells. Therefore, the mean of the log2 ratio of all hairpins targeting one gene was calculated and listed per cell line (Table 3). Gene with negative log2 ratios in 19q12 amplified cells, however with positive log2 ratios in 19q12 non- amplified cells were considered as 19q12 essential hits. Table 3: Top hits of genes essential for 19q12 amplified cell lines identified by ATARiS analysis approach Log2 ratio of Ø Log2 ratio of Ø Top Gene depletion rate in enrichment in 19q12 Comment hit # name 19q12 amplified cells amplified cells Negative log2 ratio in all 19q12 amplified cells 1 INSR -0.61 0.56 positive log2 ratio in all 19q12 non-amplified cells Negative log2 ratio in all 19q12 amplified cells 2 CDK13 -0.39 0.63 positive log2 ratio in all 19q12 non-amplified cells Negative log2 ratio only in 2 19q12 amplified cells 3 ACVRL1 -0.75 1.1 positive log2 ratio only in 2 19q12 non-amplified cells Negative log2 ratio only in 2 19q12 amplified cells 4 CDK4 -0.21 -0.01 positive log2 ratio only in 2 19q12 non-amplified cells Negative log2 ratio only in 2 19q12 amplified cells 5 NPR2 -0.74 -0.8 positive log2 ratio only in 2 19q12 non-amplified cells

2 genes INSR coding for Insulin receptor and CDK13 coding for Cyclin-dependent kinase 13 were identified for which negative log2 ratios referring to depleted hairpins in all three 19q12 amplified cell lines (OVCAR8, OVCAR4, OVCAR3), however positive log2 ratios referring to enriched hairpins in all three 19q12 non-amplified cell lines (SKOV, TOV21G, COV504) could be identified. Top hits 3-5 showed negative log2 ratios only for 2 19q12 amplified cell lines and positive log2 ratios only for 2 19q12 non- amplified cell lines respectively. Therefore, they were not considered for further hit validation. (for full hit list see http://fgcz-gstore.uzh.ch/projects/p1707/ATARiS_20150925/six_samples/ file 1707_6.gene.table.txt)

60 3. Results

3.4 Hit validation of top hits ULK3, INSR, CSNK1E and CDK13

The top hits of both analyses (ULK3, INSR, CSNK1E, CDK13) were considered for a follow up hit validation. First, the knockdown efficiency of each of the 5 shRNAs per gene was tested in OVCAR8 cells (Figure 17). Cells were stably transduced by lentiviral-mediated shRNA delivery. shCTRL samples to which shRNA samples were normalized to carried the same TRC-pLKO vector, however with a non- targeting stuffer region instead of the specific shRNA hairpin targeting the respective genes. 48h after puromycin selection, cells were harvested, mRNA extracted and mRNA levels of the respective genes analyzed by RT-qPCR. Subsequently the most efficient shRNA for each gene was chosen for further experiments.

Ak.d efficiency ULK3 B k.d. efficiency CSNK1E 1 1

0.8 0.8 * 0.6 0.6 ** ** ** ** 0.4 0.4 ** *** *** 0.2 0.2 **** **** relative mRNA expression ULK3

0 relative mRNA expressionCSNK1E 0 ns shCSNK1E shCSNK1E shCSNK1E shCSNK1E shCSNK1E shCTRLns shRNA#1 shULK3 shRNA#2shULK3 shRNA#3shULK3 shRNA#4shULK3 shRNA#5shULK3 shCTRLshCTRL shRNA#1 shRNA#2 shRNA#3 shRNA#4 shRNA#5 #1 #2 #3 #4 #4 #1 #2 #3 #4 #5 C D k.d. efficiency INSR k.d. efficiency CDK13 1 1 * 0.8 0.8

** ** ** 0.6 0.6 **

0.4 0.4 **** **** **** 0.2 **** 0.2 **** relative mRNA expressionINSR relative mRNA expression CDK13 0 0 shCTRLshCTRLns shRNA#1 shINSR shRNA#2shINSR shRNA#3shINSR shRNA#4shINSR shRNA#5shINSR shCTRLshCTRLns shRNA#1 shCDK13 shRNA#2shCDK13 shRNA#3shCDK13 shRNA#4shCDK13 shRNA#5shCDK13 #1 #2 #3 #4 #5 #1 #2 #3 #4 #5

Figure 17: Knockdown efficiency of shRNAs targeting genes identified as being essential for 19q12 amplified cells tested in OVCAR8 cells. Graphs represent relative mRNA expression levels of ULK3 (A), CSNK1E (B), INSR (C) and CDK13 (D), normalized to TPB. n=3 independent replicates, error bars represent ±SD, ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05

After determination of the most efficient shRNA targeting the respective gene, hit validation of ULK3, CSNK1E, INSR and CDK13 was performed by CFA with all 19q12 amplified cell lines (OVCAR8, OVCAR4, OVCAR3) and all 19q12 non-amplified cell lines (SKOV, TOV21G, COV504) used in the shRNA screen (Figure 18). Cells were stably transduced by lentiviral-mediated delivery of the most efficient shRNA of each gene respectively. Cells were seeded for CFAs 48h after puromycin selection and 10 days later cells were stained with crystal violet and colonies quantified. The number of colonies of knockdown samples was normalized to the number of colonies of non-targeting shCTRL samples.

61 3. Results

Based on the results of the screen, it was expected that 19q12 amplified cells show a clear dependency pattern on ULK3, CSNK1E, INSR and CDK13. Therefore, depletion of the respective genes should result in a reduced number of colonies compared to the shCTRL samples. No significant decrease in colony formation after ULK3, CSNK1E, INSR and CDK13 depletion compared to shCTRL samples should be observed in 19q12 non-amplified cells The expected decrease in cell viability after ULK3 depletion in 19q12 amplified ovarian cancer cells could only clearly be observed in OVCAR8 (Figure 18 A1). Both other 19q12 amplified cell lines OVCAR3 and OVCAR4 showed a decreased cell viability upon ULK3 depletion compared to the respective shCTRL samples, however the number of colonies was comparable to the number of colonies of the two 19q12 non-amplified cell lines SKOV and TOV21G. The cell line COV504 showed a clear dependency on ULK3 even though the k.d. efficiency of ULK3 was lower than in all other cell lines (Figure 18 B1). This pattern did not fit into the expected non-dependency pattern of 19q12 non-amplified cells. The mean of number of colonies of all ULK3 depleted 19q12 amplified cells normalized to the respective shCTRL samples was slightly lower than the mean of number of colonies of all 19q12 non-amplified cells normalized to the respective shCTRL samples (Figure 18 C1), however not significantly. Therefore, ULK3 could not be validated as 19q12 essential gene and was not considered for further experiments. CSNK1E depleted cells showed, as expected, a clear dependency pattern in 19q12 amplified cells (Figure 18 A2). Furthermore, SKOV and TOV21G cells also fit into the expected pattern of being rather resistant to CSNK1E knockdown. The only cell line in the panel which did not fit into the pattern was COV504, since it showed the same dependency pattern on CSNK1E as the 19q12 amplified cells. For CSNK1E, the mean number of colonies of all CSNK1E depleted 19q12 amplified cells normalized to the respective shCTRL samples was clearly lower than the mean of number of colonies of all 19q12 non- amplified cells normalized to the respective shCTRL samples (Figure 18 C2). Even though the difference between 19q12 amplified and 19q12 non-amplified cells was not significant due to the fact that COV504 was the only outlier in this panel, we decided to further validated CSNK1E as potential 19q12 essential hit in an extended panel of 19q12 non-amplified cell lines. The expected cell viability patter after INSR knockdown was neither consistent through 19q12 amplified cell lines not through 19q12 non-amplified cell lines (Figure 18 A3). The 2 19q12 amplified cell lines OVCAR8 and OVCAR3, as well as the 19q12 non-amplified cell lines were highly dependent on INSR reflected by almost non-existing colonies. However, the 19q12 amplified OVCAR4 and the 19q12 non-amplified cell line SKOV3 were rather resistant to INSR depletion. The mean of the numbers of colonies of all INSR depleted 19q12 amplified cells normalized to the respective shCTRL samples was slightly lower than the mean of number of colonies of all 19q12 non-amplified cells normalized to the respective shCTRL samples (Figure 18 C3), however not significantly. Therefore, INSR was not considered for further experiments.

62 3. Results

For CDK13, all 19q12 amplified cell lines showed a clear dependency on CDK13 as expected, also the 19q12 non-amplified cell lines SKOV fulfilled the expectations as being rather CDK13 resistant (Figure 18 A4). However, TOV21G and COV504 showed the same dependency pattern as all 19q12 amplified cells, which was not expected. Also for CDK13 the mean of the number of colonies of all CDK13 depleted 19q12 amplified cells normalized to the respective shCTRL samples was lower than the mean of number of colonies of all 19q12 non-amplified cells normalized to the respective shCTRL samples (Figure 18 C4). Even though the difference of the mean between 19q12 amplified and 19q12 non- amplified cells was also not significant, we decided to further analyze the dependency on CDK13 in an extended panel of 19q12 non-amplified cell lines.

63 3. Results

A B C

1)Quantification of CFA ULK3 1)k.d. efficiency ULK3 1) Mean cell lines ULK3 p=0.74 1.2 1.2 1 1 1 0.8 0.8 0.8 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0.2 0.2 relativenumber colonies of 0 0 0 relativenumber coloniesof shCTRL shULK3 shCTRL shULK3 relative mRNA expression ULK3 19q12 amplified 19q12 non- shCTRL shULK3 shCTRL shULK3 cell lines amplified cell lines

2)Quantification of CFA CSNK1E 2)k.d. efficiency CSNK1E 2) Mean cell lines CSNK1E p=0.27 1.2 1.2 1 1 1 0.8 0.8 0.8 0.6 0.6 0.6 0.4 0.4 0.4

0.2 0.2 0.2 0 0 0 relative number colonies of relativenumber colonies of shCTRLshCTRL shCSNK1Esh shCTRL shCTRL shCSNK1Esh 19q12 amplifiedCSNK1E 19q12 non-amplifiedCSNK1E shCTRL shCSNK1E relative mRNA expression CSNK1E shCTRL shCSNK1E 19q12 amplified 19q12 non- cell lines amplified cell lines 3)Quantification of CFA INSR 3)k.d. efficiency INSR 3) Mean cell lines INSR p=0.75 1.2 1.2 1

1 1 0.8 0.8 0.8 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0.2 0.2 0 0 relativenumber colonies of 0 relativenumber of colonies shCTRL shINSR shCTRL shINSR relativemRNA expressionINSR

shCTRL shINSR shCTRL shULK3 19q12 amplified 19q12 non- cell lines amplified cell lines 4)Quantification of CFA CDK13 4)k.d. efficiency CDK13 4) Mean cell lines CDK13 p=0.38 1.2 1.2 1 1 1 0.8 0.8 0.8 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0.2 0.2 0 0 relativenumber coloniesof 0 shCTRLshCTRL shCDK13sh shCTRL shCTRL shCDK13sh relative number of colonies relativenumber relative mRNA expression CDK13 19q12 amplifiedCDK13 19q12 non-amplifiedCDK13 shCTRL shCDK13 shCTRL shCDK13 19q12 amplified 19q12 non- cell lines amplified cell lines

Figure 18: Hit validation of top hits identified as being essential for 19q12 amplified cells. Hit validation was performed with 19q12 amplified cell lines (OVCAR8, OVCAR4, OVCAR3) and 19q12 non-amplified cell lines (SKOV, TOV21G, COV504), all being used in the shRNA screen A. Relative quantification of number of cell colonies depleted of ULK3 (A), CSNK1E (B), INSR (C), CDK13 (D) normalized to number of colonies of shCTRL cells. n=3 independent experiments. Error bars represent ±SD. B. Relative mRNA expression levels of ULK3 (1), CSNK1E (2), INSR (3), CDK13 (4) normalized to TBP. n=3 independent replicates, ±SD. C. Mean of relative number of colonies of ULK3 (1), CSNK1E (2), INSR (3), CDK13 (4) depleted cells of 19q12 amplified cells vs 19q12 non-amplified cells.

64 3. Results

3.5 Hit validation of CSNK1E and CDK13 in an extended panel of 19q12 non-amplified ovarian cancer cell lines

Further hit validation of CSNK1E and CDK13 with an extended panel of 19q12 non-amplified cell lines including IGROV, TYKNU and CAOV3 revealed a more distinct pattern between 19q12 amplified and 19q12 non-amplified cell lines.

A 1) Quantification CFAs CSNK1E k.d. 2) Quantification CFAs CDK13 k.d. 1.2 1.2

1 1

0.8 0.8

0.6 0.6

0.4 0.4

0.2 0.2 relativenumber colonies of relativenumber colonies of

0 0

shCTRL shCSNK1E shCTRL shCDK13 B 1) k.d. efficiency CSNK1E 2) k.d. efficiency CDK13 1.2 1.2

1 1

0.8 0.8

0.6 0.6

0.4 0.4

0.2 0.2 relativemRNA expression CDK13 relativemRNA expression CSNK1E 0 0

nsshCTRL shCSNK1E shCTRL shCDK13 C 1) mean cell lines CSNK1E 2) mean cell lines CDK13 1.2 1.2 ** ** 1 1

0.8 0.8

0.6 0.6

0.4 0.4 relativenumber colonies of 0.2 relativenumber ofcolonies 0.2

0 0 shCTRL shCSNK1E shCTRL shCSNK1E shCTRL shCDK13 shCTRL shCDK13 19q12 amplified cell lines 19q12 non-amplified cell 19q12 amplified cell lines 19q12 non-amplified cell lines lines

Figure 19: Hit validation of top hits CSNK1E and CDK13 identified as being essential for 19q12 amplified cells in an extended panel of 19q12 non-amplified cell lines (SKOV, TOV21G, COV504, IGROV, TYKNU, CAOV3 19q12 non-amplified; OVCAR8, OVCAR4, OVCAR3  19q12 amplified) A. Relative quantification of number of cell colonies depleted of CSNK1E (1) and CDK13 (2) normalized to number of colonies of shCTRL cells. n=3 independent experiments. Error bars represent ±SD. B. Relative

65 3. Results mRNA expression levels of CSNK1E (1), and CDK13 (2) normalized to TBP. n=3 independent replicates, ±SD. C. Mean of relative number of colonies of CSNK1E (1) and CDK13 (2) depleted 19q12 amplified cells vs. 19q12 non-amplified cells normalized to shCTRL samples. n=3 19q12 amplified cell lines; n=6 19q12 non-amplified cell lines. **p<0.01

The three additional 19q12 non-amplified cell lines showed only a slight decrease in cell viability after CSNK1E k.d. (Figure 19 A1). With disregard of COV504, the mean of number of colonies of CSNK1E depleted 19q12 amplified cells, normalized to the respective shCTRL samples, was significantly lower than the mean of number of colonies of CSNK1E depleted 19q12 non-amplified cells (Figure 19 C1). Also the cell viability pattern of the three additional 19q12 amplified cell lines after k.d. of CDK13 was clearly different from the pattern of 19q12 amplified cells, even though all 19q12 non-amplified cells were in general slightly affected and not fully resistant to the k.d. of CDK13 (Figure 19 A2). With disregard of COV504, the mean of number of colonies of CDK13 depleted 19q12 amplified cells, normalized to the respective shCTRL samples, was significantly lower than the mean of number of colonies of CDK13 depleted 19q12 non-amplified cells (Figure 19 B2). K.d. efficiency was determined for both genes and cell lines by RT-qPCR (Figures 19 B1 and B2). According to these results we considered both CSNK1E and CDK13 as being essential exclusively for 19q12 amplified cells. Therefore, we proceeded with further hit validation using a second cell viability assay, the Annexin V assay in order to quantitatively measure the cell death rate by labelling apoptotic cells. Furthermore, 2 different shRNAs targeting CSNK1E and CDK13 were used respectively. In this setting all 19q12 amplified cell lines OVCAR8, OVCAR4, OVCAR3, as well as the selected three 19q12 non-amplified cell lines SKOV, TYKNU and CAOV3 were used. All 19q12 amplified cells showed a decreasing cell viability over time when CSNK1E was knocked down with 2 different shRNAs (Figure 20 A). Cell viability dropped down until 20% in case of OVCAR3, whereas the cell viability of all 19q12 non-amplified cells stayed rather unaffected since at least 80- 100% of all cells were still alive 11 days after the establishment of the knockdown. Even though the knockdown of the second shRNA targeting CSNK1E mediated a less efficient knockdown, the distinct dependency pattern on CSNK1E btw 19q12 amplified and 19q12 non-amplified cell stayed the same (Figure 20 D). CFA results reflecting the long term cell viability CSKN1E depleted cells confirmed the results of the Annexin V assay that 19q12 amplified cell lines are more dependent on CSNK1E than 19q12 non-amplified cell lines (Figure 20 B). Furthermore, there a significant difference in the mean of 19q12 amplified knockdown cells compared to the mean of 19q12 non-amplified k.d. cells in terms the relative number of colonies and therefore cell viability could be determined (Figure 20 C).

66 3. Results

A OVCAR8 OVCAR4 OVCAR3 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40 cellviability(%) cellviability(%) 20 20 viabilitycell(%) 20 0 0 0 5 6 7 8 11 5 6 7 8 11 5 6 7 8 11 days after established k.d. days after established k.d. days after established k.d. shCTRL shCTRL shCTRL shCSNK1E #1 shCSNK1E #1 shCSNK1E #1 shCSNK1E #2 shCSNK1E #2 shCSNK1E #2

SKOV TYKNU CAOV3 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40 cellviability(%) cellviability(%) 20 20 viabilitycell(%) 20 0 0 0 5 6 7 8 11 5 6 7 8 11 5 6 7 8 11 days after established k.d. days after established k.d. days after established k.d. shCTRL shCTRL shCTRL shCSNK1E #1 shCSNK1E #1 shCSNK1E #1 shCSNK1E #2 shCSNK1E #2 shCSNK1E #2 B C Quantification of CFAs CSNK1E Mean cell lines CSNK1E 2 1.4 * 1.2 1.6 * 1 1.2 0.8

0.8 0.6 0.4 0.4 0.2 relativenumber ofcolonies 0 relativenumber of colonies 0 OVCAR8 OVCAR4 OVCAR3 SKOV3SKOV TYKNU CAOV3

19q12 amplified 19q12 non-amplified shCTRL shCTRL shCTRL shCSNK1E #1 shCSNK1E #2 shCSNK1E #1 shCSNK1E #2 shCSNK1E #1 shCSNK1E #2 19q12 amplified cell lines 19q12 non-amplified cell lines D k.d. efficiency CSNK1E 1.2

1

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relative mRNA expression CSNK1E OVCAR8 OVCAR4 OVCAR3 SKOV TYKNU CAOV3 19q12 amplified 19q12 non-amplified

shCRTL shCSNK1E #1 shCSNK1E #2

Figure 20: Validation of CSNK1E as being essential for 19q12 amplified ovarian cancer cells. A. Cell viability of CSNK1E depleted cells measured by FACS after Annexin V staining, 5 to 11 days after the application of shRNA mediated CSNK1E knockdown with 2 different shRNAs. Each data point represents the mean of n=3 independent experiments, error bars represent ±SD. B. Relative quantification of number of cell colonies depleted of CSNK1E normalized to number of colonies of shCTRL cells. n=3 independent experiments, error bars represent ±SD C. Comparison of the mean of relative number of colonies of CSNK1E depleted cells of 19q12 amplified cells vs 19q12 non-amplified cells. p*<0.05 D. Relative mRNA expression levels of CSNK1E normalized to TBP. n=3 independent replicates, ±SD.

67 3. Results

A OVCAR8 OVCAR4 OVCAR3 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40

cell(%) viability 20 cell(%) viability 20 cell(%) viability 20 0 0 0 5 6 7 8 11 5 6 7 8 11 5 6 7 8 11 days after established k.d. days after established k.d. days after established k.d. shCTRL shCTRL shCTRL shCDK13 #1 shCDK13 #1 shCDK13 #1 shCDK13 #2 shCDK13 #2 shCDK13 #2

SKOV TYKNU CAOV3 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40 cellviability(%) cell(%) viability 20 cell(%) viability 20 20 0 0 0 5 6 7 8 11 5 6 7 8 11 5 6 7 8 11 days after established k.d. days after established k.d. days after established k.d. shCTRL shCTRL shCTRL shCDK13 #1 shCDK13 #1 shCDK13 #1 shCDK13 #2 shCDK13 #2 shCDK13 #2 B C Quantification of CFAs CDK13 Mean cell lines CDK13 1.4 1.4 ** 1.2 1.2 * 1 1 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 relativenumber colonies of 0 0 OVCAR8 OVCAR4 OVCAR3 SKOV3 TYKNU CAOV3 relative number ofcolonies

19q12 amplified 19q12 non amplified shCTRL shCTRL shCTRL shCDK13 #1 shCDK13 #2 shCDK13 #1 shCDK13 #2 shCDK13 #1 shCDK13 #2 19q12 amplified cell lines 19q12 non-amplified cell lines D k.d. efficiency CDK13 1.2

1

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0 relative mRNA relativeexpressionmRNA CDK13 OVCAR8 OVCAR4 OVCAR3 SKOV TYKNU CAOV3 19q12 amplified 19q12 non-amplified

shCTRL shCDK13 #1 shCDK13 #2

Figure 21: Validation of CDK13 as being essential for 19q12 amplified ovarian cancer cells. A. Cell viability of CDK13 depleted cells measured by FACS after Annexin V staining, 5 to 11 days after the application of shRNA mediated CDK13 knockdown with 2 different shRNAs. Each data point represents the mean of n=3 independent experiments, error bars represent ±SD. B. Relative quantification of number of cell colonies depleted of CDK13 normalized to number of colonies of shCTRL cells. n=3 independent experiments, error bars represent ±SD C. Comparison of the mean of relative number of colonies of CDK13 depleted cells of 19q12 amplified cells vs 19q12 non-amplified cells. p*<0.05, p**<0.01 D. Relative mRNA expression levels of CDK13 normalized to TBP. n=3 independent replicates, ±SD.

68 3. Results

All 19q12 amplified cells (OVCAR8, OVCAR4, OVCAR3) showed a decreasing cell viability over time when CDK13 was knocked down with 2 different shRNAs (Figure 21 A). Cell viability decreased to ~40%, whereas the cell viability of all 19q12 non-amplified cells after CDK13 k.d was not affected. An exception was given by SKOV after CDK13 k.d. with shRNA #1, however due to one outlier experiment indicated by the big error bars (Figure 21 A). The k.d. efficiency of the second shRNA targeting CDK13 was slightly less efficient (Figure 21D). This is reflected by the CFA showing relative numbers of colonies which were in general higher for the shRNA #2 than for shRNA #1. However, the tendency in terms of cell viability was the same for both shRNAs targeting CDK13 (Figure 21 B). A significant difference in the mean of number of colonies of 19q12 amplified knockdown cells compared to the mean of number of colonies of 19q12 non-amplified k.d. cells after CDK13 k.d. could be determined for both shRNAs (Figure 21 C). In summary the validation experiments showed that the screening hits CSNK1E and CDK13 are indeed essential for 19q12 amplified ovarian cancer cells when compared to 19q12 non-amplified ovarian cancer cells.

69 3. Results

3.6 CK1ε inhibition with small molecule inhibitors

Since k.d. of CSNK1E caused a decrease of cell viability in 19q12 amplified ovarian cancer cells, we reasoned that inhibiting the gene product of CSNK1E, termed Casein Kinase 1 ε (CK1ε), should also impair cell viability of 19q12 amplified cells. We used 2 commercially available small molecular inhibitors IC261 and PF4800567 for inhibiting CK1ε.

The first inhibitor, IC261, has been shown to inhibit CK1δ (IC50 = 0.7-1.3 μM), and CK1ε (IC50 = 0.6-1.4 μM). Inhibition is reversible and in a competitive manner with respect to ATP. IC261 has also been shown to weakly inhibit casein kinase 1α1 (IC50 = 11-21 μM), PKA, CDC2 p34, and Fyn (p55) (Behrend, Milne et al. 2000, Mashhoon, DeMaggio et al. 2000). Cell viability of the 19q12 amplified cell lines OVCAR3, OVCAR4, OVCAR8 and the 19q12 non-amplified cell line SKOV, TYKNU and CAOV3 was determined by PrestoBlue assay. 6 different IC261 concentrations were applied (1 nM to 50 µM) and cell viability was determined after 24 h, 48 h, 72 h and 96 h (Figure 22). Cell viability could be quantitatively measured since the fluorescence intensity of the PrestoBlue dye correlates with the reducing power of living cells. In line with our previous results IC261 decreased cell viability of all 19q12 amplified cell lines (Figure 22A). However, cell viability of all 19q12 non-amplified cells decreased unexpectedly to the same extend (Figure 22B). Cell viability decreased for both 19q12 amplified and 19q12 non-amplified cells starting at a concentration of 100 nM, which is even below the half-maximal inhibitory concentration for CK1ε. At a concentration of 1 µM cell viability could not be further decreased with higher concentrations, but only due to longer incubation times. A concentration of 1 µm and an incubation time of 96 h was enough to kill cells completely due to a cell viability rate of less than 10%. This pattern was observed throughout all 6 cell lines and independent of the 19q12 amplification status.

70 3. Results

A B OVCAR8 SKOV 120% 120% 100% 100% 80% 80% 60% 60%

cellviability 40% cellviability 40% 20% 20% 0% 0% DMSO 1nM 10nM100nM 1uM 10uM 50uM DMSO 1nM 10nM 100nM 1uM 10uM 50uM

24h 48h 72h 96h 24h 48h 72h 96h

OVCAR4 TYKNU 120% 120% 100% 100% 80% 80% 60% 60%

cellviability 40% cellviability 40% 20% 20% 0% 0% DMSO 10nM 10nM 100nM 1uM 10uM 50uM DMSO 1nM 10nM 100nM 1uM 10uM 50uM

24h 48h 72h 96h 24h 48h 72h 96h

OVCAR3 CAOV3 120% 120% 100% 100% 80% 80% 60% 60%

cellviability 40% cellviability 40% 20% 20% 0% 0% DMSO 1nM 10nM100nM 1uM 10uM 50uM DMSO 1nM 10nM 100nM 1uM 10uM 50uM

24h 48h 72h 96h 24h 48h 72h 96h

Figure 22: CK1ε inhibitor IC261 decreases cell viability of both 19q12 amplified and 19q12 non-amplified cells. Cell viability of 19q12 amplified cells (OVCAR8, OVCAR4, OVCAR3) and 19q12 non-amplified cells (SKOV, TYKNU, CAOV) was quantitatively measured by PrestoBlue after the application of 6 different concentrations (1 nM to 50 µM) of IC261 and incubation times of 24 h, 48 h, 72 h and 96 h. Each data point represents the mean of n=3 independent experiments, error bars represent ±SD.

71 3. Results

A B OVCAR8 SKOV 140% 140% 120% 120% 100% 100% 80% 80% 60% 60% cellviability 40% cellviability 40% 20% 20% 0% 0% DMSO 1nM 10nM 100nM 1uM 10uM 100uM DMSO 1nM 10nM100nM 1uM 10uM 100uM

24h 48h 72h 96h 24h 48h 72h 96h

OVCAR4 TYKNU 140% 140% 120% 120% 100% 100% 80% 80% 60% 60% cellviability 40% cellviability 40% 20% 20% 0% 0% DMSO 1nM 10nM100nM 1uM 10uM 100uM DMSO 1nM 10nM 100nM 1uM 10uM 100uM

24h 48h 72h 96h 24h 48h 72h 96h

OVCAR3 CAOV 140% 140% 120% 120% 100% 100% 80% 80% 60% 60% cellviability cellviability 40% 40% 20% 20% 0% 0% DMSO 1nM 10nM 100nM 1uM 10uM100uM DMSO 1nM 10nM 100nM 1uM 10uM 100uM

24h 48h 72h 96h 24h 48h 72h 96h

Figure 23: CK1ε inhibitor PF4800567 decreases cell viability of both 19q12 amplified and 19q12 non-amplified cells. Cell viability of 19q12 amplified cells (OVCAR8, OVCAR4, OVCAR3) and 19q12 non-amplified cells (SKOV, TYKNU, CAOV) was quantitatively measured by PrestoBlue after the application of 6 different concentrations (1 nM to 100 µM) of PF4800567 and incubation times of 24 h, 48 h, 72 h and 96 h. Each data point represents the mean of n=3 independent experiments, error bars represent ±SD.

Similar to IC261, cell viability was also measured by PrestoBlue after treatment of the different cell lines with 6 different concentrations of PF4800567 (1 nM to 100 µM) and incubation times of 24 h,

48h, 72 h and 96 h (Figure 23). PF4800567 has been shown to inhibit casein kinase 1ε (IC50= 32 nM), but also CK1δ (IC50= 711 nM) (Walton, Fisher et al. 2009). PF4800567 did not affect cell viability of both 19q12 amplified and 19q12 non-amplified cell lines at concentrations below 100 µM. At 100 µM longer incubation times correlated with decreasing cell viability. Furthermore, 19q12 non-amplified showed a lower cell viability than 19q12 amplified cells at

72 3. Results concentrations of 100 µM, which was exactly the opposite pattern than expected. Since a concentration of 100 µM inhibits CK1δ as well (Walton, Fisher et al. 2009), it needs to be considered that the reduced cell viability might not be induced by CK1ε inhibition but rather by CK1δ inhibition. In conclusion, CK1ε inhibition by using the small molecular inhibitors IC261 and PF4800567 did not substantiate our previous results by showing a distinct cell viability pattern between 19q12 amplified and 19q12 non-amplified cells. Therefore, a phenotype rescue experiment would have been reasonable in order to test if the observed pattern is actually driven by depletion of CSNK1E and not by other effects. However due to time constraints we decided to continue focusing on CDK13. Since no small molecular inhibitors against CDK13 were available at the time point we planned to perform inhibitor experiments, we decided to directly continue with phenotype rescue experiments.

73 3. Results

3.7 CDK13 phenotype rescue experiments

3.7.1 Testing the specificity of antibodies against CDK13

An important requirement for any further analyses on CDK13 as potential essential gene for 19q12 amplified cancer cells was a specific antibody against CDK13 in order to proof that shRNAs targeting CDK13 also decrease CDK13 protein levels. Several antibodies against CDK13 were tested and a specific monoclonal mouse antiCDK13/CLC2L5 antibody (Abcam) was found confirming that all 5 shRNA targeting CDK13 lead to a downregulation of CDK13 on protein level (Figure 24). K.d. efficiency of CDK13 induced by the 5 different shRNAs varied between cell lines.

Figure 24: Test of knockdown efficiency of CDK13 on protein level. CDK13 k.d. in 19q12 amplified cells (A) and 19q12 non- amplified cells (B) was mediated by lentiviral delivery of 5 different shRNA and protein levels were determined by western blotting.

3.7.2 Test of CDK13 rescue constructs

Since knockdown of CDK13 decreases cell viability in 19q12 amplified ovarian cancer cells, we wanted to confirm that this phenotype is not an artefact and driven by the effect of another targeted and silenced gene. Therefore, we cloned a N-terminally HA-tagged and an untagged cDNA of CDK13 into two inducible lentiviral delivery plasmids pLKO-TRC and pLKO-TET (tetracycline-inducible), respectively and used them for phenotypic rescue experiments. For this, the cDNA of CDK13 from the human ORFeome 8.1 library was amplified with a forward primer containing a N- terminal HA-tag and a reverse primer containing the stop coding triplet at the 3` end of the cDNA sequence. The PCR product was cloned into pLKO-TRC and pLKO-Tet lentiviral delivery vectors, in order to express CDK13 fusion proteins with a N-terminal HA-tag. Furthermore, a CDK13 overexpression construct without HA-tag was cloned. In order to test the constructs, 293T cells were transduced via shRNA mediated lentiviral

74 3. Results delivery and relative mRNA and protein expression levels of CDK13 were investigated by RT-qPCR and western blot respectively (Figure 25 A and 25B). mRNA samples were normalized to shCTRL sample.

Figure 25: Test of CDK13 overexpression constructs. A. Relative mRNA expression levels of CDK13 normalized to TBP and shCTRL after CDK13 depletion with shRNA #1 (served as control), CDK13 overexpression (pLKO-TRC vector), CDK13 overexpression with N-terminal HA-tag (pLKO-TET-inducible vector), CDK13 overexpression with N-terminal HA-tag (pLKO-TRC vector) B. Immunoblot of corresponding CDK13 protein and HA-CDK13 fusion protein expression levels.

After induction of exogenous CDK13 expression with constructs TRC-CDK13, TET-HA-CDK13 and TRC- HA-CDK13, mRNA levels of CDK13 were elevated up to 2-fold (Figure 25 A). The TRC-HA-CDK13 construct expressing CDK13 with a N-terminal HA-epitope showed the best induction of CDK13 expression on mRNA level due to a 2.1 fold induction. With the TET-HA-CDK13 construct expressing a tetracycline-inducible expression of CDK13 with N-terminal HA-epitope only a 1.3 fold induction of CDK13 mRNA levels after 2 days of doxycycline treatment could be achieved. Exogenous expression of CDK13 of both HA-constructs on protein level could be validated by western blotting with an HA- specific antibody (Figure 25 B). Also on protein levels a slight difference of CDK13 expression induced by the TRC-HA-CDK13 construct compared to the TET-HA-CDK13 construct could be identified, however only when CDK13 was detected by the HA-specific antibody. In summary, all overexpression constructs resulted in increased CDK13 mRNA and protein levels when compared to normal CDK13 expression in the non-targeting shCTRL sample.

3.7.3 Phenotypic rescue of CDK13 depleted 19q12 amplified cell lines

After the confirmation that all three different CDK13 overexpression constructs are able to induce exogenous expression of CDK13, the nucleotide sequence of the TRC-HA-CDK13 construct expressing CDK13 with N-terminal HA-tag was altered by site directed mutagenesis, in order to generate a recue construct. For this, the third nucleotide of a base triplet of 3 different triplets within the binding region of shCDK13 #1 was changed, however the code of the original amino acid sequence of CDK13 remained the same. Two different constructs (OE6_3 and OE 10_1) with differently mutated nucleotides in 3 triplets were generated. As result of these nucleotide changes shCDK13 #1 was thought to not be able

75 3. Results to recognize the specific binding site on the CDK13 sequence anymore and therefore not to be able to induce RNAi. Each 19q12 amplified cell line was stably transduced with a shCTRL construct, the shCDK13 #1 construct, the two different overexpression constructs OE6_3 and OE 10_1, furthermore with each of the overexpression constructs plus shCDK13 #1. Both constructs (OE6_3 and OE 10_1) showed a slight induction of CDK13 mRNA expression (Figure 26 A). In OVCAR8 cells, exogenously induced CDK13 mRNA expression levels were higher than in OVCAR4 and OVCAR3. Due to only slightly increased CDK13 mRNA expression levels, it was not possible to notice increased CDK13 protein levels after exogenous induced expression compared to shCTRL samples (Figure 26 B). In all 3 cell lines, construct OE6_3 induced a higher expression of CDK13 than construct OE10_1, which could only be detected on the immunoblot by detecting the HA-tag of the CDK13 fusion protein. Furthermore, mRNA levels of OE6_3 + shCDK13 #1 samples did not decrease and were comparable to mRNA levels of OE6_3, whereas OE10_1 + shCDK13 #1 expression samples showed decreased mRNA levels which were comparable to shCDK13 #1 k.d. Also CDK13 protein levels were decreased in the OE10_1 + shCDK13 #1 samples and comparable to shCTRL samples. Therefore, only construct OE6_3 successfully prevented the downregulation of CDK13 both on mRNA and on protein level and served as CDK13 rescue construct. Nevertheless, CDK13 was slightly exogenously expressed based on the western blots detecting the HA-tag of the exogenously expressed CDK13 protein. CFAs revealed that exogenous expression of CDK13 with both constructs OE6_3 and OE 10_1, increased cell proliferation by 1.5- to 2-fold for (Figure 26 D). Exogenous expression of CDK13 with the construct OE6_3 plus additional k.d. with shCDK13 #1 revealed a cell survival rate of 1-fold, in the OVCAR8 and OVCAR4 cells, and 1.3 fold for OVCAR3 cells. These results showed that the phenotype induced by endogenous CDK13 expression could be rescued by additional introduction of not silenced exogenously induced CDK13 expression with construct OE6_3. Construct OE10_1 was also able to partially rescue the phenotype of CDK13 depletion up to 0.6- 1 fold and therefore to a lower extend than construct OE6_3. The Annexin V time revealed that the phenotype of CDK13 depletion was rescues by overexpression of CDK13 with construct OE6_3 in all three cell lines due to the fact that the survival rate was elevated to similar levels of the shCTRL samples (Figure 26 E). However, construct OE10_1 could only partially rescue the CDK13 depleted phenotype when co-expressed with shCDK13 #1. In conclusion, by rescuing the apoptotic phenotype of CDK13 depleted HGSOC cells, we confirm that CDK13 is essential for the cell survival of 19q12 amplified HGSOC cells. Furthermore, overexpression of CDK13 induces increased cell proliferation.

76 3. Results

Figure 26: Overexpression of CDK13 promotes increased cell proliferation and rescues apoptosis induced by depletion of CDK13. A. Relative mRNA expression levels of CDK13 of 19q12 amplified ovarian cancer cells (OVCAR8, OVCAR3, OVCAR3) after constitutive CDK13 depletion, constitutive overexpression of CDK13 by 2 different constructs (6_3 and 10_1) and constitutive CDK13 depletion induced by shCDK13 plus constitutive overexpression of CDK13. n=3 biological replicates. Error

77 3. Results bars represent ± SD. B. Protein expression levels of CDK13. Expression levels of Actin served as loading CTRL. C. CFA of 19q12 amplified ovarian cancer cells (OVCAR8, OVCAR3, OVCAR3) after constitutive CDK13 depletion, constitutive overexpression of CDK13 by 2 different constructs (6_3 and 10_1) and phenotype rescue of constitutive depleted CDK13 induced by shCDK13 plus constitutive overexpression of CDK13. D. Quantification of colony formation assays. n=3 biological replicates. Error bars represent ± SD. E. Annexin V time course experiment with same expression constructs as mentioned in A or C.

78 3. Results

3.8 In vivo tumor growth of CDK13 depleted subcutaneous tumors of mouse xenograft models

3.8.1 Preparation and test of cell lines with tetracycline-inducible CDK13 knockdown

Based on our results obtained so far, it seems likely that CDK13 plays a crucial role in cell survival of 19q12 amplified cells. Thus we proceeded with mouse xenografts by subcutaneously injecting tetracycline -inducible CDK13 k.d. cells. First, we established cell lines with a tetracycline-inducible expression system in order to promote the constitutive expression of shCDK13 upon doxycycline treatment.

Figure 27: CDK13 knockdown efficiency of tet-inducible induction of CDK13 k.d. in OVCAR3, OVCAR8, SKOV, TYKNU cells. Cells were treated with 2µg/mL doxycycline for 72h. A. CDK13 mRNA levels after knockdown with 3 different tet-inducible shRNAs constructs (shCDK13 #1, #2, #3). n=3 technical replicates, mean values ±SD, ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05. B. CDK13 protein level after knockdown of CDK13 with tet-shCDK13 #2.

The 3 shRNA constructs leading to the most efficient k.d. of CDK13 assessed in part 3.4, were cloned into the tet-pLKO expression vectors and cell lines OVCAR8, OVCAR3, SKOV and TYKNU were transduced. K.d efficiency of CDK13 upon doxycycline treatment for 72h was tested on mRNA level and

79 3. Results protein level (Figure 27). Since shCDK13 #2 induced the most efficient k.d. of CDK13, the k.d. efficiency on protein level was tested only for this construct. Also on protein level a signification reduction of CDK13 could be observed. Therefore, tet-shCDK13 #2 was further used for the mouse xenograft models. Both cell viability assays (CFA and Annexin V time course) were performed in order to test if the phenotype upon CDK13 depletion can also be observed with the 2 tet-inducible k.d. constructs tet- shCDK13# 1 and tet-shCDK13#2 (Figure 28). Knockdown efficiency was tested in samples harvested 72h after doxycycline treatment. According to mRNA levels the second shRNA construct was more efficient than the first construct (Figure 28 D). This pattern is also reflected by the cell viability measured by CFA. The relative number of CDK13 depleted colonies by doxycycline induced expression of shRNA#2 was lower than the relative number of CDK13 depleted colonies by doxycycline induced expression of shRNA #1 (Figure 28 A). A significant difference in terms of relative numbers of colonies could be observed between CDK13 depleted 19q12 amplified versus 19q12 non-amplified cell lines (Figure 28 B). The Annexin V time course assay revealed that the cell viability of 19q12 amplified CDK13 depleted cell lines was decreasing in a time dependent manner, whereas the cell viability of 19q12 non-amplified cell lines after CDK13 depletion was not affected (Figure 28 C). Furthermore, the higher k.d. efficiency of shCDK13 #2 correlated with a lower cell viability rate in 19q12 amplified cells. According to these results we were able to recapitulate the phenotypic pattern of CDK13 depletion using doxycycline inducible shCDK13 #1 and shCDK13 #2

80 3. Results

A B Quantification CFA after tet-inducible CDK13 k.d. Mean tet-incudible CDK13 k.d. 1.2 1.2 * * 1 1

0.8 0.8

0.6 0.6

0.4 0.4 relative number ofcolonies

relativenumber ofcolonies 0.2 0.2

0 0 tet-shCTRL tet-shCTRL tet-shCTRL tet-shCTRL tet-shCTRL tet-shCTRL tet-shCTRL tet-shCTRL tet-shCDK13 #1 tet-shCDK13 #1 tet- tet- shCDK13 #1 tet- shCDK13 #1 tet- shCDK13 #1 tet- shCDK13 #1 tet- shCDK13 #1 tet- shCDK13 #1 tet-shCDK13 #2 tet-shCDK13 #2 tet-shCDK13 #2 tet-shCDK13 #2 tet-shCDK13 #2 tet-shCDK13 #2 tet- shCDK13 #2 tet- shCDK13 #2 OVCAR8 OVCAR4 OVCAR3 SKOV TYKNU CAOV3 19q12 amplified 19q12 non- cell lines amplified cell lines 19q12 amplified 19q12 non-amplified C OVCAR8 tet-shCDK13 OVCAR4 tet-shCDK13 OVCAR3 tet-shCDK13 100 100 100 80 80 80 60 60 60 40 40 40 20 20 20 cellviability(%) cellviability(%) cellviability(%) 0 0 0 5 6 7 8 11 5 6 7 8 11 5 6 7 8 11 days after established k.d. days after established k.d. days after established k.d. tet-shCTRL tet-shCTRL tet-shCTRL tet- shCDK13 #1 tet- shCDK13 #1 tet- shCDK13 B8 tet- shCDK13 #2 tet- shCDK13 #2 tet- shCDK13 B9

SKOV tet-shCDK13 TYKNU tet-shCDK13 CAOV3 tet-shCDK13 100 100 100 80 80 80 60 60 60 40 40 40

20 20 cellviability(%) 20 cellviability(%) cellviability(%) 0 0 0 5 6 7 8 11 5 6 7 8 11 5 6 7 8 11 days after established k.d. days after established k.d. days after established k.d. tet-shCTRL tet-shCTRL tet-shCTRL tet- shCDK13 #1 tet- shCDK13 #1 tet- shCDK13 #1 tet- shCDK13 #2 tet- shCDK13 #2 tet- shCDK13 #2 D k.d. efficiency

1.2 1 0.8 0.6 0.4 0.2 0 ns ns ns ns ns ns Relative mRNA Relativeexpression CDK13 tet-shCDK13 #1 tet-shCDK13 #2 tet-shCDK13 #1 tet-shCDK13 #2 tet-shCDK13 #1 tet-shCDK13 #2 tet-shCDK13 #1 tet-shCDK13 #2 tet-shCDK13 #1 tet-shCDK13 #2 tet-shCDK13 #1 tet-shCDK13 #2 OVCAR3 OVCAR4 OVCAR8 SKOV TYKNU CAOV3

Figure 28: Tetraycyline-inducible k.d. of CDK13. A. Relative quantification of number of colonies of CDK13 k.d. cells induced with 2 different constructs tet-shCDK13 #1 and #2 normalized to number of colonies of tet-shCTRL cells. n=3 independent experiments, error bars represent ±SD. B. Mean number of colonies of tet-shCDK13 depleted 19q12 amplified cells vs 19q12 non-amplified cells. C. Cell viability of tet- shCDK13 cells measured by FACS after Annexin V staining, 5 to 11 days after the

81 3. Results application of tet-inducible shRNA mediated CDK13 knockdown. Each data point represents the mean of n=3 independent experiments, error bars represent ±SD. D. Relative mRNA expression levels of tet-shCDK13 normalized to TBP. n=3 independent replicates, ±SD.

3.8.2 Mouse xenograft pilot experiment

We started in vivo xenograft mouse models with CDK13 depleted subcutaneous tumors derived from 19q12 amplified cell lines (OVCAR8 and OVCAR3) and 19q12non-amplified cell lines (SKOV and TYKNU) with the primary goal of testing the subcutaneous tumor engraftment. For this, we subcutaneously injected 1x106 cells of each cell line in 10 6-week old BALB/cAnNRj-Foxn1nu/nu mice with tet-inducible shCDK13 and shCTRL constructs, respectively (Figure 29). For OVCAR8, OVCAR3 and SKOV the subcutaneous injection of 1x106 cells is a well-established cell number (Mitra, Davis et al. 2015, Hernandez, Kim et al. 2016). Unfortunately, no data was available on TYKNU and thus we decided to use as well 1x106 cells for subcutaneous injection. After tumors had reached a size of 100 mm3, 5 mice per group received doxycycline containing chow (Provimi Kliba 3432 with 200mg/kg doxycycline (Sigma)) and 5 mice control chow (Provimi Kliba 3432). Experiments were stopped when tumors had reached a maximum tumor size of 1000 mm3 or before if any signs of pain were observed or max. 70 days after injection of cells.

82 3. Results

Figure 29: Scheme of pilot experiment of in vivo xenograft mouse models. 1x106 tet-inducible shCDK13 cells of 2x 19q12 amplified cell lines (OVCAR8 and OVCAR3) and 2x 19q12 non-amplified cell lines (SKOV and TYKNU) were injected in 10 mice per cell line. tet-inducible shCDK13 cells were injected into the right flank, tet-inducible shCTRL cells were injected into the left flank. After tumors were engrafted and had reached a size of 100 mm3, 5 mice of each cell line group received doxycycline containing chow in order to induce the CDK13 k.d. and 5 mice received CTRL chow. Experiments were stopped at a max. tumor size of 1000 mm3 or before if any signs of pain were observed.

Tumors in mice injected with 1x106 19q12 amplified OVCAR8 cells started to appear approx. 30 days after the subcutaneous injection (Figure 30 A). Within a time period of 10-14 days all mice showed tumors on both sides except one mouse without any visible tumors and one mouse only with one visible tumor on the right side. This tumor appearance pattern did not change until the end of the experiment on day 69. The experiment was stopped at day 69, one day prior to the maximum duration of 70 days after cell injection according to the animal license. Mice received standard chow (Provimi Kliba 3437) until it was changed to Doxycycline containing chow (Provimi Kliba 3432 with 200 mg/kg doxycycline (Sigma)) or CTRL chow (Provimi Kliba 3432) on day 45. Mean body weight of mice in the doxycycline chow group was similar to the mice in the CTRL chow group during the whole experiment (Figure 30 B). In terms of tumor growth, the CTRL chow group showed similar linear tumor growth curves for both shCTRL (left flank) and shCDK13 (right flank) tumors until the end of the experiment on day 69 (Figure 30 C). The doxycycline chow group showed similar linear growth curves until day 52 and 7 days after starting with doxycycline administration, shCDK13 tumors started to grow faster than

83 3. Results shCTRL tumors (Figure 30 D). However, on day 55, 10 days after doxycycline chow start, shCDK13 tumors started to decrease slowly. This tendency was persistent until the experiment was stopped on day 69. shCTRL tumors on the other hand kept the tendency of constantly increasing the tumor sizes until the experiment was stopped. On day 69 all mice were euthanized and tumor weights were determined after dissection. Weights of shCDK13 tumors were normalized to the weight of shCTRL tumors (Figure 30 F). Mouse # 387 of the control chow group did not show any visible tumors on both sides until the end of the experiment, however had developed enormous metastases which were visible after opening the thorax (Figure 30 G). Mouse # 384 did not show any visible shCTRL tumor, however after opening we discovered a deeply located tumor with a tumor weigh twice as big as the shCTRL tumor weight. In the doxycycline chow group all mice had developed tumors which were measurable from the outside. Furthermore, and with one exception, all shCDK13 tumors weighed less than the shCTRL tumors (Figure 30 H). The mean tumor weight of shCDK13 tumors of mice in the control chow group was slightly but not significantly lower than the mean tumor weight of shCTRL tumors (Figure 30 K). In contrast, in the doxycycline chow group, the mean tumor weight of shCDK13 tumors was significantly lower than the tumor weight of shCTRL tumors, confirming our in vitro observations that CDK13 is essential for the survival of 19q12 amplified ovarian cancer cells. CDK13 knockdown was confirmed by qRT-PCR and western blotting from all mice having received doxycycline containing chow and from 2 control chow mice (Figures 30 L, M).

84 3. Results

Figure 30: CDK13 depletion in 19q12 amplified tumors derived from OVCAR8 cells reduces tumor growth xenograft models. A. Tumor appearance over time after injection of 1x106 19q12 amplified OVCAR8 cells. B. Mean body weight of mice of doxycycline chow (green) and CTRL chow group (yellow). n= 5 mice per group. Error bars indicate ±SEM C. Mean of tumor growth development of shCTRL tumors (left flank) and shCDK13 tumors (right flank) of CTRL chow group. n=3 mice, mean value ±SEM D. Mean of tumor growth development of shCTRL tumors (left flank) and shCDK13 tumors (right flank) of

85 3. Results doxycycline chow group. n= 5 mice, mean value ±SEM E. Individual relative final tumor weight of mice in CTRL chow group. F. Corresponding representative set of pictures of CTRL chow mice. G. One mouse had no visible and measurable subcutaneous tumors but metastases. H. Individual relative final tumor weight of mice in doxycycline chow group. I. Corresponding representative set of pictures of doxycycline chow mice. K. Mean of final relative tumor weight of CTRL and doxycycline chow group. n= 4 tumors per group, mean value ±SEM. L. Relative mRNA expression of CDK13 of tumors of 2 representative mice from CTRL chow group and relative mRNA expression of tumors of all 5 doxycycline chow mice. M. Protein levels of CDK13 and Actin protein in tumors of 2 representative mice from the CTRL chow group and all 5 mice of the doxycycline chow group.

Mice injected with cells of the 19q12 amplified cell line OVCAR3 did not grow any tumors (Figure 31A). Therefore, we could not separate the mice into two groups for the administration of the Doxycycline containing and CTRL chow respectively. Mice were healthy and increased body weights slightly over time (Figure 31B). We stopped the experiment 59 days after the injection of OVCAR3 cells, since even in case of tumor appearance at this late stage, it would not have been possible to finish the experiment including doxycycline administration until day 70, the approved length of the experiment according to our animal license. Subsequent dissection of these mice proved that none of them had developed subcutaneous or deeper located tumors.

A B OVCAR3 10 25

8 20

6 15

4 10

numberof mice 2 5 average body weight (g) 0 0 1 6 10 13 17 20 24 27 31 34 38 41 45 48 52 55 59 1 10 17 24 31 38 45 52 59 both sides days after injection left side = shCTRL days after injection right side = shCDK13 no tumor

Figure 31: Xenograft experiment with the 19q12 amplified cell line OVCAR3. A. No tumors developed within 59 days after subcutaneous injection of OVCAR3 cells B. Average body weight of mice. N= 10 mice. Error bars represent ±SEM

Tumors in mice injected with 19q12 non-amplified SKOV cells started to appear approx. 25 days after the subcutaneous injection (Figure 32A). Within a time period of 15-20 days all mice showed tumors on both sides except for one mouse that had no visible tumors on both sides and for two mice that had visible tumors only on the right side (shCDK13). The experiment was stopped on day 52 because some tumors had reached a volume of 1000 mm3 and some mice had lost more than 15% of their initial body weight, which are both limitation criteria according to our animal license. Tumors had reached measurable mean tumor sized of about 100 mm3 on day 45 and chow could be changed to doxycycline and CTRL chow. Mean body weight of mice in the doxycycline chow group was similar to the mice in the CTRL chow group during the whole experiment (Figure 32B). Towards the end of the experiment the mean body weight of mice in the doxycycline chow group was slightly lower than the mean body weight of mice in the CTRL chow group. The shCTRL tumors were growing slower than the shCDK13 tumors, which was true for both, the CTRL and the doxycycline chow group (Figure 32 C, D). This was due to the fact that the cells of the majority of shCTRL tumors on the left side were injected deeper

86 3. Results than the cells of the shCDK13 tumors, as we discovered when dissecting the mice. Due to the issue that most shCTRL tumors were located too deep in the tissue and not subcutaneously they were not properly measurable. Therefore, we missed the time point when tumors had reached an actual volume of 100 mm3 and started too late with the chow change. In fact, tumors must have had a higher tumor volume at the time point of the chow change. Furthermore, they showed a fast increase in tumor volume. Therefore, Doxycycline/CTRL chow could only be administered for 7 days before the experiment had to be stopped due to the above mentioned limitation criteria that some mice had developed tumors over a measurable size of 1000 mm3 and some mice showed signs of cachexia. On day 52 all mice were euthanized and tumor weights were determined after dissection (Figure 32 E, H). Weights of shCDK13 tumors were normalized to the weights of shCTRL tumors. Mouse # 389 of the control chow group did not show any visible tumors on both sides, and also no detectable tumors under the skin after dissection. Mouse #391 did not show any visible tumor on the shCRTL side from the outside, however we discovered a deeply located tumor of the same volume as the shCTRL tumor after dissection. Even though the shCTRL and the shCDK13 cells were differently located, the mean tumor weight of shCDK13 tumors of mice in the control chow group was only slightly and not significantly lower than the mean tumor weight of shCTRL tumors. In the doxycycline chow group shCDK13 tumor weights were surprisingly lower than shCTRL tumors and the mean tumor weight of shCDK13 tumors was significantly lower than the tumor weight of shCTRL tumors (Figure 32G). Considering the absolute tumor weight of the tumors, it seems that shCTRL tumors of the doxycycline chow group had a higher average tumor volume than the shCTRL tumors of the doxycycline chow group, however the difference was not significant (Figure 32 K). CDK13 knockdown was confirmed by qRT-PCR and western blotting from all mice having received doxycycline containing chow, except for one mouse without any tumors and from 2 control chow mice (Figures 32 L, M). K.d. of CDK13 was less efficient than in OVCAR8 mice due to the fact that SKOV mice received doxycycline containing chow only for 7 days (Figure 30 L, Figure 32 L).

87 3. Results

Figure 32: Xenograft Models of 19q12 non-amplified cell line SKOV3. A. Tumor appearance over time after injection of 1x106 19q12 amplified SKOV cells. B. Mean body weight of mice of doxycycline chow (green) and CTRL chow group (yellow). n= 5 mice per group. Error bars indicate ±SEM C. Mean of tumor growth development of shCTRL tumors (left flank) and shCDK13 tumors (right flank) of CTRL chow group. n=3 mice, mean value ±SEM D. Mean of tumor growth development of shCTRL tumors (left flank) and shCDK13 tumors (right flank) of doxycycline chow group. n= 5 mice, mean value ±SEM E. Individual relative final tumor weight of mice in CTRL chow group. F. Corresponding representative set of pictures of CTRL chow mice. G. 88 3. Results

Individual relative final tumor weight of mice in doxycycline chow group. H. Corresponding representative set of pictures of doxycycline chow mice. I. Mean of final relative tumor weight of CTRL chow and doxycycline chow group. n= 4 tumors per group, mean value ±SEM. K. Mean of absolute final tumor weight of CTRL chow and doxycycline chow group. n= 4 tumors per group, mean value ±SEM L. Relative mRNA expression of CDK13 of tumors of 1 representative mouse from CTRL chow group and relative mRNA expression of tumors of 4 doxycycline chow mice. M. Protein levels of CDK13 and Actin protein in tumors of 1 representative mouse from the CTRL chow group and 4 mice of the doxycycline chow group.

Tumors in mice injected with cells of the 19q12 non-amplified cell line TYKNU started already to appear 7 days after subcutaneous injection. Within a time period of approx. 15 days all mice showed tumors on both sides except for one mouse that showed no visible tumors and for one mouse that had a visible tumor only on the right side (shCDK13). This pattern of tumor appearance did not change until the end of the experiment on day 69 (Figure 33 A). The day of chow change to doxycycline and CTRL chow was determined on day 23 when all tumors had reached measurable mean tumor sizes of about 100mm3. The experiment was stopped at day 69, one day prior to the maximum duration of 70 days after cell injection according to the animal license. The mean body weight of mice in the doxycycline chow group was comparable to the mice in the CTRL chow group and slightly increased during the whole experiment. Also, switch to doxycycline and CTRL chow on day 23 after injection did not affect the tendency of the mean body weight (Figure 33 B). In the CTRL chow group, a similar linear tumor growth was measured for both, shCTRL (left flank) and shCDK13 (right flank) tumors (Figure 33 C). In the doxycycline chow group similar linear tumor volumes could also be measures for both shCTRL (left flank) and shCDK13 (right flank) tumors. As expected for 19q12 amplified tumors, doxycycline chow did not induce a decrease of the tumor volume of shCDK13 tumors (Figure 33 D). On day 69 all mice were euthanized and tumor weights were determined after dissection. Weights of shCDK13 tumors were normalized to the weight of shCTRL tumors (Figure 33 E, G). Mouse # 411 of the doxycycline chow group did not show any visible tumors on the left (shCTRL) side, and also no detectable tumor under the skin after dissection. The tumor on the right side was measurable, however burst after dissection because it only consisted of blood and a capsule which was hardly measurable after dissection and was therefore not considered as real tumor weight. Mouse #417 did also not have any measurable tumors on both sides, when inspected from the outside and also after dissection. In both groups, the CTRL chow group and doxycycline chow group tumor weights of shCDK13 tumors were similar to tumor weights of shCTRL tumors. The mean tumor weight of shCDK13 tumors in the doxycycline chow group was slightly lower than the mean of the shCTRL tumors and the mean of shCDK13 tumors in the CTRL chow group (Figure 33 I). CDK13 knockdown was confirmed by qRT-PCR and western blotting from all mice which developed tumors and having received doxycycline containing chow and from 1 control chow mice (Figures 33 K, L).

89 3. Results

Figure 33: CDK13 depletion in 19q12 non- amplified tumors does not affect tumor growth in xenograft models. A. Tumor appearance over time after injection of 1x106 19q12 amplified TYKNU cells. B. Mean body weight of mice of doxycycline chow (green) and CTRL chow group (yellow). n= 5 mice per group. Error bars indicate ±SEM C. Mean of tumor growth development of shCTRL tumors (left flank) and shCDK13 tumors (right flank) of CTRL chow group. n=3 mice, mean value ±SEM D. Mean of

90 3. Results tumor growth development of shCTRL tumors (left flank) and shCDK13 tumors (right flank) of doxycycline chow group. n= 5 mice, mean value ±SEM E. Individual relative final tumor weight of mice in CTRL chow group. F. Corresponding representative set of pictures of CTRL chow mice. G. Individual relative final tumor weight of mice in doxycycline chow group. H. Corresponding representative set of pictures of doxycycline chow mice. I. Mean of final relative tumor weight of CTRL chow and Doxycycline chow group. n= 4 tumors per group, mean value ±SEM. K. Relative mRNA expression of CDK13 of tumors of 1 representative mouse from CTRL chow group and relative mRNA expression of tumors of 3 doxycycline chow mice. L. Protein levels of CDK13 and Actin protein in tumors of 1 representative mouse from the CTRL chow group and 3 mice of the doxycycline chow group.

3.8.3 Mouse xenograft main experiment

The mouse xenograft pilot experiments showed that CDK13 promotes growth of tumor xenografts derived from 19q12 amplified cells, since k.d. of CDK13 resulted in decreased tumor volumes only in xenografts derived from 19q12 amplified cells, but not from 19q12 non-amplified cells. Results of the pilot experiments should be confirmed in main experiments.

Figure 34: Scheme of main experiment of in vivo xenograft mouse models. 2x106 tet-inducible shCDK13 cells of 19q12 amplified cell line OVCAR8 and the 19q12 non-amplified cell line TYKNU were injected in 20 mice per cell line. tet-inducible shCDK13 cells were injected into the right flank, tet-inducible shCTRL cells were injected into the left flank. After tumors were engrafted and had reached a size of 100 mm3, 10 mice of each cell line group received doxycycline containing chow in order to induce the CDK13 k.d. and 10 mice received CTRL chow. Experiments were stopped at a max. tumor size of 1000 mm3 or before if any signs of pain were observed.

For the main experiments cell lines with the best engraftment according to the pilot experiment were chosen including the 19q12 amplified cell line OVCAR8 and the 19q12 non-amplified cell line TYKNU. We increased the number of cells by 2 fold in the main experiment compared to the pilot experiment since we wanted to accelerate the tumor engraftment and growth. Furthermore, the number of 6-

91 3. Results week old BALB/cAnNRj-Foxn1nu/nu mice was doubled to 20 mice per cell line (Figure 34). According to the pilot experiment, mice of each cell line were separated into two groups with 10 mice each as soon as the tumors had reached a mean size of 100 mm3. One group received doxycycline containing chow and one group CTRL chow as in the pilot experiment. Mice of both cell lines were euthanized 30 days after doxycycline/CTRL chow administration. Injection of 2x106 OVCAR8 cells accelerated the tumor appearance compared to the injection of 1x106 in the pilot experiment, however did not accelerate the increase of tumor volumes. Tumors started to appear from day 5 on, within a time frame of 10-15 days (Figure 35 A). On day 23 all mice had developed tumors, except for one mouse (#548) of the doxycycline group, which developed only small tumors over time which completely disappeared on both flanks over time. Furthermore, another doxycycline group mouse (#557) had to be euthanized earlier because of abnormal body weight gain due to a systemic inflammation with increased spleen and metastases. The mean body weight of mice was constantly slightly increasing and also did not change after the chow change to Doxycycline/CTRL on day 45 when the mean tumor size of 100 mm3 was reached (Figure 35 B). For the CTRL chow group tumor volumes were increasing linear with no difference between the shCTRL and shCDK13 tumors until day 58 and 11 days after the chow change to CTRL chow. Starting from day 58 shCTRL tumors were increasing slightly faster than shCDK13 tumors, however without any statistical significance (Figure 35C). However, in the doxycycline chow group there was a clear trend of impeded tumor growth progression of the shCDK13 tumors starting approx. 10 days after doxycycline administration, which we did not observe for the shCTRL tumors (Figure 35 D). For both groups the CTRL and the doxycycline chow group tumor volume growth curves were normalized to a mean tumor volume of 100 mm3 at the day of the doxycycline/CTRL chow start on day 47. Considering the mean of the relative tumor weight in the CTRL chow group, no statistical difference between the shCTRL and the shCDK13 tumors was determined. However, in the doxycycline chow group the mean tumor weight of shCDK13 tumors was significantly lower than the mean tumor weight of shCTRL tumors. Furthermore, the mean of shCDK13 tumors of the doxycycline chow group was also significantly lower than the mean of the shCDK13 tumors of the CTRL chow group (Figure 35 E). CDK13 expression was significantly downregulated in shCDK13 tumors of the doxycycline chow group based on mRNA and protein levels (Figure 35 F).

92 3. Results

A20 B 30 18 16 25 14 20 12 10 15 8 start of Doxy/CTRL feed 6 10 4 5 2 mean bodyweight (g) 0 0 1 2 5 9 1216192326303337404447515458616568727577 1 2 5 9 1216192326303337404447515458616568727577 both sides days after injection CTRL feed days after injection left side DoxycyclineDoxy feed right side start of Doxy/CTRL feed Cno tumor D 300 450 400 250 start of CTRL feed 350 200 300 start of Doxy feed 250 150 200 100 150

mean mean absoluteof 100 50 tumor volume (mm3) 50 mean absolute of tumor

0 volume (mm3) normalized 0 1 2 5 9 1216192326303337404447515458616568727577 1 2 5 9 1216192326303337404447515457616568727579 shCTRL CTRL feed days after injection shCTRL Doxy feed days after injection shCDK13 CTRL feed shCDK13 Doxy feed Ep=0.56 * F 1.2 * 1.4 **** 1 1.2 0.8 1 0.8 0.6 0.6 0.4

mean mean relative 0.4 mean mean relative 0.2 mRNA expression tumorweight (g) 0.2 0 0 shCTRL shCDK13 shCTRL shCDK13 shCTRL shCDK13 shCTRL shCDK13 CTRL feed Doxycycline feed CTRL feed Doxycycline feed

Figure 35: CDK13 depletion in 19q12 amplified tumors derived from OVCAR8 cells reduced tumor growth in xenograft models. A. Tumor appearance over time after injection of 2x106 19q12 amplified OVCAR8 cells. B. Mean body weight of mice of Doxycycline chow (green) and CTRL chow group (yellow). n= 10 mice per group. Error bars indicate ±SEM C. Mean of relative tumor growth development of shCTRL tumors (blue) and shCDK13 tumors (red) normalized to a determined tumor volume of 100mm3 at the start of CTRL chow administration on day 32. n=8 mice, mean value ±SEM D. Mean of relative tumor growth development of shCTRL tumors (blue) and shCDK13 tumors (red) normalized to a determined tumor volume of 100mm3 at the start of doxycycline chow administration. n= 10 mice, mean value ±SEM E. Absolute mean tumor weight (g) of shCTRL tumors and shCDK13 tumors of CTRL chow group (n=8 mice) and doxycycline chow group (n=10 mice). F. Mean of relative mRNA expression of shCTRL tumors and shCDK13 tumors of CTRL chow group (n=8 mice) and doxycycline chow group (n=10 mice).

93 3. Results

The TYKNU xenograft models developed tumors appearing from day 4 onwards (Figure 36 A). However, the increasing the cell number to 2x106 TYKNU cells did not accelerate tumor growth. Two mice showed a rejection of the tumor cells over time since tumors started to decrease after an initial engraftment phase with measurable tumors which had completely disappeared at day 75 and were not detectable when dissected on day 77. Body weight was slightly increasing over time (Figure 36 B). Standard chow was changed to CTRL and doxycycline containing chow on day 45 after the injection of cells. For both groups, the CTRL chow and the doxycycline chow group shCDK13 tumors volumes were increasing slightly faster than the shCTRL tumors, indicating a potential smaller cell number of shCTRL cells being injected, which is also reflected by the final tumor weight (Figure 36 C, D). However, the difference of tumor growth between shCTRL and shCDK13 tumor was not statistically significant, neither in the CTRL chow group, not in the doxycycline chow group. As expected for 19q12 non- amplified xenografts, k.d. of CDK13 by doxycycline containing chow did not evoke a decrease of the tumor volumes (Figure 36 D). For both groups, the CTRL and doxycycline chow group, tumor volume growth curves were normalized to a mean tumor volume of 100 mm3 at the day of the doxycycline/CTRL chow starting on day 32. The real tumor volume comprising only tumor tissue was difficult to determine due to the fact that some TKYNU tumors, independently of CDK13 expression levels, developed blood filled tumors which were growing very fast and big. This is also indicated by the big error bars. The mean of absolute tumor weight confirmed these results since there was no significate different of tumor weight btw the shCTRL and shCDK13 tumors in between the CTRL and Doxycycline chow group. CDK13 mRNA levels were significantly reduced in shCDK13 tumors of the doxycycline chow group (Figure 36 F).

94 3. Results

A20 B 25 18 16 20 14 12 15 10 start of CTRL/Doxy feed 8 10 6 numberof mice 4 5

2 averagebody weight (g) 0 0 1 4 8 11151822252932363943465053576062 1 4 8 1115182225293236394346505357606268

both sides days after injection CTRL feed days after injection left side = shCTRL right side = shCDK13 start of Doxy/CTRL feed Doxycycline feed Cno tumor D 1000 600

800 500 400 600 start of Doxy feed start of CTRL feed 300 400 200 mean normalized

mean mean normalized 200

tumor volume(mm3) 100 tumorvolume(mm3) 0 0 1 1 4 8 11151822252932363943465053576062 1 4 8 11151822252932363943465053576062 shCTRL CTRL feed days after injection shCTRL Doxy feed days after injection shCDK13 CTRL feed shCDK13 doxy feed

Ep=0.556 F 1.2 0.8 p=0.630 ** 0.7 1 0.6 0.8 0.5 0.4 0.6

0.3 Relative 0.4 mean absolute tumor (g) weight 0.2 0.1 mRNA expression 0.2 0 0 shCTRL shCDK13 shCTRL shCDK13 shCTRL shCDK13 shCTRL shCDK13 CTRL feed Doxycycline feed CTRL feed Doxycycline feed

Figure 36: CDK13 depletion in 19q12 non- amplified tumors does not affect tumor growth in xenograft models. A. Tumor appearance over time after injection of 2x106 19q12 amplified TYKNU cells. B. Meam body weight of mice of doxycycline chow (green) and CTRL chow group (yellow). n= 10 mice per group. Error bars indicate ±SEM C. Mean of relative tumor growth development of shCTRL tumors (blue) and shCDK13 tumors (red) normalized to a determined tumor volume of 100mm3 at the start of CTRL chow administration on day 32. n=8 mice, mean value ±SEM D. Mean of relative tumor growth development of shCTRL tumors (blue) and shCDK13 tumors (red) normalized to a determined tumor volume of 100mm3 at the start of doxycycline chow administration. n= 10 mice, mean value ±SEM E. Absolute mean tumor weight (g) of shCTRL tumors and shCDK13 tumors of CTRL chow group (n=8 mice) and doxycycline chow group (n=10 mice). F. Mean of relative mRNA expression of shCTRL tumors and shCDK13 tumors of CTRL chow group (n=8 mice) and Doxycycline chow group (n=10 mice

In conclusion, we could confirm that CDK13 is essential for 19q12 amplifed HGSOC cells in in vivo xenograft models, as we demonstrated that k.d. of CDK13 decreases progression of tumors derived from human 19q12 amplified cells, whereas CDK13 depleted tumors, derived from 19q12 non- amplified cells, further progress in growth.

95 4. Discussion

4. Discussion

4.1 Gene amplification as characteristic feature of HGSOC

Key molecular features of HGSOC include a high frequency of TP53 mutations (<95%) and alterations affecting the DNA damage repair via HR (~50%), however a low overall frequency of other somatic mutations (Cancer Genome Atlas Research 2011). Furthermore, HGSOC are characterized by a high frequency of copy number alterations (46%) with the most prevalent amplifications of the genes CCNE1, MYC and MECOM (Cancer Genome Atlas Research 2011, Domcke, Sinha et al. 2013). By analyzing data of the TCGA (Cerami, Gao et al. 2012, Gao, Aksoy et al. 2013) the CCLE database (Marum 2012), we discovered that in most cases amplification of CCNE1 also comprises amplification of up to 9 other genes, which are all located at the same chromosomal locus 19q12 (Figure 5 C, Figure 10). We found out that 19q12 is amplified in 70% of all HGSOC and can therefore be considered as major genomic feature of HGSOC (Figure 6). Besides CCNE1, also URI1 is a known oncogenic driver gene of the 19q12 locus and both genes have been associated with primary treatment failure of platinum based chemotherapy, shorter progression free survival and poor survival outcome in different types of cancer (Etemadmoghadam, deFazio et al. 2009, Theurillat, Metzler et al. 2011, Yang, Gu et al. 2011, Tummala, Gomes et al. 2014, Gu, Liang et al. 2015, Patch, Christie et al. 2015, Wang, Garabedian et al. 2015). Since targeted therapies for HGSOC are not well stablished so far we aimed to identify new therapy options for HGSOC by investigating genetic dependencies and therefore molecular vulnerabilities which are specific for 19q12 amplifed HGSOC. For this, we performed a pooled shRNA screen in 19q12 amplified vs. 19q12 non-amplified HGSOC targeting all kinases of the human genome, followed by an in vitro and in vivo hit validation. Cell lines which were chosen for the screen showed amplification variations of 19q12 genes between cell lines and within the same cell lines (Figure 10). All 19q12 non- amplified cell lines (SKOV, TOV21G, COV504; IGROV, TYKNU, CAOV3) carryed one copy of each 19q12 gene per allele, except COV504, which has a potential monoallelic deletion of the whole 19q12 locus. The 19q12 amplified cell lines OVCAR8 and OVCAR3 showed differences in copy number variations even between 19q12 genes. In both cell lines the gene UQCRSF1 was not amplified. Furthermore, in OVCAR8 URI1 exhibited a higher copy number than all other 19q12 genes and in OVCAR3 6 genes incl. CCNE1 and URI1 showed higher copy number variation values than the 3 other genes. The phenomenon of interlocus gene copy number variations was also observed in tumor tissue samples registered in the TCGA database (Figure 5 C). One striking observation was, that genes in the center of the 19q12 locus were more frequently amplified (19-22%) than genes in the flanking regions of the 19q12 locus. This could be explained by the hypothesis that amplifications arise individually induced

96 4. Discussion by different amplification mechanisms (Matsui, Ihara et al. 2013). HGSOC are characterized by high genomic instability, a hallmark of cancer (Shih Ie and Kurman 2004, Kuo, Guan et al. 2009). One characteristic of genomic instability in the frequent occurrence of DNA single and double strand breaks and the consecutive failure of proper DNA damage repair. Since ~50% of all HGSOC exhibit HR deficiencies (Cancer Genome Atlas Research 2011), it has to be assumed that most DSBs are not corrected by the highly conserved and precise HR, but rather by the error prone NHEJ repair mechanism generating an even higher affinity for genomic instability. Furthermore, both SSB and DSB might provide an opportunity for the formation of copy number variations based on either the breakage fusion bridge cycle or the double rolling circle replication mechanism (Hastings, Lupski et al. 2009). Depending on which chromosomal site the breaks appear it might be possible that only certain genes and not the whole chromosomal locus is affected by the amplification mechanism. The observation that genes localized in the center of the 19q12 locus are more frequently amplified, might be explained by the fact that these genes are more predisposed for DSB breaks followed by repair mechanism which generate amplifications. These amplifications resulting in high expression levels of the respective genes might convey a particular selective advantage contributing to certain pathway dependencies and therefore to cancer cell growth and survival.

4.2 19q12 specific survival dependencies

4.2.1 19q12 specific dependency on the oncogenic driver genes URI1 and CCNE1

One of the most frequently amplified genes within the 19q12 locus are URI1 and CCNE1, both known as oncogenic driver genes conveying survival dependencies especially for 19q12 amplified ovarian cancer cells (Nakayama, Nakayama et al. 2010, Theurillat, Metzler et al. 2011). As demonstrated in Annexin V assay, 19q12 amplified cells are more dependent on URI1 and CCNE1 than 19q12 non- amplified cells. (Figure 12 and 13). However, long term cell survival was also impaired in 19q12 non- amplified cells in case of URI1 and CCNE1 depletion as demonstrated in the CFA assay. This might be explained based on the assumption that 19q12 amplified cells are exclusively dependent on 19q12 mediated survival signaling and miss alternative survival signaling pathways, whereas 19q12 non- amplified cells can compensate for the loss of 19q12 genes over a certain period of time due to alternative and partially compensating survival mechanism. Therefore, it can be supposed that for 19q12 non-amplified cells, the demand threshold for 19q12 mediated survival signaling is lower than for 19q12 amplified cells, which explains the clear segregation pattern between 19q12 amplified and non-amplified cells in terms of cell viability. However, one exception was given by the 19q12 non- amplified cell line COV504. It was expected that this cell line can compensate for the URI1 and CCNE1 loss over a short period of time, as it was observed for the other 2 non-amplified cell lines SKOV and

97 4. Discussion

TOV21G. Instead, cell viability of COV504 cells decreased after both URI1 and CCNE1 depletion and showed the same cell viability pattern as 19q12 amplified cell lines. This phenomenon could be explained by the fact that COV504 cells have a monoallelic 19q12 deletion reflected by the low CNV value of 1.24 compared to the normal standard of CNV=2 referring to 2 alleles per gene and also by the low URI1 and CCNE1 protein expression levels (Figure 11 C). It can be assumed that in case of additional k.d. of URI1 and CCNE1, protein levels drop under a specific threshold which is critical for the survival of COV504 cells.

4.2.2 19q12 specific gene cluster and pathway dependencies

The aim the pooled shRNA screen of this study was to discover genes which are essential for the survival of 19q12 amplified genes. For this, 518 different human kinases were genetically silenced by RNAi with approx. 5 hairpins per gene. Consecutive bioinformatical analysis was applied by using the ATATRiS algorithm, which identified similar phenotypic patterns across all screened hairpins targeting one gene and assigning them to genes solutions. All genes for which gene solutions could be found were displayed as a heatmap showing which genes are essential or not for which cell line (Figure 16). A 19q12 specific dependency pattern/ signature could be observed since the 19q12 amplified cell lines OVCAR3 and OVCAR4 showed a similar dependency pattern that segregated opposite to the dependency pattern of the 19q12 non-amplified cell lines SKOV and TOV21G. Unexpectedly, the third 19q12 amplified cell line OVCAR8 showed an opposite segregation pattern to the other 2 amplified cell lines OVCAR3 and OVCAR4, but similar to the non-amplified cell lines SKOV and TOV21G. Furthermore, also COV504 showed a segregation pattern opposite to the expected 19q12 non-amplified pattern and similar to the 19q12 signature. Since the objective of this study was not to investigate this unexpected segregation pattern, but to identify genes which are essential exclusively for 19q12 amplified cells, but not for non-amplified cells the, only a small follow up analysis of pathway dependencies according to the segregation pattern of the heatmap was performed using the STRING database (http://string- db.org/cgi/input.pl?UserId=QuXR65MCmh7k&sessionId=OUHCBt46DUrk&input_page_show_search) Analyzing essential genes which clustered in the cell lines OVCAR3 OVCAR4 and COV504 revealed that axon guidance and RAS/MAPK signaling components are enriched in all 3 cell lines. Furthermore, Ubiquitin C (UBC) represents a central component in the network. UBC gene transcription is induced during stress conditions in order to remove damaged/unfolded proteins (Ryu, Maehr et al. 2007). Therefore, it can be assumed that these cell lines are primarily dependent on an intact protein homeostasis, which would be in accordance with the dependency on URI1 as component of the prefoldin-like/URI1 chaperone complex. OVCAR8, SKOV and TOV21G cell lines showed an enrichment for the neurotrophin, platelet and also for RAS/MAPK signaling. The fact that all cell lines, independent of the 19q12 amplification status, show RAS/MAPK signaling dependency would speak for the fact that

98 4. Discussion aberrant regulation of this signaling pathway was an early event in the tumorigenesis of HGSOC which occured before 19q12 amplifications developed. Independent of the occurrence of the 19q12 amplification during tumorigenesis, it can be assumed that this event represents a leading tumorigeneic event in terms of genetic dependencies which is supported by the fact that 2 19q12 amplified cell lines display a very similar dependency pattern which is exactly the opposite to 2 19q12 non-amplified cell lines. However, this segregation pattern could also be explained by the assumption that all cell lines with similar gene dependencies originate from the same primary tissue. Even though all used cell lines in the screen are from the subtype HGSOC, it has to be considered that HGSOC is a highly heterogeneous disease originating from different primary tissues of origin, most prominently from the fallopian tube, and involving the ovary secondarily (Dubeau 1999, Dubeau 2008, Kurman and Shih Ie 2010). This might also be the explanation for the fact that OVCAR8 segregated opposite to the other 19q12 amplified cell lines OVCAR3 and OVCAR4. Furthermore, the fact that OVCAR8 has a higher copy number only of URI1 compared to all other genes might be because this amplification event occurred later as a result of genomic instability conveying a specific survival advantage for this cell line depending on the selection pressure. Furthermore, it was discovered that OVCAR8 exhibits a BRCA1 methylation (Stordal, Timms et al. 2013). Since BRCA deficiencies and have been demonstrated to be mutually exclusive with CCNE1/19q12 amplifications (Etemadmoghadam, George et al. 2010), OVCAR8 cell might not have developed 19q12 specific pathway dependencies after the aquisition of the URI1 amplification. For further investigations in terms of potential 19q12 specific pathway dependencies and the chronological occurrence of 19q12 amplifications during tumorigenesis, detailed bioinformatical analyses with tissue samples would be necessary, which considers the correct primary origin tissue, the entire genomic profile and selection pressure, e.g. by administered chemo- or targeted therapy, etc.

4.2.3 Identification of kinases essential for 19q12 amplified HGSOC

Since the major goal of this project was to identify genes exclusively essential for 19q12 amplified HGSOC, the segregation pattern was not further taken into account. Only the genes which were essential for the 19q12 amplified cell lines OVCAR3, OVCAR4, OVCAR8, however not essential for the 19q12 non-amplified cell lines SKOV, TOV21G and COV504 were further considered. According to the ATARiS analysis 2 hits, INSR and CDK13, fulfilled the strict requirements and were considered for further hit validation. According to the own developed analysis 5 hits, ULK3, CSNK1E, ACVRL1, CDK2 and BCR were identified, out of which the first 2 hits were considered for further hit validation. In total 2 hits, CSNK1E and CDK13, could be validated using 2 cell viability assays, the Annexin V and the CFA assays.

99 4. Discussion

4.2.3.1 Identification of CSNK1E as 19q12 essential gene

The first successfully validated hit was CSNK1E coding for casein kinase 1 epsilon (CK1ε). CK1ε is one of seven mammalian isoforms (α,β,γ1,γ2,γ3, δ, ε) of the casein kinase family, a group of ubiquitous and highly conserved serine/threonine-specific kinases, encoded by distinct genes (Fish et al, 1995; Ko et al, 2002; Peters et al, 1999; Price, 2006). All casein kinases share a high sequence homology in their kinase domains (53%–98% identical), but show considerable variation in the length and primary structure of the C-terminal non-catalytic domains, which are responsible for substrate specificity (Behrend, Milne et al. 2000, Knippschild, Kruger et al. 2014). Casein kinases phosphorylate key regulatory proteins in the control of cell differentiation, proliferation, chromosome segregation and circadian periodicity (Knippschild et al, 2005; Ko et al, 2002; Meng et al, 2010). CK1ε has been shown to be important in regulating cell division and tumor growth in several human cancers by phosphorylating key proteins in the Wnt/β-catenin signaling pathway (Brockschmidt et al, 2008; Frierson et al, 2002; Peters et al, 1999; Polakis, 2007; Price, 2006). CK1ε has been shown to be overexpressed in ovarian cancer cell lines of different subtypes and CK1ε inhibition suppresses growth in vitro and in vivo (Rodriguez, Yang et al. 2012). We showed that CK1ε is essential in particular for HGSOC with 19q12 amplification, since k.d. of CSNK1E induced a significant decrease of cell survival in 19q12 amplified HGSOC cells compared to 19q12 non-amplified cells (Figure 19 C1, Figure 20C). Furthermore, in our first validation study it could be observed that cell lines with mutant p53 (OVCAR3, OVCAR4, OVCAR8, COV504) were more sensitive to CSNK1E k.d. than cell lines with wild type p53 (SKOV, TOV21G) (Figure 18 A2). This observation would go in line with the postulation that CSNK1E is synthetic lethal to mutant p53 (Tiong, Chang et al. 2014). Furthermore, Behrend, Milne et al. 2000 showed that pharmacological inhibition of CK1ε was shown to induce apoptosis, which is enhanced upon p53 loss, since cells with non-functional p53 undergo postmitotic replication developing an DNA content of 8n, which is accompanied by a high amount of micronucleated and apoptotic cells, whereas cells with active p53 arrest in G1 and are blocked to enter S phase. This suggests a potential role for p53 in regulating apoptosis dependent on the availability of CK1ε and the interplay between p53 and CK1ε might be necessary to sense correct cell division in order to prevent genomic instability and aneuploidy (Behrend, Milne et al. 2000). However, our second validation study with an extended panel of 19q12 non-amplified cell showed that the cell lines IGROV, TYKNU and CAOV3, which are also TP53 mutated, were rather resistant to CSNK1E k.d. due to a cell survival rate of 50-80% after CSNK1E depletion for 14 days. Therefore, it could be assumed that the mutational status of TP53 might play a pivotal role and cell lines with a heterozygous mutation of TP53 might be more susceptible to CSNK1E k.d. than cell lines with homozygous loss of TP53. However, this question remains elusive and further bioinformatical studies assessing the exact TP53 mutation status of the used cell lines would be necessary.

100 4. Discussion

The distinct cell viability pattern between 19q12 amplified and 19q12 non-amplified cell lines after downregulation of CSNK1E by RNAi, which we could observe in our study, could not be confirmed by pharmacological inhibition of CK1ε in a further study we performed. Cell viability of all cell lines was decreasing independently of the 19q12 amplification status after inhibition of CK1ε with 2 different small molecular inhibitors, IC261 and PF4800567 (Figure 22, Figure 23). IC261 triggered a reduction of cell viability at concentrations starting from 1 µM, also independent of the p53 mutation status of the respective cell lines. According to Behrend, Milne et al. 2000 we would have expected that at least SKOV3, the only cell line with wild type p53, is resistant to CK1ε inhibition, however this was not the case. In addition to CK1ε, IC261 also inhibits CK1δ and IC50 values for both CK1 isoform are similar (Behrend, Milne et al. 2000, Mashhoon, DeMaggio et al. 2000). Therefore, it has to be assumed that the phenotypic effects are also triggered by the inhibition of CK1δ. Downregulation of CK1δ has also been shown to induce cell cycle arrest and apoptosis in a variety of tumor cell lines of different origin (Cheong, Nguyen et al. 2011, Schittek and Sinnberg 2014). CK1ε inhibition with PF4800567 showed an effect on cell viability at a concentration of 100 µM, more than 3000 times higher than the half maximal inhibitory concentration for CK1ε. This concentration also exceeded the half maximal inhibitory concentration of CK1δ by 140 times (Walton, Fisher et al. 2009). Therefore, it needs to be assumed that the decreased of cell viability was caused by another effect than inhibition of CK1ε or CK1δ. Also Cheong et al, 2011 observed no decrease of cell viability after CK1ε inhibition with PF4800567 and postulated that only the combined inhibition of CK1ε or CK1δ induces cell death whereas single inhibition of CK1ε is not sufficient. We can`t confirm this hypothesis since we showed that genetic silencing of CSNK1E clearly inhibits cell growth and induces apoptosis (Figures 18,19,20). Regarding both experiments with 2 different CK1ε inhibitors it has to be concluded that inhibition of a gene by RNAi and the pharmacological inhibition of its encoded protein has different phenotypic outcomes. Pharmacological inhibition only blocks the function of a protein but the protein is still present. This implies that the inhibited protein may lack a certain activity but may still interact with some binding partners or assemble into functional macromolecular complexes. We also can`t exclude that the observed phenotypic pattern after CSNK1E silencing is indeed induced by gene silencing exclusively of CSNK1E and not by off-target effects, causing cellular toxicity and innate immune responses which trigger apoptosis. Overexpression of CSNK1E with a construct which is not recognized by the shRNA due to mutated bases in the shRNA binding region of the CSNK1E cDNA sequence, would have elucidated this issue. Assuming the fact that downregulation of CSNK1E induces apoptosis indeed, especially of 19q12 amplified HGSOC, the potential functional relationship between CK1ε and 19q12 still remains elusive. A potential link was provided by the study of Rodriguez et al, 2012. They revealed that CK1ε co- immunoprecipitates and co-localizes at mitochondria with ANT2 (Adenine nucleotide translocase 2),

101 4. Discussion an integrate mitochondrial membrane protein responsible for the ADP/ATP exchange between the mitochondrial matrix and the cytosol (Chevrollier, Loiseau et al. 2011, Rodriguez, Yang et al. 2012). Rodriguez et al. 2012 investigated that ANT2 is overexpressed in ovarian tumors and CK1ε inhibition reduces ANT2 levels in mitochondria resulting in lower ATP levels which renders ovarian cancer cells more susceptible to chemotherapeutic agents. Interestingly, ANT2 was found in a mass spectrometry analysis identifying URI1 associated mitochondrial proteins (Helene Jonasch, unpublished). Therefore, it could be hypothesized that ANT2, as downstream target of CK1ε, is facilitating the delivery of ATP to mitochondrial proteins e.g. to S6K1 which promotes cell survival by phosphorylating Bad. As mentioned in the introduction the negative feedback regulation of S6K1 signaling involving URI1 is abrogated in 19q12/URI1 amplified and overexpressed HGSOC. This is due to the fact that accumulated URI1 leads to constant entrapping of PP1γ and active S6K1 signaling generating a high demand of ATP for phosphorylation of S6K1-Bad survival signaling (Theurillat, Metzler et al. 2011). Therefore, it would be required to investigated if inhibition of ANT2 lowers S6K1 phosphorylation activity. The potential connection between CK1ε and 19q12 is also supported be the fact that overexpression of both URI1 and ANT2 have independently been associated with conveying chemo-resistance. Therefore, it would be interesting to investigated if downregulation of ANT2 reduces S6K1 survival signaling. Furthermore, it could be tested if the combined silencing of CSNK1E and the potential downstream target ANT2, as well as URI1, would induced enhanced chemo-sensitivity in 19q12 amplified HGSOC.

4.2.3.2 Identification of CDK13 as 19q12 essential gene

CDK13 was the second hit we could validate. CDK13 is involved in the regulation of transcription and exhibits a N-terminal arginine/serine rich domain, a feature of proteins which are involved in RNA processing and pre-mRNA splicing (Even, Durieux et al. 2006, Malumbres 2014). It was demonstrated that CDK13 interacts with p32, a subunit of the splicing factor Serine/arginine-rich splicing factor 1 (SRSF1) and directly phosphorylates serine residues of SRSF1 affecting alternative pre-mRNA splicing (Even, Durieux et al. 2006). RNA polymerase II subunit B1 (RPB1), the largest subunit of RNA Polymerase II, is also a phosphorylation target of CDK13 (Greifenberg, Honig et al. 2016). However, phosphorylation of the same residues can be also mediated by CDK9, CDK7 and CDK12 (Bosken, Farnung et al. 2014). CDK12 is the closest paralog to CDK13 since both kinases share 30% sequence identity in their C- and N-terminal domain and 90% in their kinase domain. Furthermore, CDK12 and CDK13 share the same cyclin subunit, cyclin K (Chen, Wong et al. 2007, Blazek, Kohoutek et al. 2011). However, CDK12 and CDK13 are involved in different biological functions. Furthermore, CDK12 and CDK13 are not mutually substitutive, since k.d. of either one does not affect the abundance of the other protein (Blazek, Kohoutek et al. 2011). CDK12 is involved in the transcription of DNA damage response (DDR) genes, since k.d. of CDK12 but also of Cyclin K leads to downregulation of DDR genes

102 4. Discussion and their gene products like BRCA, ATR and components of the Fanconi Anemia pathway (Blazek, Kohoutek et al. 2011, Liang, Gao et al. 2015). Since CDK12 is recurrently mutated in about 6% of HGSOC (Cancer Genome Atlas Research 2011), inhibition of CDK12 was evaluated as potential therapeutic strategy. It was demonstrated that k.d. of CDK12 sensitizes cells to DSB inducers and PARP inhibition. As mentioned in the introduction, PARP inhibitors show promising results in HR deficient tumors exhibiting a socalled BRCAness signature, due to phenotypes similar to BRCA mutation carriers and therefore analogous treatment susceptibilities (Ashworth 2008). Since about 50% of HGSOC exhibit HR deficiencies, PARP inhibition represents one of the prominent targeted therapy options for a large cohort of HGSOC patients. However, as in most therapies, resistance to PARP inhibitors is also emerging. Importantly, depletion of CDK12 was discovered to re-stablish PARP-sensitivity by ablating restored HR (Johnson, Cruz et al. 2016). Despite the close sequence homology between CDK12 and CDK13, CDK13 does not affect the expression of DDR genes, but is involved in the transcription of small nucleolar ribonucleic acids (snoRNAs) (Liang, Gao et al. 2015). We identified CDK13 as essential gene for 19q12 amplified ovarian cancer cells, since downregulation of CDK13 induced a significant decrease of cell viability of 19q12 amplified compared to non-amplified cell lines (Figure 14 C2, Figure 16 C). Furthermore, we could demonstrate that the phenotypic pattern induced by k.d. of CDK13 is not an artefact, but the result of an on-target effect since decreased cell viability could be rescued by a specific CDK13 overexpression construct which is not recognized by the specific shRNA due to site-directed mutations within the shRNA binding sequence of the CDK13 cDNA (Figure 21). 2 overexpression constructs OE6_3 and OE 10_1 were cloned. It was demonstrated that k.d. of endogenous CDK13 and additional re-introduction of CDK13 with the construct OE6_3 could reconstitute cell viability and decrease the apoptotic rate compared to CDK13 k.d. cells (Figure 26 D, E). Construct OE10_1 failed to fully rescue the phenotype after CDK13 depletion (Figure 26 D, Figure 26 E), which is also reflected by the decreased CDK13 mRNA levels after introduction of the hairpin and the overexpression construct (Figure 26 A). In this case, it needs to be assumed that the overexpression construct OE10_1 was still partially recognized by the CDK13 shRNA construct. The difference between both overexpression constructs OE6_3 and OE 10_1 could be explained by the fact the both construct exhibit different site directed mutations and the shRNA might still have an affinity to bind to the mRNA of the CDK13 OE10_1 construct, which results in the inhibition of the gene expression. Furthermore, overexpression of CDK13 with both OE constructs induced increased cell proliferation reflected by the approx. 2-fold induction of relative number of colonies compared to control cells (Figure 26 D), even though the overexpression of CDK13 on mRNA levels was only induced by up to 1.4 fold and hardly noticeable on protein levels (Figure 26 A, Figure 26 B). This could be explained by the fact that CDK13 has a high turnover rate due to the fact that a high abundance of CDK13 might generate

103 4. Discussion proteotoxic stress and is therefore not tolerated, resulting in degradation of CDK13 already on mRNA level. In order to test if pharmacological inhibition of the gene product of CDK13 induced the same phenotype as after RNAi, selective small molecule inhibitors would have been necessary. However, no CDK13 inhibitor was available at the time point we planned these experiments. The first CDK13 inhibitor, THZ531, which binds covalently to the ATP binding pocket, however does not interfere with the binding affinity of cyclin K, was published in August 2016. In addition to CDK13, this inhibitor was also demonstrated to inhibit CDK12, even though with a lower binding affinity, furthermore CDK7 and CDK9. THZ531 was demonstrated to reduce Ser2 phosphorylation of RNA pol II and substantial loss of DDR genes, furthermore genes which encode transcription factors and enhances like RUNX1, MYB, TAL1 (Zhang et al 2016). If THZ531 also affects the transcriptional regulation of CDK13 specific target genes which include snoRNAs, could be investigated in further studies. Evidence suggests that both CDK13 and CDK12 play a substantial role in the transcription of specific target genes which are essential for the survival of cancer cells. Furthermore, k.d. of both genes as well as pharmacological inhibition of the kinase activity by binding of THZ531 to ATP binding pocket of both kinases, was demonstrated to result in potent induction of apoptosis (Zhang, Marjani et al. 2016). Therefore, THZ531 might be a potent inhibitor of oncogenic cell survival, however the underlying mechanisms which finally induce apoptosis still need to be unraveled. We discovered CDK13, but not CDK12 as essential gene for 19q12 amplified HGSOC and demonstrated that depletion of CDK13 is sufficient to induce apoptosis in 19q12 amplified HGSOC. Therefore, we assume that apoptosis induced by CDK13 depletion might be due to transcriptional inhibition of CDK13 specific target genes distinct from CDK12 target genes. Inhibition of CDK12, but not CDK13, has been demonstrated to induce apoptosis in BRCA mutated/HR deficient and PARP resistant tumors (Ashworth 2008). Since CDK13 and BRCA mutationsare synthetic lethal (Etemadmoghadam, Weir et al. 2013), we postulate that depletion/inhibition of CDK13 would also evoke the same effects of PARP sensitivity restoration in HR deficient HGSOC, as it was demonstrated for CDK12. Accordingly, therapy options could be classified due to the BRCA mutation and HR functionality status. That means patients with BRCA/HR deficiency would receive a CDK12 inhibitor, whereas BRCA wt/ HR sufficient patients would receive a CDK13 inhibitor. The requirement for a CDK13 specific therapy would be a selective CDK13 inhibitor. With THZ531 it was demonstrated that blocking of the ATP binding pocket of CDK13 and therefore inhibition of the enzyme activity can not be facilitated in a CDK13 specific manner. Therefore, impairing CDK13 activity by inhibiting specific binding regions of CDK13 to target genes or identifiying common binding motives of CDK13 target genes would need to be investigated for selective targeting. It might also be the case that CDK13 does not directly interact with DNA but with transcription factors or coactivators.

104 4. Discussion

Disruption of CDK13 and its potential transcriptional interactors could then represent a potent inhibition mechanism, which induces CDK13 specific apoptosis. Since we could validate CDK13 also in in vivo xenograft experiments, pharmacological inhibition of CDK13 in the in vivo setting in further experiments would add clinical relevance to the identification of this 19q12 essential target. We showed that k.d. of CDK13 decreases growth of tumors derived from 19q12 amplified OVCAR8 cells (Figure 25, Figure 29), whereas depletion of CDK13 in 19q12 non-amplified cells did not affect tumor growth (Figure 33, Figure 36). In further xenograft experiments it could be tested if the phenotypic pattern induced by CDK13 downregulation could be also induced by pharmacological inhibition of CDK13. In addition, factors influencing the selectivity of the drug and therefore challenge the treatment would need to be investigated, e.g. drug transport and delivery, metabolism and impact of microenvironment. In general, the induction of xenografts by subcutaneous injection of tumor cells is a very well established method to monitor the growth of tumors after a specific inhibition of a potential therapeutic target in vivo. The accessibility of this site contributes to the relative ease of this method since tumor growth can be easily measured (Morton and Houghton 2007, Chaudary, Pintilie et al. 2012). However, the microenvironment plays a tremendous role especially in terms of drug efficiacy (Morin 2003). Therefore, it has to be considered that subcutaneous models for studying pharmacological inhibition of CDK13 in HGSOC may not be suitable since the subcutaneous microenvironment may not reflect that of the original tumor of which the xenograft was derived from (John, Kohler et al. 2011). Recapitulation of the original tumor microenvironment has a greater likelihood of occurring in orthotopic models (Chaudary, Pintilie et al. 2012). Also in our xenograft experiments we potentially faced the impact of the microenvironment since our OVCAR3 xenograft models did not engraft after the injection of 1x 106 cells within a time period of 60 days (Figure 31). The same cell number was also injected in OVCAR8 and SKOV cells, which started to engraft as tumors 25 days after the injection and TYKNU even started to engraft after 6 days. Similar observations were made by Hernandez, Kim et al. 2016, who reported that OVCAR3 cells only successfully engrafted intraperitoneally, but not subcutaneously (Hernandez, Kim et al. 2016). Also in SKOV cells, we assume that the microenvironment influenced the growth of the tumors. We noticed that the shCTRL tumor of the doxy chow group were located below the subcutaneous tissue and therefore deeper than the CTRL tumors of the CTRL chow group. This can be only explained due to technical issued regarding the injection into the muscle tissue, however not due to the injection of more cells since the same cell suspension was used for both groups. The interesting part was that the deeper located shCTRL tumors tumor of the doxycycline chow group had higher final tumor weights than CTRL chow group. Therefore, we assume that the microenvironment of the muscle tissue conveys better growth conditions presumably due to a better vascularization and nutrient availability. Due to the injection issue resulting in big shCTRL tumors in the doxycycline chow group, the corresponding shCDK13 tumors showed a

105 4. Discussion significantly lower tumor weight, even though we expected no difference between both side since CDK13 k.d. should not have affected the tumor size of CDK13 depleted tumors. In order to study the impact of CDK13 downregulation or inhibition in a setting which provides a more accurate reflection of the tumor microenvironment, patient-derived tumor tissue xenograft models could be established. An option would be an ovarian tissue specific downregulation of CDK13 by expressing the k.d. construct under control of the Müllerian oviductal glycoprotein (OVGP-1) promoter. Due to recent evidence that HGSOC originate from precursor lesions in the epithelium of the fallopian tube, known as STIC (Gagner and Mittal 2005, Kindelberger, Lee et al. 2007, Kurman and Shih Ie 2010), Sherman-Baust, Kuhn et al. 2014 developed a genetically engineered ovarian cancer mouse model based on fallopian tube transformation which mimics the development of HGSOC by expressing the SV40 large T-antigen under the control of the mouse Ovgp1 promoter, a Müllerian- specific promoter highly active in the fallopian tube (Sherman-Baust, Kuhn et al. 2014). Accordingly, ovarian tissue specific downregulation of CDK13 could be achieved by expression the k.d. construct under control of the Müllerian OVGP-1 promoter.

4.2.3.3 Connection between 19q12 and CDK13

As mentioned above, CDK13 is involved in the transcription of snoRNAs (Liang et al, 2015). snoRNAs are small noncoding RNAs function in complex with specific protein molecules, which all together assemble to the snRNP complexes facilitating post-transcriptional modifications of other RNAs. (Maxwell and Fournier 1995, Girardot, Cavaille et al. 2012). Most snoRNAs are encoded within introns of genes and are released from the pre-mRNA via splicing dependent pathway or endonuclolytic cleavage (Watkins, Dickmanns et al. 2002). There are two major families of snoRNAs H/ACA box and C/D box snoRNAs which are categorized based on conserved sequence motives and their association with common core proteins (Balakin, Smith et al. 1996, Watkins, Dickmanns et al. 2002). H/ACA snoRNas function in the site-specific isomerization of uridine to pseudouridine, while the C/D box snoRnas direct 2`-O methylation of ribose moieties within rRNA and certain spliceosomal snRNAs (Watkins, Dickmanns et al. 2002). Since 2′-O-methylated nucleotides and pseudouridines are restricted to the functionally essential regions of ribosomal and small nuclear RNAs, they are expected to contribute to the function of the ribosome and the spliceosome, respectively (Kiss 2001). CDK13 is involved the expression and processing of snoRNAs since depletion of CDK13 results in reduced levels of snoRNAs (Liang et al, 2015). Since we showed that CDK13 is specifically required for HGSOC with amplification of the chromosomal locus 19q12, the functional connection still remains elusive. We hypothesize that a potential connection might exist via URI1, one of the most prominent genes within the 19q12 amplicon, which has been identified to contribute/promote to tumorigenesis in different types of cancer (Theurillat, Metzler et al. 2011, Tummala, Gomes et al. 2014, Buren, Gomes et al. 2016,

106 4. Discussion

Lipinski, Britschgi et al. 2016). URI1 is a component of the prefoldin-like/URI1 complex and part of a chaperone network being involved in the proper folding of newly synthetized and misfolded proteins (Siegert, Leroux et al. 2000, Gstaiger, Luke et al. 2003, Cloutier and Coulombe 2010). The prefoldin- like/URI1 complex associates with the RT2P complex which provides ATP for the chaperone function. Furthermore, the R2TP complex, consisting of 2 ATPases TIP48 and TIP49 and the 2 proteins Protein interacting with Hsp90 1 (Pih1) and TPR (tetratricopeptide repeat)-containing protein associated with HSP (heat-shock protein) 90 (Tah1), is involved in the assembly of both C/D box and H/ACA box snoRNPs (Watkins, Dickmanns et al. 2002, Zhao, Kakihara et al. 2008). Pih1 and Tah1 have been identified as Heat shock protein 90 (Hsp90) -interacting cochaperones which have been suggested to regulated the ATP availability for HSP90, furthermore to facilitate as co-chaperones the recruitment of client protein to Hsp90 (Zhao, Davey et al. 2005, Eckert, Saliou et al. 2010). HSP90 and Tah1 are assumed to stabilize the R2TP complex, whereas Pih1 and the 2 ATPases TIP48 and TIP49 have been demonstrated associate with NOP58, a core snoRNP compex protein. Depletion of Pih1, TIP48 or TIP49 results in a reduced accumulation of snoRNP complexes and an increase of apoptosis in particular under stress conditions (Watkins, Dickmanns et al. 2002, Zhao, Kakihara et al. 2008). The investigation of this tightly regulated network suggests that HSP90 and the Prefoldin-like complex in combination with the RT2P module facilitates both RNA polymerase and snoRNA assembly which might contribute to its established role in cell proliferation and oncogenic transformation (Calderwood, Khaleque et al. 2006, Boulon, Pradet-Balade et al. 2010). This can be explained due to the fact that tumor cells are dependent on specific molecular chaperones that support the tumor intrinsic non-oncogene addiction in order to protect them from proteotoxic stress (Luo, Solimini et al. 2009). This is strongly supported by the fact that failure of the chaperone system due to depletion of specific network components induces apoptosis (Lipinski, Britschgi et al. 2016). CDK13 seems to be part of this network due to its transcriptional regulation of snoRNAs. As demonstrated in this study, k.d. of CDK13 leads to induction of apoptosis of 19q12 amplified HGSOC cells and derived tumors. Therefore, we hypothesize that apoptosis is triggered by impaired expression and processing of snoRNAs induced by CDK13 depletion. As a consequence, snoRNP complexes cannot be established due to missing snoRNA and properly function as snoRNP complexes facilitating post- transcriptional modifications of other RNAs. This triggers a high burden of stress the tumor cells can`t cope with. Since it is assumed that 19q12 amplified HGSOC are highly dependent of the tightly regulated chaperone network in order to cope with the oncogenic stress due to genomic instability and misfolded proteins, any failure of this network increases the stress burden. Amplification of 19q12 genes correlates with high expression levels resulting in a high protein abundance. If URI1 is highly abundant and ready to assemble snoRNA complexes, however there is a lack in the delivery pipline, since snRNP complexes fail to assemble due to missing expression/processing of snoRNA due to CDK13

107 4. Discussion depletion, the system breaks down since the proteasome is unable to cope with the excessive supply of URI1 which results in apoptosis. However, in 19q12 non-amplified cells, URI1 is not overabundant and can be successfully removed by the proteasome. The excessive supply of URI1 and it`s chaperone network might be also an explanation why the proteasome inhibitor bortezomid showed great sensitivity in 19q12 amplified cells (Etemadmoghadam, Weir et al. 2013). Another explanation could be that in 19q12 amplified cells, CDK13 facilitates the expression of other snoRNAs than in 19q12 non- amplified cells due to it`s alternative splicing capacity (Watkinas, Dickmanns et al. 2002). The CDK13 regulated expressed snoRNAs in 19q12 amplified cells might be more crucial for cell survival than the differencially CDK13 expressed snoRNAs in 19q12 non-amplified cells.

Figure 37: Hypothesized model of the prefoldin-like/URI1 complex interacting with snoRNP complexes via the R2TP module. CDK13 is involved in the transcriptional regulation of snoRNAs which build snoRNP complexes with proteins like NOP58. NOP58 directly interacts with components of the R2TP module suggesting its function in assembling snoRNP complexes in combination with either HSP90 and/ or the prefoldin complexes. Both HSP90 and prefoldin-like/URI1 complex have also been associated with the assembly of RNA pol II complexes which are also affected by CDK13 phosphorylating and activating components the of RNA pol II complex.

In conclusion, CDK13 has been demonstrated to play a crucial function in cellular processes contributing to the survival of 19q12 amplified HGSOC or even in the maintenance of 19q12 specific oncogenic pathway dependencies. It still remains elusive, if there is a functional relationship between 19q12 and CDK13. In further studies it could be investigated if after k.d. of specific network components e.g. TIP48, TIP49, PIH, Tah1 the same 19q12 dependency/segregation pattern in terms of cell viability can be observed as after CDK13 k.d. Furthermore, RNA sequencing experiments could reveal if CDK13 facilitates the expression of a different set of snoRNAs in 19q12 amplified cells than in 19q12 non-amplified cells.

108 4. Discussion

These experiments and also the above mentioned suggestions of further studies involving the test of a CDK13 selective small molecule inhibitor and ovarian tissue specific in vivo models could be a further step in the evaluation of CDK13 as suitable therapeutic target for 19q12 amplified HGSOC. Due to the highly heterogeneity of HGSOC, targeting CDK13, as well as other specific targets in a combinatorial therapy, might provide a promising therapy option. In addition, the further investigation of robust biomarkers depending of the genetic profile of the heterogeneous tumor of the patient and the development of reliable diagnostic tools would be a breakthrough in the envisioned goal of efficacious personalized medicine for patients with HGSOC, but also with any other kind of cancer.

109 5. Materials and Methods

5. Materials and Methods

5.1. Cell culture techniques

5.1.1 Cell maintenance/passaging

Cell culture was performed in a laminar flow hood. Cells were cultivated in a 2D monolayer at 37°C and

5% CO2 in a humidified incubator. According to information of the cell line supplier respective cell culture medium (Gibco) was used supplemented with fetal calf serum (FCS) (Amimed) or tetracycline- free FCS (BioConcept) as listed in table 4. For cell maintenance, cells were split when a confluency of 70-90% was reached. For this, cells were washed once with 1x phosphate buffered saline (PBS) (Biochrom) and incubated with 2 mL 1x Trypsin (Gibco) per 15 cm dish for 10-20min. After detachment, cells were re-suspended in the respective medium and 1/10 of cells were transferred into a new 15 cm dish for further cultivation in 25 mL medium. To seed cells for experiments, cell numbers were determined by a Z2TM Coulter® Counter (Beckman Coulter) measuring cells in a size range of 8 µM to 13 µM.

5.1.2 Freezing cells

Cells were washed once with 1x PBS and treated with 2 mL 1x Trypsin per 15 cm dish. After detachment cells were re-suspended in the respective medium and transferred into a 15 mL Falcon tube. After centrifugation at 800 g for 5 min supernatant medium was removed and cells were re-suspended in FCS with 10% Dimethyl sulfoxide (DMSO) and transferred into cryotubes. Tubes were frozen in a freezing container at -80°C. After 24 h cryotubes were transferred into liquid nitrogen tanks.

5.1.3 Thawing cells

Frozen aliquots were thawed by placing the cryotube in a 37 °C water bath for 1-2 min. Thawed cells were transferred into a 15 mL falcon tube and centrifuged at 800 g for 5 min at RT. Supernatant medium was removed and cells were re-suspended in the respective medium and transferred into a 10 cm dish.

110 5. Materials and Methods

5.1.4 Mycoplasm test

Cells were tested for mycoplasma contamination before the start of any experiments by using the PCR mycoplams test kit II (AppliChem). Furthermore, cell lines were tested again before using for mouse xenograft models.

111 5. Materials and Methods

Table 4: Cell line information

LOT Cell line Medium Tissue Disease Origin References Supplier Catalog number number RPMI-1640 Glutamax (Karlan, Jones et al. American Type Culture CAOV-3 human ovary adenocarcinoma 54 years ATCC® HTB-75™ 61465095 +10% FCS 1994) Collection (ATCC) (van den Berg- DMEM 2mM L- Public Health England COV504 serous serous Bakker, Hagemeijer 7071902 11K033 glutamine + 10%FCS culture collections et al. 1993) HEK DMEM + 2mM L- human embryonic - fetus - ATCC ATCC® CRL-11268™ 59587035 293T/17 glutamine + 10% FCS kidney MCDB 105 :Medium human ovarian (Tsao, Mok et al. Prof. Viola Heinzelmann, HOSE6-3 - - - - 199 (1:1) + 10% FCS surface epitheliµM 1995) University Hospital Basel RPMI-1640 Glutamax serous (Benard, Da Silva et IGROV human ovary 47-year-old patient National Cancer Institute - - + 10% FCS carcinoma al. 1985) RPMI-1640 Glutamax serous ascites of 60-year-old (Hamilton, Young et OVCAR-3 human ovary National Cancer Institute - 507708 + 10% FCS carcinoma patient al. 1983) RPMI-1640 Glutamax serous (Hamilton, Young et OVCAR-4 human ovary 42-year-old patient National Cancer Institute - 507673 + 10% FCS carcinoma al. 1984) RPMI-1640 Glutamax serous (Hamilton, Young et OVCAR-8 human ovary 64-year-old patient National Cancer Institute - 507712 + 10% FCS carcinoma al. 1984) RPMI-1640 Glutamax serous ascites of 64-year-old (Fogh, Wright et al. SKOV3 human ovary ATCC ATCC® HTB-77™ - + 10% FCS carcinoma patient 1977) RPMI-1640 Glutamax clear cell ovary of 62-year-old (Provencher, Lounis TOV-21G human ovary ATCC ATCC® CRL-11730™ - + 10% FCS carcinoma patient, grade 3, stage III et al. 2000) Japanese Collection of MEM Glutamax + TYKNU human ovary serous carinoma - (Yoshiya 1986) Research Bioresources JCRB0234.0 7182013 10% FCS Cell Bank (JCRB)

112 5. Materials and Methods

5.2 Transfection of cell lines

5.2.1 Transient DNA plasmid transfection of 293T cells for lentiviral production

2x 106 293T/17 cells were seeded into 10 cm dishes 48 h before the transfection. For each transfection a DNA solution was prepared containing following plasmids and concentrations: - construct/plasmid of interest (10 µg) - pMD2.G envelope plasmid (6.5 µg) - psPAX packaging plasmid (7.5 µg) Plasmids of interest included pLKO1-TRC (#10878 Addgene) plasmids carrying short hairpin sequences from the full genome TRC 1.0/1.5 library (Sigma Aldrich) and TET-pLKO-puro (#21915 Addgene) plasmids carrying short hairpin RNA (shRNA) sequences. Furthermore, pLKO1-TCR, tet-pLKO-puro and pTRIPZ (Thermo scientific) plasmids carrying cDNA sequences of the human ORFeome 8.1 collection (GE Dharmacon). All plasmid clones, provided as bacterial glycerol stocks by NEXUS personalized health technologies, were purified with NucleoSpin Plasmid Kit (Macherey Nagel) according to manufacturer`s instructions. Full plasmid list including all used shRNA constructs including the kinome library constructs are listed in supplemental table S2. DNA solutions with the total amount of 24 µg DNA were pipetted into a 15 mL falcon tubes containing 2.4 mL serum-free Dulbecco’s Modified Eagle’s medium (DMEM). 45 µL Polyethylenimine (PEI) (Sigma- Aldrich) stock solution (1mg/mL) was added into each vial. After vortexing briefly, transfection solutions were incubated for 10 min. Medium of 293T/17 cells was replaced by 6 mL DMEM + 0.5 % FCS per dish. Transfection solution was added dropwise to the cells. Medium was changed 6 h after transfection with 10 mL DMEM + 10% FCS per dish. Lentiviral particles were harvested approx. 42 h after transfection and once again 24 h after the first harvest. For this, viral particles containing medium was collected and filtered through a 0.45 µM filter and stored at -80°C or directly used for infection.

5.2.2 Viral infection/transduction of host cells

1 mL virus containing medium (either fresh or freshly thawed from -80°C) was used to infect approx. 5x105 host cells seeded per well of a 6-well dish. After 24 h, cells were split into 10 cm dishes and selected with puromycin containing medium (2 μg/mL final concentration) for 48 h before seeding for experiments.

113 5. Materials and Methods

5.3 Cloning

5.3.1 Cloning of CDK13 overexpression constructs

For cloning of CDK13 overexpression constructs with and without N-terminal HA-tag, the pDONR23 plasmid # OHS6084-202638988 of the human ORFeome 8.1 collection (GE Dharmacon) containing the cDNA sequence of CDK13 was purified with NucleoSpin Plasmid Kit (Macherey Nagel) according to manufacturer`s instructions. For the overexpression construct without HA-tag, the CDK13 cDNA sequence was amplified with the CDK13overexpr_fw2 (Primer #19, supplemental table S2) primer with GC clamp, AgeI restriction site, Kozak sequence and 21 first 5`end nucleotides of CDK13 cDNA and CDK13overexpr_rev2 (Primer #20, supplemental table S2) primer containing GC clam, EcoRI site and reverse complement sequence of the first 25 nucleotides of the 3`end. For the overexpression constructs CDK13_HA_Nter_fw containing (Primer #21, supplemental table S2) primer containing GC clamp, AgeI restriction site, Kozak sequence, HA-tag sequence and 21 first 5`end nucleotides of CDK13 cDNA and CDK13overexpr_rev2 (Primer #20, supplemental table S2) was used. Individual annealing temperatures for primers were calculated according to the TM calculator (Thermo Scientific) calculating the annealing temperature only for partial sequences of the primers containing the 20 N- and C-terminal nucleotides of the CDK13 cDNA sequence. Amplification via PCR was performed according to the protocol of Phusion® High-Fidelity DNA Polymerase (New England Biolabs). Both, the amplified product and the destination vectors TET-pLKO-puro, pTRIPZ, pLKO.1-TRC were digested with AgeI-HF and EcoRI-HF restriction enzymes according to the “double digest finder” protocol (New England Biolabs). Restriction digest was loaded on a 2% agarose gel expecting 2 bands at a size of 1875 bp (stuffer) and 7026bp for TRC-pLKO; 1875bp (stuffer) and 8758 bp (cut vector) for the TET-pLKO vector; 837 bp (stuffer) and 12483 bp (cut vector) for the TRIPZ vector. Bands of cut vectors were cut out of the gel and purified with Qiaquick Gel Extraction Kit (Quiagen) according to the manufacturer`s instructions. Digested amplified PCR products and destination vectors were ligated according to the T4 ligase protocol (M0202) (New England Biolabs). Ligated products were transferred into chemically competent, calcium chloride treated, bacteria of the E.coli strain DH5α. For this transformation one vial per ligation reaction of DH5α was thawed from -80° on ice. 15 µL of each ligation reaction was added to competent bacteria and incubated on ice for 30min. Bacteria were heat shocked for 60sec at 42° and incubated on ice for another 5min. 300 µL Lysogeny broth (LB) medium without antibiotics was added and vial was incubated 30min in a 37°C shaker. Cells were plated on LB- agar plates with 100 μg/mL ampicillin (AppliChem) and incubated at 37°C overnight. The next day colonies were picket from the plates and inoculated in LB medium containing ampicillin (100 μg/mL). Bacterial cultures were incubated overnight. The next day plasmid purification was performed using

114 5. Materials and Methods

NucleoSpin Plasmid Kit (Macherey Nagel). After purification a restriction digest was performed with AgeI-HF and EcoRI-HF restriction enzymes according to the “double digest finder” protocol (New England Biolabs) and 5ul of the digested product was loaded on a 2% agarose gel. 2 bands were expected of a size of 1000 bp (CDK13 sequence) and 7026bp for TRC-pLKO, 8758 bp for TET-pLKO and 12483bp for pTRIPZ vector. Samples with bands at the expected size were sent for sequencing. For this, plasmids with a concentration of 60-100 ng/µL in a total volume of 12 µL in addition to 3 µL of 10 µM sequencing primers (LKO1_5 sequencing primer for TRC-pLKO; H1 sequencing primer (Primer #26, supplemental table S2) for TET-pLKO and LNCX sequencing primer (Primer #28), supplemental table S2) for pTRIPZ were send to Microsynth (Balgrist) for sequencing. Sequencing reports were analyzed with CLC workbench (Quiagen). Samples of plasmids with aberrant sequences e.g. single base mutations or deletions in the CDK13 coding sequence were discarded.

5.3.2 Cloning of CDK13 rescue constructs

For cloning CDK13 rescue constructs which were not supposed to be recognized by shRNA#1 construct primers were ordered containing exchanged nucleotides within the CDK13 sequence recognized by shRNA#1. For this forward primers containing the shRNA#1 binding sequence were designed with 3 exchanged nucleotides of 3 different nucleotide triplets affecting the last nucleotide of each triplet. Nucleotide exchange was not supposed to result in an amino acid exchange. Forward primers CDK13 mut P1_6_3_fw (Primer #22, supplemental table S2) and CDK13 mut P1_10_1_fw (Primer #24, supplemental table S2) and the corresponding reverse complement sequences as respective reverse primers CDK13 mut P1_6_3_rev (Primer #23, supplemental table S2) and CDK13 mut P1_10_1_rev (Primer #25, supplemental table S2) were used. Furthermore, TET-pLKO and TRC-pLKO plasmids containing the cDNA sequence of CDK13 with N-terminal HA-tag, produced as described in 5.3.1. were used as PCR templates. In the next PCR step according to the site directed mutagenesis protocol (Agilent technologies) with reagents of the Phusion® High-Fidelity DNA Polymerase kit (New England Biolabs), whole plasmids were re-amplified with incorporation of mutated bases due to the specific primers. After the PCR and gel purification of the product with Qiaquick Gel Extraction Kit (Quiagen) a Dpn I digestion was performed in order to digest the methylated parental DNA template but not newly synthetized templates. 5 µL of DpnI digest was transformed in DH5α cells. After overnight culturing of clones picked from colonies and subsequent plasmid purification samples with H1 sequencing primer (Primer #26, supplemental table S2) were send for sequencing to Microsynth as mentioned in 5.3.1. Only intact sequences containing specifically introduced mutated bases at the required places and no other mutations or deletions within the CDK13 cDNA sequence were considered.

115 5. Materials and Methods

5.3.3 Cloning of tetracycline-inducible shRNA constructs

For the cloning of tetracycline (tet)-inducible shCDK13 constructs, primers were designed according to the “all-in-one” system for the inducible expression of shRNA protocol (Wee, Wiederschain et al. 2008, Wiederschain, Wee et al. 2009). Three different tet-inducible shCDK13 constructs were cloned. Forward (fw) primers contained a AgeI restriction site, shRNA sense strand, loop, antisense strand and a termination sequence (Primers #30,32,34, supplemental table S2). Reverse (rev) primers contained a EcoRI restriction site, shRNA sense strand, loop, antisense strand and a termination sequence (Primers #31,33,35, supplemental table S2). Tet-pLKO-puro (#21915 Addgene) was digested with AgeI- HF and EcoRI-HF restriction enzymes according to the “double digest finder” protocol (New England Biolabs). After restriction digest and gel electrophoresis 1 band at 1875 bp (stuffer) and another at 8758 bp (cut vector) was expected. Cut vector was gel purified. Annealing of primers/oligonucleotides was performed according to the protocol. Ligation of cut TET-pLKO vector and annealed oligonucleotides was performed according to the T4 ligase protocol (M0202) (New England Biolabs) and transformed in DH5α E.coli as mentioned in 5.3.1. After overnight culturing of clones picked from colonies and subsequent plasmid purification samples were send for sequencing to Microsynth as mentioned in 5.3.1. Only intact sequences were considered.

5.4 Transcription Analyses

5.4.1 Quantitative PCR (qPCR)

For transcription analysis on mRNA level, attached cells on culture plates were washed once with 1x PBS and 350 µL RA I buffer of the NucleoSpin RNA II kit (Macherey Nagel) and 7 µL 0.5M Tris(2- carboxyethyl)phosphine hydrochloride solution (TCEP) (Sigma) were directly added on the plate leading to detachment of cells. Cell solutions were collected in 1.5 mL Eppendorf tubes and were either frozen at -80% or RNA extraction was proceeded immediately according to the manufacturer`s instructions of the NucleoSpin RNA II kit. RNA concentration was determined by Nanodrop and RNA samples were stored at -80°C or directly transcribed to cDNA using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems). For reverse transcription concentrations between 500 ng and 2000ng RNA were used. cDNA samples were stored at -20°C or directly used for qPCR. A mastermix was prepared containing 10 µL KAPA Sybr Fast (KAPA Biosystems), 6 µL H2O and 2 µL of premixed PCR primers (fw and rev, 10 µM) per qPCR reaction. Primers of target and housekeeping genes are listed in supplemental table S2, primer # 1-18. 1000 ng cDNA was provided per well in a LightCycler 480 Multiwell Plate 96 (Roche) and 18 µL of the pre-mixed mastermix was added. The qPCR was performed

116 5. Materials and Methods on a LightCycler 480 (Roche) instrument using the standard SYBR Green qPCR protocol (45 cycles). Cycle threshold (CT) values were transformed into relative mRNA expression levels by using the 2-ΔΔCT method (Heid, Stevens et al. 1996, Livak and Schmittgen 2001). 18S ribosomal RNA, TATA box binding protein (TBP) and hypoxanthine phosphoribosyltransferase 1 (HPRT) were used as non-regulated housekeeping-genes for normalization.

5.4.2 Western Blotting

For transcription analysis on protein level, cell samples were harvested on ice. For this, cells in culture plates were rinsed once with ice cold 1x PBS. 1mL of 1xPBS was added again and cells were scratched from the plated with a cell scraper and collected in a 1.5 mL eppendorf tube. Samples were centrifuged for 4min at 4000g, 4°C in a tabletop centrifuge. Supernatant was completely sucked up and samples were re-suspended in 50-300µL TNN buffer (50 mM Tris-HCL pH 7.5; 250 mM NaCl, 5 mM EDTA, 0.5% NP-40; 50 mM NaF, 1: 100 cOmplete (Roche), 1:50 PhoSTOP (Roche)) depending on the pellet size. Samples were incubated on ice for 20min and centrifuges for 10min, full speed, 4°C in a tabletop centrifuge. Supernatant was transferred into new Eppendorf tubes. Total protein concentration was determined by Bradford protein assay (Biorad) according to the manufacturer`s instructions. Samples were adjusted to equal protein concentrations of 20-50 ug total protein with TNN buffer. Depending on the protein concentration volumes were adjusted to 20-50 µL. Volumes within one series was equal. 5x Lämmli buffer (20% glycerol, 4% SDS, 0.2% bromophenol blue, 200 mM DTT) was added to a final concentration of 1x per sample. Samples were boiled at 95°C for 5min and shortly centrifuged before being loaded on a gel. Samples were either stored at -20° and re-boiled for 1 min or directly loaded on a 4-20% Mini-PROTEAN TGX Stain-Free Gel, 10 well (Biorad). Running conditions were followed according to the manufacturer`s instructions, however a self-made running buffer (250 mM Tris-HCl, 1% SDS, 1.92 M Glycine) was used. Transfer was performed with Trans-Blot® Turbo™ Mini PVDF Transfer Packs according to the manufacturer`s instructions using the pre-programmed standard SD protocol (up to 1.0 A; 25 V, 30 min) of the Trans-Blot Turbo™ machine. After transfer, PVDF membranes were blocked with TBST (50 mM Tris-HCl, 150 mM NaCl, 10% Tween 20) for 30 min, RT. Membranes were incubated with antibodies listed in table 5.2 overnight on a rolling platform. The following day antibody solution was retrieved and membranes were washed 5 times with 1xTBST within 30 min-1 h. Membranes were incubated with secondary antibodies for 1h, RT and washed again 5 times with 1xTBST within 30min-1h. Signals were elicited by incubating membranes for approx. 1 min with WesternBright ECL- HRP Substrate (Witec). Signals were visualized with Fusion Solo S (Vilber).

117 5. Materials and Methods

Table 5: Antibody information

Target clonality host target MW Supplier Catalog Application protein species kDa number β-actin monoclonal mouse human, 42 Sigma Aldrich A5316 Western Blot 1:5000 mouse, rat HA monoclonal mouse Covance MMS-101R Western Blot 1:1000 URI1 monoclonal mouse human 90 self-made Gstaiger et al, Western Blot 1:100 2001 CCNE1 monoclonal mouse human 50 Santa Cruz sc-248 Western Blot 1:500 GAPDH polyclonal rabbit human, 37 Abcam ab37168 Western Blot 1:500 mouse, rat CDK13/ monoclonal mouse human 170 Abcam ab58309 Western Blot 1:100 CDC2L5 Goat anti- polyclonal goat mouse - Life technologies 62-6520 secondary Ab Mouse IgG Western Blot 1:5000 (H+L) HRP Goat anti- polyclonal goat rabbit - Life technologies 65-6120 secondary Ab Rabbit IgG Western Blot 1:5000 (H+L) - HRP

5.5 Bioinformatical analysis

5.5.1 Copy number variation determination

Copy numbers of genes of the chromosomal locus 19q12 were determined by using the CCLE_copynumber_byGene_2013-12-03 dataset of the DNA Copy Number (41.6GB) Affy SNP Affymetrix SNP6.0 array release provided by the Cancer Cell Line Encyclopedia (CCLE) database. In this dataset raw Affymetrix CEL files were converted to a single value for each probe set representing a SNP allele or a copy number probe. Copy numbers were then inferred based upon estimating probe set specific linear calibration curves, followed by normalization by the most similar HapMap normal samples. Segmentation of normalized log2 ratios (specifically, log2(CN/2)) was performed using the circular binary segmentation (CBS) algorithm. 2 is referring to the diploidy of the genome. Absolute CNV values were calculated by (2^CN)*2. Absolute CNV values =2 represent the “normal” copy number of n=1 per allele. Therefore, copy numbers above the CNV threshold of 2 and above the log2(CN/2) =0.04 are referred to as amplified.

5.5.2 mRNA expression determination

Relative mRNA expression levels of 19q12 genes were taken from CCLE_Expression_2012-09-29 dataset displaying RMA-normalized mRNA expression data of the mRNA expression (8.0GB) Gene expression Affymetrix U133+2 arrays release provided by the CCLE database.

118 5. Materials and Methods

Raw Affymetrix CEL files were converted to a single value for each probe set using Robust Multi-array Average (RMA) and normalized using quantile normalization. Either the original Affymetrix U133+2 CDF file or a redefined custom CDF file (ENTREZG - v15) was used for the summarization. The mean of RMA normalized mRNA expression values of 19q12 genes of the 19q12 amplified cell lines OVCAR3, OVCAR4, OVCAR8 was calculated and compared to the mean of RMA normalized mRNA expression values of the 19q12 non-amplified cell lines TOV21G, COV503, IGROV and CAOV3

5.6 RNAi screen

5.6.1 Preparation of pooled kinome shRNA library

A shRNA library containing shRNA constructs against kinases of the human genome was established by selecting 5 shRNA constructs per gene depending of the availability of the constructs of the full genome TRC 1.0/1.5 library (Sigma Aldrich) provided by NEXUS personalized health technologies. In total 2688 clones of shRNA constructs including controls were picked with the lab automation platform (EVO 100 Liquid Handling Robot, TECAN) from different glycerol stock plates arrayed in a 96-well format and transferred into 96-well deep well block containing Terrific Broth (TB) medium + Carbenicillin (100 µg/mL) per well. Cultures were shaken at 300rpm, 37°C for 17h. 100 µL of the cultures were transferred into 96-well pates containing 50% glycerol using the TECAN automation platform. Plates were temporarily stored in a platform included freezer (Liconic- STX44 DF) at -20° until the storage capacity had reached a capacity of 20 plates. Then plates were manually transferred and stored in -80°C. From the arrayed kinome library existing in 36 x 96-well plates, clones were picked again with the TECAN automation platform and transferred into deep well blocks containing 1 mL TB medium + Carbenicillin (100 µg/mL). Deep well blocks were shaken at 300 rpm, 37°C for 17h. Cultures which did not grow when automatically picked are listed in table 5.3.

Table 6: Missing bacterial cultures of TRC clones Gene TRC number TRC library plate and place Comment KIAA1804 TRCN0000003211 AAB66 G1 picked by hand and grown TSSK6 TRCN0000037459 AAF37 F6 does not grow at all SGK1 TRCN0000040175 AAF67 F3 picked by hand and grown MET TRCN0000009851 BH-002 F12 does not grow at all ERBB4 TRCN0000009836 BH-002 A11 does not grow at all ERBB4 TRCN0000018328 BH-002 A12 does not grow at all INCENP TRCN0000074143 AAJ45 G4 picked by hand and grown INCENP TRCN0000074144 AAJ45 G5 picked by hand and grown

119 5. Materials and Methods

5 µL of each culture was transferred again with lab automation platform into new deep well blocks containing 1 mL TB medium + Carbenicillin (100 µg/mL) in order to equalized the cultures in terms of optical density which roughly correlates with the amount of containing plasmids per culture. Deep well blocks were shaken again at 300 rpm, 37°C for approx. 14 h until OD600= 1 was reached. Two samples per deep well block served as OD600 reference for the whole block. Cultures of all deep well blocks were pooled and distributed into 2 L flasks containing about 1,5 L bacterial culture each. Cultures were distributed into 8x 250 mL flasks for centrifugation at 5000 rpm, 15 min, 4°C. (Heraeus Megafuge 40R centrifuge, Thermo Scientific). For plasmid purification NucleoBond Xtra Maxi Plus (Macherey Nagel) was performed following the low copy plasmid protocol for low copy plasmids until step 7 and continuing with loading the column as described in high copy plasmid purification. Differences from the protocol included: 1. precipitation was performed at 7500 rpm, 45 min, 4°C 2. pellet was washed with 70% EtOH, 7500 rpm, 25 min, RT

After reconstitution of DNA with H2O DNA was measured using a Nanodrop (yield of 3-4 µg/µL in ca. 1,5 mL total volume).

5.6.2 Production of lentiviral particles containing plasmids of 2688 constructs

In total 15 transfections of 293T/17 cells in 10cm dishes were performed in order to achieve a total amount of 150 mL lentiviral kinome shRNA library stock solution. Transfection and lentiviral production was proceeded as described in 5.2.1 In parallel 2 transfections of 293T/17 cells in 10cm dishes were performed in order to achieve a total amount of 20 mL green fluorescence protein (GFP) virus solution needed for MOI determination as describes in 5.2.3.

5.6.3 Multiplicity of infection (MOI) determination by lentiviral titering

A major requirement of a pooled screen is to reduce the likelihood of multiple integrations per cell and the emergence of combinatorial phenotypes. The probability of 1 integration per cell is statistically defined by a MOI = integrations/cell <0.7. Accurate determination of the MOI=0.7 in target cell lines to be screened by a relative titer estimate compared to a standard curve of a serial dilution of a GFP control virus allowed subsequent infection of target cell lines at intended efficiencies (Sims, Mendes- Pereira et al. 2011). An MOI = 0.7 of 6 different ovarian cancer cell lines (OVCAR3, OVCAR4, OVCAR8, COV504, SKOV3, TOV21G) and 1 ovarian surface epithelial cell line (HOSE6-3) was determined

120 5. Materials and Methods according to an adapted protocol of the Broad institute (Relative Viral titering with a Resazurin cell viability assay, revision date 20.10.2012) A standard curve of a serial dilution of a GFP control virus had to be determined via FACS analysis. For this, 40000 cells of each target cell line were seeded per well of a 12-well dish in a total volume of 1mL. In addition, the infection rates of a serial dilution of the kinome shRNA library viruses, were determined by a PrestoBlue cell viability assay (Thermo Scientific) in parallel. For this assay 3400 cells were seeded per well of two 96-well plates in a total volume of 85 µL (=40000 cells/mL). One plate was infected with serial dilutions of the GFP control virus, the other plate was infected with serial dilutions of the kinome shRNA library containing virus. Both virus stock solutions, the GFP and the kinome shRNA library a 1:2 dilution series was prepared starting with a 1:2 dilution until 1:2000 dilution. For the FACS experiment, 0.5 mL medium was applied to the first well of the 12-well FACS plate, 0.5 mL of the first dilution (1:2) of the GFP virus to the second well, etc. until dilution 1:2000 dilution in 12.well. For the PrestoBlue assay, 42.5 µL medium was applied to all wells of the first column of the 96-well plate of both plates. To the second column of the first 96-well plate 42.5 µL of 0.5 GFP-virus dilution was applied, to the second column of the second plate 42.5 µL of 1:2 kinome library virus dilution, etc. until dilution 1:2000 for both viruses. Dilutions were represented by 8 replicates corresponding to one row of a 96-well plate. After incubation for 30 h, medium of the 12-well FACS plate was removed completely and replaced by 2mL new medium without Puromycin. Medium of the Presto Blue 96-well plates was removed and replaced by 170 µL Puromycin containing medium. After 48 h medium was changed again. After additional 24 h cells were prepared for FACS analysis and PrestoBlue assay. For FACS cells were washed once with 1x PBS and trypsinized. After detachment cell were re-suspended in 1x PBS + 10% FCS, transferred into FACS tubes and spun down at 400 g, 3 min, 4°C. Cell pellets were re-suspended in 300 µL 1x PBS+ 5% FCS and stored on ice until FACS sorting. The percentages of GFP-positive cells of the different dilutions was determined by FACS sorting of GFP-positive cells (Accuri FACS, BD Biosciences). For each cell line the dilution for which 50% of the cells were GFP-positive was wanted since 50% GFP positive cell correspond to a MOI = 0.7 (Figure 37).

121 5. Materials and Methods

Figure 38: Lentiviral titer estimation assay. The % of infected cells is determined by flow cytometry by observing the % of GFP+ cells in the transduced cell sample. When the % of infected cells is at or below 20%, the # of integrations is (with good approximation) equivalent to the # of transduced cells. At higher transduction efficiencies, the fraction of transduced cells bearing multiple integrations becomes higher and higher, so that the increase in % of transduced cells relative to integration events/cell is no longer linear (User Manual Packaging and Transduction of Lentiviral Constructs, Cellecta).

For the PrestoBlue assay, plates were washed once with 1x PBS on an automated plate washer HydroSpeed device, 10x PrestoBlue stock solution was diluted to 1x with 1x PBS and 100 µL were applied manually per well of a 96-well plate with a multichannel pipet. After 1h incubation, fluorescence intensity (excitation wavelength: 560nm; emission wavelength: 590nm) was measured by the Infinite M1000pro plate Reader (TECAN). For each cell line there was one plate with cells injected with different dilutions of GFP viruses and one plate with cells injected with different dilutions of kinome viruses. Due to the FACS analysis it was known which of the GFP virus dilutions was inducing an infection efficiency of 50% corresponding to a MOI = 0.7 in which cell line. These virus dilutions corresponded to specific relative light unit (RLU) values which could be determined by PrestoBlue assay for each cell line measuring GFP plates. Since every dilution was represented by 8 replicates the mean value was calculated. The optimal individual gain which was set for measuring each GFP plate was applied to measure the corresponding kinome virus plate. The mean RLU value corresponding to a GFP virus dilution inducing an infection efficiency of 50% corresponding to a MOI = 0.7 was set as reference and applied to the kinome plate. Therefore, it could be calculated which kinome virus dilution was corresponding to an infection efficiency of 50% and therefore a MOI of 0.7.

122 5. Materials and Methods

5.6.4 Infection of cell lines

After the determination of kinome virus dilutions leading to an injection rate of 50% corresponding to a MOI=0.7, cells lines were expanded in 3-4x 15cm dishes/cell line. 5,386 x106cells per cell line were injected with the according virus dilution aiming at 1 infection per cell allowing an initial hairpin coverage of approx. 200 per hairpin. The amount of kinome virus needed for each cell line is listed in table 5.4.

Table 7: Amount of virus being used for infection of 5386000 cells of according cell line cell line to be infected amount of virus (µL) OVCAR8 600 OVCAR4 1500 OVCAR3 600 SKOV 500 TOV21G 700 COV504 1600 HOSE6_3 1500

After 30h medium was replaced by puromycin containing medium (2 μg/mL final concentration). 24h later medium was changed one more and again 24h later cell numbers of each transduced cell line were determined. 2,688 x106 cells/cell line were harvested right after selection, referred to as initial pools. Further 2,688 x106 cells/cell line, referred to as end pools, were seeded into 2x 15cm dishes and cultivated over 12 populations doublings or 32 days. Whenever a confluence of 85-95% was reached cells were split down to 2,688 x106 cells/cell line/2 dishes in order to maintain a hairpin coverage of 1000 per hairpin.

5.6.5 Isolation of genomic DNA (gDNA)

After harvesting initial and end pools of each cell line, genomic DNA was isolated. For this, cells were re-suspended cells in 1200 µL SALT-X solution (1% SDS, 200 mM NaCl, 10 mM EDTA, pH 8.0, 50 mM Tris/HCl) supplemented by 40 µL Proteinase K solution (20 mg /mL in 50 mM Tris/HCl pH 8.0, 1 mM

CaCl2). After incubation for 5-10 min at 50°C while gently shaking, 600 µL saturated NaCl was added and shaken vigorously (no vortexing). Samples were centrifuged (5-10 min, full speed, 4°) and supernatant was transferred in 15 mL falcon tube. 840 µL Isopropanol was added, mixed by inversion and incubated for 3min. Afterwards samples were centrifuge (20-30 min, full speed, RT) and supernatant was carefully removed with a pipette. Pellet was washed 1x with 70% EtOH and centrifuged (15 min, full speed, RT). Pellet was dried for approx. 10min at RT and re-suspended in 100- 300µL TE buffer (10 mM Tris-HCl, 1mM EDTA) and incubated for 30min at 65°C. gDNA concentration was determined by Nanodrop.

123 5. Materials and Methods

5.6.6 Amplification of hairpins sequences with barcode specific primers

To calculate the amount of gDNA that corresponds to the specific representation=1000 for each hairpin a specific formula developed by Strezoska was used (Strezoska, Licon et al. 2012). They defined that the mass of the human genome equals 6.58 x 10-12 g/genome. Multiplying this number with the number of assumed integrations per genome (2688 hairpins x 1000 representation) resulted in the total amount of gDNA =17.6µg per cell line sample. Since the maximal amount of gDNA as template for PCR was 250ng, 70 PCR reactions à 50µL per sample were performed in 96-well format. In total the hairpin sequences of 14 samples (7 initial and 7 end pool samples) were amplified with different forward primers containing different barcodes (Primer #37-50, supplemental table S2) and the same P5 reverse primer (primer #36, supplemental table S2).

Figure 39: Scheme of TRC-pLKO vectors of TRC 1.0/1.5 library carrying short hairpin sequences between EcoRI and AgeI restriction sites. P7 fw primer aligns with 17 nucelotides (nt) to the TCR-pLKO vector before the EcoRI restriction site.; P5 reverse primer aligns with 19 nt before AgeI restriction site. Both primers amplify sense, loop and antisense strand of short hairpins sequences plus restriction sites EcoRI and AgeI flanking regions; in total a PCR product of approx. 220bp. Overlaps of both primers are only necessary for sequencing.

After amplification of short hairpin sequences, reactions were pooled and loaded on 2% agarose gel. Per sample several pockets were necessary due to the volume of 3.5 mL per sample. After gel electrophoresis bands at approx. 220 bp were cut out and gel purified using the MinElute PCR purification kit (Quiagen) following the manufacturer`s instructions. Gel purification step was repeated due to unspecific bands in some samples at 500 bp and 100 bp. Samples with concentrations of 50 ng/µL were send to the Functional Genomics Center Zurich.

124 5. Materials and Methods

5.6.7 Illumina Sequencing

Sequencing of all 14 samples was performed at the Functional Genomics Center Zurich. In order to quantify each individual sample and normalized each sample concentration, a quantitative PCR was performed using the Quantification of Gene Expression using SYBR Green in the Eco™Real-Time PCR System protocol (Illumina). Equimolar samples of 8pM each were pooled and loaded on a single lane for sequencing. Samples could be distinguished due to their specific barcodes. For sequencing a TruSeq SR Cluster Kit v4-cBot-HS (Illumina, Inc, California, USA) was used which provides reagents that bind samples to complementary adapter oligos for cluster amplification on single-read flow cells. Illumina HiSeq 2500 provided single end sequencing of 126 bp. 2 Hiseq runs were performed.

5.6.8 Bioinformatic analysis

Bioinformatic analysis was performed by Lennart Opitz and Dr. Weihong Qui, Functional Genomics Center Zurich. All files can be accessed via http://fgcz-gstore.uzh.ch/projects/p1707/ (username and password will be provided upon request). After sequencing samples were demultiplexed due to their specific barcodes and a quality analysis was performed using FASTQC (Babraham Bioinformatics), which included per base sequence quality, per tile sequence quality, per sequences quality scores, per base sequence content, per base N content, sequences length distribution, sequence duplication levels, overrepresented sequences, adapter content, Kmer content. For detailed explanation of features of quality analysis see user manual (http://www.bioinformatics.babraham.ac.uk/projects/fastqc/Help/3%20Analysis%20Modules/). After quality control analysis, raw sequencing reads were trimmed and the first 26 bases of each hairpin (sense strand) in raw reads were identified and aligned to the reference hairpin sequences (list see table xy) using bowtie (Langmead, Trapnell et al. 2009). Files can be found in following folders: - Count_20150815/ (first Hiseq run) - Count_20150821/ (second Hiseq run) Maximal two mismatches were tolerated per alignment. After counting of the best alignments count normalization and differential representation analyses were performed using R bioconductor package edgeR (Robinson, McCarthy et al. 2010, Dai, Sheridan et al. 2014). Files can be found in following folders: - Differential_Expression_EdgeR_7293_2015-08-20--09-36-26/ (OVCAR8; first Hiseq run) - Differential_Expression_EdgeR_7293_2015-08-20--09-39-08/ (OVCAR4; first Hiseq run) - Differential_Expression_EdgeR_7293_2015-08-20--09-39-55/ (OVCAR3; first Hiseq run) - Differential_Expression_EdgeR_7293_2015-08-20--09-40-26/ (SKOV; first Hiseq run) - Differential_Expression_EdgeR_7293_2015-08-20--09-40-57/ (TOV21G; first Hiseq run)

125 5. Materials and Methods

- Differential_Expression_EdgeR_7293_2015-08-20--09-41-28/ (HOSE6-3; first Hiseq run) - Differential_Expression_EdgeR_7293_2015-08-22--10-09-11/ (OVCAR8; second Hiseq run) - Differential_Expression_EdgeR_7293_2015-08-22--10-09-45/ (OVCAR4; second Hiseq run) - Differential_Expression_EdgeR_7293_2015-08-22--10-10-26/ (OVCAR3; second Hiseq run) - Differential_Expression_EdgeR_7293_2015-08-22--10-08-38/ (SKOV; second Hiseq run) - Differential_Expression_EdgeR_7293_2015-08-22--10-08-05/ (TOV21G; second Hiseq run) - Differential_Expression_EdgeR_7293_2015-08-22--10-10-51/ (HOSE6_3; second Hiseq run) Furthermore, the results of 2 HiSeq runs were combined. - HiSeq_combined/ In order to create top hit lists of genes which are essential for 19q12 amplified ovarian cancer cells, 2 analysis approaches with the aligned read counts for each cell line were continued. In the first analysis approach the first step was to identify all hairpins that are depleted in the non- amplified cell lines (COV504, SKOV3, TOV21G, HOSE). Criteria for depletion was that the read count numbers of the initial pools had to be lower than the read count number of the initial pools. Furthermore, only genes with a read count number of >50 were considered and the depletion rate between initial and end pool had to be minimum -10% for all hairpins of on gene. As second step all genes being depleted in 19q12 amplified cells (OVCAR8, OVCAR3, OVCAR4) were identified, cut-off= 0 reads in initial pools. As third step all essential genes from the final list which are depleted in both the amplified and the non-amplified cell lines were removed, ending up with a list of genes being exclusively depleted in the amplified cell lines but not in the non-amplified cell lines, consisting of 58 genes which were depleted in 19q12 amplified cell, but not in non-amplified cells. However, reads until 50 have not been considered. As fourth step the average of the different hairpin leading to depletion in the amplified cell lines were calculated creating a top hit list of genes with a negative depletion rate, consisting of 18 genes. These 18 were further evaluated by number of reads, number of valid hairpins (remove false reads), and a consistent depletion pattern in OVCAR3, OVCAR4, and OVCAR8 8. Genes for which a consistent depletion pattern within all hairpins in all 19q12 amplified cell lines, however a consistent enrichment pattern for all 19q12 non-amplified cell lines were considered as top 5 hits including Unc-51 like kinase 3 (ULK3), CSNK1ε (Casein Kinase ε), ACVRL1 (Activin A Receptor Like Type 1), Cyclin dependent kinase 2 (CDK2), Breakpoint cluster region (BCR). A less biased method for the identification of genes essential for 19q12 amplified cells was applied using Analytic Technique for Assessment of RNAi by Similarity (ATARiS) performed by Dr. Weihong Qui (Shao, Tsherniak et al. 2013). In order to create a top hit list of 19q12 essential genes, only genes for which “gene solutions” could be found were considered by identifying significantly similar phenotypic patterns across all screened hairpins targeting one gene. 3 distinct phenotypic patters could be distinguished in this screen.

126 5. Materials and Methods

4. depletion  normalized read count numbers initial pool > end pool (negative log2 ratio) 5. enrichment  normalized read count numbers initial pool

5.6.9 Hit validation

The first top hits of both analyses (ULK3, INSR, CSNK1E, CDK13) identified as being essential for 19q12 amplified ovarian cancer cells were considered for a follow up hit validation. For this aim, two cell viability assays, the Colony Formation Assay (CFA) and the Annexin V assay were performed in parallel. The first step was to purify plasmids of all 5 hairpin constructs per gene separately using NucleoSpin Plasmid Midi Kit (Macherey Nagel). Furthermore, for each construct lentiviruses were produced separately and transformation with subsequent puromycin selection of respective cell lines listed in table 3 was performed as described in part 5.2.1 and 5.2.2.

5.6.9.1 Cell viability assays

Cells for the CFA and Annexin V assay were seeded in parallel from the same transformation with cell numbers listed in table 3 and the cell line specific medium containing puromycin (2 mg/mL). Cells for CFA were seeded in triplicated in 6-well plates, cells for the Annexin V assay cells were seeded in triplicates in 12-well plates. Table 8: cell numbers seeded for cell viability assays (CFA and Annexin V) for hit validation Cell line cell number CFA cell number Annexin V

OVCAR8 5000 10000 OVCAR3 8000 15000 OVCAR4 8000 15000 SKOV 5000 10000 TYKNU 10000 10000 CAOV 12000 20000 IGROV 15000 - TOV21G 8000 - COV504 15000 -

5.6.9.1.1 Colony Formation Assay

After cells were seeded for CFA, culture medium was replaced by new medium containing puromycin (2mg/mL) every third day. 14 days after the establishment of the respective k.d. and 10 days after

127 5. Materials and Methods seeding, CFA plates were analyzed. After medium removal und 1 washing step with 1x PBS, cells were stained and fixed with crystal violet solution (0.5% crystal violet, 70% Methanol). After an incubation time of 20min by dunking the plates into H2O filled 5L beakers. After drying, plates were scanned and colonies were quantified as relative surface coverage referring to relative number of colonies using Image J. For this Tiff files were converted into gray scale (Image type 8bit). Threshold was set to separate background from signal (image  adjust  threshold). Each well was selected by a circle and relative number of colonies were analyzed by setting measurement. Mean values of triplicates were calculated and k.d. samples were normalized CTRL samples.

5.6.9.1.2 Annexin V Assay

Supernatant of each well of cells in 12-well plates was collected in separate FACS tubes, being stored on ice. Supernatant from washing step with 1xPBS was also collected in the corresponding tubes. Cells were trypsinzed with 1x trypsin and after 5-15 min depending on the respective cell line, detached cells were re-suspended 0.5mL in culture medium also collected in the corresponding tubes. Samples were centrifuged at 400 g for 3 min, at 4°C (Heraeus Megafuge 40R centrifuge, Thermo Scientific). Supernatant was carefully sucked up and cells were re-suspended in Annexin V binding buffer (140 mM NaCl, 2.5 mM CaCl2, 10 mM HEPES pH 7.4, stored at 4°C). Samples were centrifuged again at 400 g for 3 min, at 4°C, supernatant removed and re-suspended in 300 µL Annexin V binding buffer with 1µL (1:300 ratio) Annexin V – FITC conjugate (Life Technologies) per sample. Samples were stored in the dark for 20 min and placed back in ice until being FACS sorted. The samples were measured on a

Accuri C6 Flow Cytometer (BD Biosciences) by the BD CSampler Software counting 3´000 events per sample. Color compensation was performed using Annexin V single stained samples. Percentage of Annexin V positive cells was assessed by measuring FITC-Annexin V (logarithmic scale, horizontal axis) with detector FL1 (detects λemission = 533/30). For the time course experiment this procedure was repeated every 24 hours starting from day 5 after the establishment of the respective k.d. until day 8 and once again on day 11. For the data analysis percentage of viable cells (Annexin V negative) of knockdown samples was normalized to CTRL samples of the same day.

Left over cells from the same transformation used for seeding of CFA and Annexin V samples were used for determination of the k.d. efficiency of the respective gene. For this left over cells were centrifuged at 800g for 5min, RT and washed once with 1xPBS. RNA extraction and determination of relative mRNA expression levels was performed as described in 5.4.1

128 5. Materials and Methods

5.6.9.1.3 PrestoBlue assay

The PrestoBlue cell viability assay was performed as part of the MOI determination of cell lines being infected with the kinome viruses (see 5.2.3) as well as for inhibitor experiments with small molecule inhibitors against CK1ε. For the inhibitor experiments 3000 cells/well of a 96-well plate were seeded per cell line of the cell lines OVCAR8 and SKOV; 4000 cells/well of a 96-well plate were seeded per cell line of the cell lines OVCAR4, OVCAR3, TYKNU, CAOV. For each inhibitor cells were seeded in 6 rows of 4 different plates per cell line due to 4 different time points to be measures (24h, 48h, 72h, 96h). IC261 was diluted in DMSO in series of 1nM, 10nM, 100nM, 1µM, 10µM, 50µM; PF4800567 was diluted in DMSO in series of 1nM, 10nM, 100nM, 1µM, 10µM, 100µM. Each dilution was applied to 8 replicates of one row on 4 separate plates. After 24h, 48h, 72h, 96h cells were washed 3x with 1xPBS on the automated plate washer HydroSpeed (Tecan). 100 µL of 1x PrestoBlue solution diluted in 1x PBS was applied manually per well of a 96-well plate with a multichannel pipet. The reagent was incubated with the cells for 1h in the dark at RT. Fluorescence intensity was measured (excitation wavelength: 560nm, emission wavelength: 590nm) with an Infinite M1000pro plate reader (Tecan) setting an optimal gain for each plate. Mean of Relative light units (RLU) of 8 replicates per dilution was calculated and normalized to mean of DMSO CTRL.

5.7 Mouse xenografts models

5.7.1 Husbandry of BALB/cAnNRj-Foxn1nu/nu

6-week-old female BALB/cAnNRj-Foxn1nu/nu mice (Janvier) were directly delivered to the maintenance facility EPIC and were allowed to acclimatize to the new surrounding for 14 days prior to the experiment start. Standard mouse ear punch were used for animal identification in order to differentiate between different groups and individual animals within groups (Carpenter 2005, Fish, Brown et al. 2008).

5.7.2 Establishment of human tumor xenografts in BALB/cAnNRj-Foxn1nu/nu mice

Cell lines OVCAR8, OVCAR3, SKOV, TYKNU were send to be tested for h-IMPACT Profile II (Idexx). The test includes PCR evaluation for Hepatitis A, Hepatitis B, Hepatitis C, HIV1, HIV2, HTLV 1, HTLV 2, Mycoplasma species and Treponema pallidum. Test results for all cell lines were negative. The establishment of human tumor xenografts derived from human ovarian cancer cell lines was performed according to (Morton and Houghton 2007) with adaptions as follows. OVCAR8, OVCAR3,

129 5. Materials and Methods

SKOV and TYKNU carrying constructs of either tet-shCTRL or tet-shCDK13 were expanded to 5x 15cm dishes for each cell line and construct. Harvest of cell took place during exponential growth phase (confluence of >90%). After trypsination cells were re-suspended in RMPI +10%FCS and cell number was determined by Coulter Counter. For each cell line and construct a total number of 2x107 was prepared, for the pilot experiment 3x107 cells were prepared. Cells were centrifuged at 225 g and 20°C for 5min and supernatant medium was discarded. Cells were re-suspended in 2mL (pilot experiment) or 3mL (main experiment) ice cold 1xPBS and counted again in order to proof the cell number of 1x 10^6/100 µL and then stored on ice until injection. Before injection of BALB/cAnNRj-Foxn1nu/nu mice cell suspension was agitated in order to prevent cells from settling down and then withdrawn from the sterile tube into a syringe with the needle (26G) removed. Mouse was anesthetized with isoflourane and kept under anesthesia during injection. Skin on right flank was lifted in order to separate it from the underlying muscle and 100 µL tet-shCDK13 cell suspension was injected with a 26G needle. Left flank was injected with 100 µL tet-shCTRL cell suspension afterwards. After injection mice were directly put back into their cages and checked for alertness.

5.7.3 Animal monitoring/ Tumor measurement

Mice were monitored every other day according to different measures including body weight, body and coat condition, posture, activity and alertness and tumor sizes were measured twice per week by a caliper. For calculating the tumor volumes following formula was used: V= (LxWxH)/2 (V= tumor volume, W= tumor width, L = tumor length, H = tumor high (Monga, Wadleigh et al. 2000). As soon as the tumors had reached a size of 100mm3 mice were allocated into two groups of 5 mice each (pilot experiment) or 10 mice (main experiment). One group received chow (#3432 Provimi Kliba) containing 200mg/kg doxycycline (Sigma-Aldrich) and the other group control chow (#3432 Provimi Kliba without Doxycycline). Before the feed change to Doxycycline or control feed mice received standard chow (#3432 Provimi Kliba). In the pilot experiment mice were euthanized 69 days after the injection of cells and 1 day prior to the maximal duration of the xenograft experiment according to the license ZH127/16. Euthanasia was performed by gradually introducing compressed CO2 in a specific CO2 chamber until mouse was fallen asleep and not breathing anymore. In the main experiment TKYNU mice were euthanized 62 days after the injection of cells and OVCAR8, 47 days after the injection and 30 days after the start of doxycycline feed for both cell lines. Mice showing any signs of pain or after a decrease of <15% of their body weight were euthanized earlier.

130 5. Materials and Methods

5.7.4 Test of CDK13 knockdown efficiency in tumor samples

After euthanasia, pictures of mice were taken from the whole body, long axis of the back, tumors dissected afterwards and tumor weight was determined. Tumor pieces of approx. 20-100 mm3 depending on the tumor size were taken for RNA and protein extraction and snap frozen in liquid nitrogen before being stored at -80°C. Furthermore, tissue samples for histology were taken and stored in vials containing 4% PFA. For RNA extraction tubes with 350ul RA I buffer of (Nucleospin RNA kit, Machery nagel) and 7µL 0.5 M TCEP (sigma) were provided and frozen tissue pieces were added together with one magnetic bead per tube. Tissue was disrupted by using the Tissue Lyser II (Retsch/Quiagen) for 2 min at a frequency of 30 1/s. RNA extraction of lysed tissue was performed according to the Nucleospin RNA kit and cDNA transcription and qPCR was performed as described in 5.2.1.2 For protein extraction tissue samples were disrupted as mentioned above, however with 200-1000 µL TNN buffer instead of RA1 depending on size of tissue piece.

131 References

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Supplementary figures

Supplementary Figure 1: Mouse Xenograft Main experiment TYKNU mice of CTRL feed group. A. Corresponding representative set of pictures of all 10 CTRL feed mice. B. Absolute final tumor weight of individual CTRL feed mice. C. Mean of absolute final tumor weight of CTRL feed mice. n=8 mice. Error bars indicate ±SEM. D. Final relative tumor weight of individual CTRL feed mice normalized to shCTRL tumors =1. E. Mean of relative final tumor weight of CTRL feed mice. n=8 mice. Error bars indicate ±SEM.

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Supplementary Figure 2: Mouse Xenograft Main experiment TYKNU mice of Doxycycline feed group. A. Corresponding representative set of pictures of all 10 Doxycycline feed mice. B. Absolute final tumor weight of individual Doxycycline feed mice. C. Mean of absolute final tumor weight of Doxycycline feed mice. n=8 mice. Error bars indicate ±SEM. D. Final relative tumor weight of individual Doxycycline feed mice normalized to shCTRL tumors =1. E. Mean of relative final tumor weight of Doxycycline feed mice. n=8 mice. Error bars indicate ±SEM.

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Supplementary Figure 3: Mouse Xenograft Main experiment OVCAR8 mice of CTRL feed group. A. Corresponding representative set of pictures of all 10 CTRL feed mice. B. Absolute final tumor weight of individual CTRL feed mice. C. Mean of absolute final tumor weight of CTRL feed mice. n=8 mice. Error bars indicate ±SEM. D. Final relative tumor weight of individual CTRL feed mice normalized to shCTRL tumors =1. E. Mean of relative final tumor weight of CTRL feed mice. n=8 mice. Error bars indicate ±SEM.

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Supplementary Figure 4: Mouse Xenograft Main experiment OVCAR8 mice of Doxycycline feed group. A. Corresponding representative set of pictures of all 10 Doxycycline feed mice. B. Absolute final tumor weight of individual Doxycycline feed mice. C. Mean of absolute final tumor weight of Doxycycline feed mice. n=8 mice. Error bars indicate ±SEM. D. Final relative tumor weight of individual Doxycycline feed mice normalized to shCTRL tumors =1. E. Mean of relative final tumor weight of Doxycycline feed mice. n=8 mice. Error bars indicate ±SEM.

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Supplemental Tables

Table S1: List of primers Primer Primer name Application Sequence (5`-3`) number 1 18s fw qPCR housekeeping gene GTT CCG ACC ATA AAC GAT GCC 2 18s rev qPCR housekeeping gene TGG TGG TGC CCT TCC GTC AAT 3 HPRT_fw qPCR housekeeping gene CCT GGC GTC GTG ATT AGT GAT 4 HPRT_rev qPCR housekeeping gene AGA CGT TCA GTC CTG TCC ATA A 5 TBP_fw qPCR housekeeping gene TGG ACT GTT CTT CAC TCT TGG C 6 TBP_rev qPCR housekeeping gene TTC GGA GAG TTC TGG GAT TGT 7 CCNE1_fw qPCR AAG GAG CGG GAC ACC ATG A 8 CCNE1_rev qPCR ACG GTC ACG TTT GCC TTC C 9 URI1_fw qPCR GTG GTC ACT AAC TGC CAA GAG 10 URI1_rev qPCR TGA GTC TTT CTC GAA GGG CAT TA 11 CDK13_fw qPCR AAG CCC GTA TTC ATC TAG GCA 12 CDK13_rev qPCR CAG CAG CCT TAG TTG CTT CTG 13 CSNK1E_fw qPCR CGT GTG GGG AAC AAG TAC CG 14 CSNK1E_rev qPCR GAT GTT GGC ACC CAG GTA GAT 15 ULK3_fw qPCR TCG ACA TCC CCA CAT TGT GC 16 ULK3_rev qPCR GGC AGA ATC CTG CGG GTA TG 17 INSR_fw qPCR CGG CCT CTA CAA CCT GAT GAA 18 INSR_rev qPCR TAC GGG ACC AGT CGA TAG TGG 19 CDK13overexp_fw2 cloning CDK13 OE construct GCC GAC CGG TAC GAT GCC GAG CAG CTC GGA CAC G 20 CDK13overexp_rev2 cloning CDK13 OE construct GCG CGA ATT CTC AGT ATG GTA ACC CTC TGC CTC TGC CT 21 CDK13_HA_Nter_fw cloning CDK13 OE construct GCC GAC CGG TAC GAT GTA CCC ATA CGA TGT TCC AGA TTA CGC TCT GCC TGA AGA TAA AGA A 22 CDK13 mut P6_3_fw cloning CDK13 rescue construct GAA ACT CCG TTG TCT ACT AGC TGA TTT AC 23 CDK13 mut P6_3_rev cloning CDK13 rescue construct GTA AAT CAG CTA GTA GAC AAC GGA GTT TC 24 CDK13 mut P10_1_fw cloning CDK13 rescue construct GAA ACT CCG ATG CCT TCT AGC AGA TTT AC 25 CDK13 mut P10_1_rev cloning CDK13 rescue construct GTA AAT CTG CTA GAA GGC ATC GGA GTT TC 26 H1 TET-pLKO sequencing primer TCG CTA TGT GTT CTG GGA AA 27 LKO1.5 TRC-pLKO sequencing primer GAC TAT CAT ATG CTT ACC GT 28 LNCX TRIPZ sequencing primer AGC TCG TTT AGT GAA CCG TCA GAT C 29 pDONR223 pDONR223 sequencing primer TTT TCC CAG TCA CGA CGT TGT AAA ACG ACG GCC AGT 30 tet-shCDK13 B10 cloning tet-inducible CDK13 k.d AAT TAA AAA CGA CGT AGT TTC ATT GGA AAT CTC GAG ATT TCC AAT GAA ACT bottom ACG TCG 31 tet-shCDK13 B10 top cloning tet-inducible CDK13 k.d CCG GCG ACG TAG TTT CAT TGG AAA TCT CGA GAT TTC CAA TGA AAC TAC GTC GTT TTT 32 tet-shCDK13 B8 cloning tet-inducible CDK13 k.d AAT TAA AAA CGA TGT CTT CTT GCT GAT TTA CTC GAG TAA ATC AGC AAG AAG bottom ACA TCG 33 tet-shCDK13 B8 top cloning tet-inducible CDK13 k.d CCG GCG ATG TCT TCT TGC TGA TTT ACT CGA GTA AAT CAG CAA GAA GAC ATC GTT TTT 34 tet-shCDK13 B9 cloning tet-inducible CDK13 k.d AAT TAA AAA GCT GAT AGC TTA CGA GGA AAT CTC GAG ATT TCC TCG TAA bottom GCT ATC AGC 35 tet-shCDK13 B9 top cloning tet-inducible CDK13 k.d CCG GGC TGA TAG CTT ACG AGG AAA TCT CGA GAT TTC CTC GTA AGC TAT CAG CTT TTT 36 P5 primer fw primer for Illumina sequencing AATGATACGGCGACCACCGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCT ATCTTGTGGAAAGGACGA 37 P7-barcode-1 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT ATC ACG GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 38 P7-barcode-2 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT CGA TGT GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 39 P7-barcode-3 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT TTA GGC GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 40 P7-barcode-4 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT TGA CCA GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 41 P7-barcode-5 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT ACA GTG GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 42 P7-barcode-6 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT GCC AAT GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 43 P7-barcode-7 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT CAG ATC GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 44 P7-barcode-8 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT ACT TGA GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 45 P7-barcode-9 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT GAT CAG GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 46 P7-barcode-10 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT TAG CTT GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 47 P7-barcode-11 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT GGC TAC GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 48 P7-barcode-12 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT CTT GTA GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 49 P7-barcode-13 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT AGT CAA GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT 50 P7-barcode-14 barcode containing rev primer Illumina sequencing CAA GCA GAA GAC GGC ATA CGA GAT AGT TCC GTG ACT GGA GTT CAG ACG TGT GCT CTT CCG ATC TAT TCT TTC CCC TGC ACT

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Table S2 : List of short hairpin RNAs used in shRNA screen and hit validation Gene Gene full name TRC ID shRNA sequence

AAK1 AP2 associated kinase 1 TRCN0000001943 CCGGCCAGGTGTGCAAGAGAGAAATCTCGAGATTTCTCTCTTGCACACCTGGTTTTT AAK1 AP2 associated kinase 1 TRCN0000001945 CCGGGCCACCAACAAATTCCAGAATCTCGAGATTCTGGAATTTGTTGGTGGCTTTTT AAK1 AP2 associated kinase 1 TRCN0000001946 CCGGCCCAGTAAGACAACAGCCAAACTCGAGTTTGGCTGTTGTCTTACTGGGTTTTT AAK1 AP2 associated kinase 1 TRCN0000194857 CCGGCTCACTTGTATCACTCCAAATCTCGAGATTTGGAGTGATACAAGTGAGTTTTTTG AAK1 AP2 associated kinase 1 TRCN0000001942 CCGGCCAGGCTTTCAATCAACCCAACTCGAGTTGGGTTGATTGAAAGCCTGGTTTTT AATK apoptosis-associated tyrosine kinase TRCN0000021437 CCGGTGGCTATGACACCGAGAACTACTCGAGTAGTTCTCGGTGTCATAGCCATTTTT AATK apoptosis-associated tyrosine kinase TRCN0000021435 CCGGCTGCACCTTCATCGCAACAATCTCGAGATTGTTGCGATGAAGGTGCAGTTTTT AATK apoptosis-associated tyrosine kinase TRCN0000021436 CCGGAGTGGCCTCAACGAGAAGAATCTCGAGATTCTTCTCGTTGAGGCCACTTTTTT AATK apoptosis-associated tyrosine kinase TRCN0000021438 CCGGCAACGTGTCAGCCAACAACAACTCGAGTTGTTGTTGGCTGACACGTTGTTTTT ABL1 c-abl oncogene 1, receptor tyrosine kinase TRCN0000001499 CCGGCCAGCTCTACTACCTACGTTTCTCGAGAAACGTAGGTAGTAGAGCTGGTTTTT ABL1 c-abl oncogene 1, receptor tyrosine kinase TRCN0000001500 CCGGGAAAGAGATCAAACACCCTAACTCGAGTTAGGGTGTTTGATCTCTTTCTTTTT ABL1 c-abl oncogene 1, receptor tyrosine kinase TRCN0000001501 CCGGCCCGTTCTATATCATCACTGACTCGAGTCAGTGATGATATAGAACGGGTTTTT ABL1 c-abl oncogene 1, receptor tyrosine kinase TRCN0000001502 CCGGCCTTCATCCCTCTCATATCAACTCGAGTTGATATGAGAGGGATGAAGGTTTTT ABL1 c-abl oncogene 1, receptor tyrosine kinase TRCN0000010626 CCGGCCGAGTTGGTTCATCATCATTCTCGAGAATGATGATGAACCAACTCGGTTTTT v-abl Abelson murine leukemia viral oncogene ABL2 TRCN0000002031 CCGGGCGAACAGATATTACCATGAACTCGAGTTCATGGTAATATCTGTTCGCTTTTT homolog 2 (arg, Abelson-related gene) v-abl Abelson murine leukemia viral oncogene ABL2 TRCN0000002032 CCGGCGGTCAGTATGGAGAGGTTTACTCGAGTAAACCTCTCCATACTGACCGTTTTT homolog 2 (arg, Abelson-related gene) v-abl Abelson murine leukemia viral oncogene ABL2 TRCN0000002033 CCGGCCCTCAAACTCGCAACAAATTCTCGAGAATTTGTTGCGAGTTTGAGGGTTTTT homolog 2 (arg, Abelson-related gene) v-abl Abelson murine leukemia viral oncogene ABL2 TRCN0000199548 CCGGCCACTGAGAGTGACCCTAATCCTCGAGGATTAGGGTCACTCTCAGTGGTTTTTTG homolog 2 (arg, Abelson-related gene) v-abl Abelson murine leukemia viral oncogene ABL2 TRCN0000199920 CCGGGATGGGCTGGTGACAACATTACTCGAGTAATGTTGTCACCAGCCCATCTTTTTTG homolog 2 (arg, Abelson-related gene) ACVR1 activin A receptor, type I TRCN0000000442 CCGGCGGATGGTGAGCAATGGTATACTCGAGTATACCATTGCTCACCATCCGTTTTT ACVR1 activin A receptor, type I TRCN0000000443 CCGGGACAGCACTTTAGCAGATTTACTCGAGTAAATCTGCTAAAGTGCTGTCTTTTT ACVR1 activin A receptor, type I TRCN0000000445 CCGGGTGGATTGTTTCGATTCTTATCTCGAGATAAGAATCGAAACAATCCACTTTTT ACVR1 activin A receptor, type I TRCN0000194668 CCGGCTTGCACTGTTACTCTTAATTCTCGAGAATTAAGAGTAACAGTGCAAGTTTTTTG ACVR1 activin A receptor, type I TRCN0000195081 CCGGCTGGTCTGTCTTTGGATAATACTCGAGTATTATCCAAAGACAGACCAGTTTTTTG ACVR1B activin A receptor, type IB TRCN0000001810 CCGGCCACTGCTGCTACACTGACTACTCGAGTAGTCAGTGTAGCAGCAGTGGTTTTT ACVR1B activin A receptor, type IB TRCN0000010151 CCGGGGGAAGCAGAGATATACCAGACTCGAGTCTGGTATATCTCTGCTTCCCTTTTT ACVR1B activin A receptor, type IB TRCN0000010160 CCGGCCACTGCTGCTACACTGACTACTCGAGTAGTCAGTGTAGCAGCAGTGGTTTTT ACVR1B activin A receptor, type IB TRCN0000196244 CCGGGCTGCCATATTACGACTTAGTCTCGAGACTAAGTCGTAATATGGCAGCTTTTTTG ACVR1B activin A receptor, type IB TRCN0000196765 CCGGGAATTGCTCATCGAGACTTAACTCGAGTTAAGTCTCGATGAGCAATTCTTTTTTG ACVR1C activin A receptor, type IC TRCN0000001826 CCGGCGGAGGAATTGTTGAGGAGTACTCGAGTACTCCTCAACAATTCCTCCGTTTTT ACVR1C activin A receptor, type IC TRCN0000001827 CCGGGCTCCTGAAATGCTTGATGATCTCGAGATCATCAAGCATTTCAGGAGCTTTTT ACVR1C activin A receptor, type IC TRCN0000196393 CCGGGACTGAAGTGTGTATGTCTTTCTCGAGAAAGACATACACACTTCAGTCTTTTTTG ACVR1C activin A receptor, type IC TRCN0000196633 CCGGGAAGACTATATCTCAACTTTGCTCGAGCAAAGTTGAGATATAGTCTTCTTTTTTG ACVR2A activin A receptor, type IIA TRCN0000000556 CCGGCAGGAAGTTGTTGTGCATAAACTCGAGTTTATGCACAACAACTTCCTGTTTTT ACVR2A activin A receptor, type IIA TRCN0000000552 CCGGCCTTAAATGAACTACTGCTATCTCGAGATAGCAGTAGTTCATTTAAGGTTTTT ACVR2A activin A receptor, type IIA TRCN0000000554 CCGGGCTAATGTGGTCTCTTGGAATCTCGAGATTCCAAGAGACCACATTAGCTTTTT ACVR2A activin A receptor, type II TRCN0000194990 CCGGCGTGTTATGGTGACAAAGATACTCGAGTATCTTTGTCACCATAACACGTTTTTTG ACVR2A activin A receptor, type II TRCN0000194991 CCGGCCTTCTCCATTACTAGGTTTGCTCGAGCAAACCTAGTAATGGAGAAGGTTTTTTG ACVR2B activin A receptor, type IIB TRCN0000000447 CCGGCTTTGGCTTGGCTGTTCGATTCTCGAGAATCGAACAGCCAAGCCAAAGTTTTT ACVR2B activin A receptor, type IIB TRCN0000000448 CCGGCTGCTGGCTAGATGACTTCAACTCGAGTTGAAGTCATCTAGCCAGCAGTTTTT ACVR2B activin A receptor, type IIB TRCN0000000450 CCGGGAGGCCCACCATTAAAGATCACTCGAGTGATCTTTAATGGTGGGCCTCTTTTT ACVR2B activin A receptor, type IIB TRCN0000195571 CCGGCCCAGCTCATGAATGACTTTGCTCGAGCAAAGTCATTCATGAGCTGGGTTTTTTG ACVR2B activin A receptor, type IIB TRCN0000195669 CCGGCATCATCACATGGAACGAACTCTCGAGAGTTCGTTCCATGTGATGATGTTTTTTG ACVRL1 activin A receptor type II-like 1 TRCN0000000354 CCGGCTGCGGATCAAGAAGACACTACTCGAGTAGTGTCTTCTTGATCCGCAGTTTTT ACVRL1 activin A receptor type II-like 1 TRCN0000000355 CCGGTCCAGAGAAGCCTAAAGTGATCTCGAGATCACTTTAGGCTTCTCTGGATTTTT ACVRL1 activin A receptor type II-like 1 TRCN0000000356 CCGGCAGTCCAGAGAAGCCTAAAGTCTCGAGACTTTAGGCTTCTCTGGACTGTTTTT ACVRL1 activin A receptor type II-like 1 TRCN0000195497 CCGGCCGGGAGACTGAGATCTATAACTCGAGTTATAGATCTCAGTCTCCCGGTTTTTTG ACVRL1 activin A receptor type II-like 1 TRCN0000199138 CCGGCAGGAGCACCTGATTCCTTTCCTCGAGGAAAGGAATCAGGTGCTCCTGTTTTTTG ADCK1 aarF domain containing kinase 1 TRCN0000021499 CCGGCCATTCCTGGTATGTGCCATTCTCGAGAATGGCACATACCAGGAATGGTTTTT ADCK1 aarF domain containing kinase 1 TRCN0000021501 CCGGCGGAAGAATTCCGCCTGAATTCTCGAGAATTCAGGCGGAATTCTTCCGTTTTT ADCK1 aarF domain containing kinase 1 TRCN0000021502 CCGGCTTCAACTTATGGCAGATCAACTCGAGTTGATCTGCCATAAGTTGAAGTTTTT ADCK1 aarF domain containing kinase 1 TRCN0000021503 CCGGGAAGAAGAATACCTGTTCATTCTCGAGAATGAACAGGTATTCTTCTTCTTTTT ADCK1 aarF domain containing kinase 1 TRCN0000195590 CCGGCCACTGAGGACTTAGAGATTCCTCGAGGAATCTCTAAGTCCTCAGTGGTTTTTTG ADCK2 aarF domain containing kinase 2 TRCN0000021396 CCGGCGCTCTGTTGGTGAAATTCTTCTCGAGAAGAATTTCACCAACAGAGCGTTTTT ADCK2 aarF domain containing kinase 2 TRCN0000021397 CCGGGCTGAGCTGATCCTGCATCATCTCGAGATGATGCAGGATCAGCTCAGCTTTTT ADCK2 aarF domain containing kinase 2 TRCN0000021394 CCGGTGCTTGGTTTGAGGGTCTGTTCTCGAGAACAGACCCTCAAACCAAGCATTTTT

156 Supplement

ADCK2 aarF domain containing kinase 2 TRCN0000021398 CCGGGCTGACCTGGTTGGATCAAATCTCGAGATTTGATCCAACCAGGTCAGCTTTTT ADCK2 aarF domain containing kinase 2 TRCN0000196835 CCGGGCCTTCTCTCTAGTGTCTTTACTCGAGTAAAGACACTAGAGAGAAGGCTTTTTTG chaperone, ABC1 activity of bc1 complex homolog (S. ADCK3 TRCN0000021504 CCGGCCACGGTTTCTGTTGCTAAATCTCGAGATTTAGCAACAGAAACCGTGGTTTTT pombe) chaperone, ABC1 activity of bc1 complex homolog (S. ADCK3 TRCN0000021508 CCGGCCCGAGAACAAGCAGCACAAACTCGAGTTTGTGCTGCTTGTTCTCGGGTTTTT pombe) chaperone, ABC1 activity of bc1 complex homolog (S. ADCK3 TRCN0000021505 CCGGGCGGGACAAGTTGGAATACTTCTCGAGAAGTATTCCAACTTGTCCCGCTTTTT pombe) chaperone, ABC1 activity of bc1 complex homolog (S. ADCK3 TRCN0000021507 CCGGGCATCCAGGATGATGCCTTTACTCGAGTAAAGGCATCATCCTGGATGCTTTTT pombe) ADCK3 aarF domain containing kinase 3 TRCN0000195738 CCGGCGAAATCCATAGAGATGAAGTCTCGAGACTTCATCTCTATGGATTTCGTTTTTTG ADCK4 aarF domain containing kinase 4 TRCN0000007330 CCGGCGTTATGCAGATCAGACTCATCTCGAGATGAGTCTGATCTGCATAACGTTTTT ADCK4 aarF domain containing kinase 4 TRCN0000007332 CCGGTGGGCCAACTTCCTGTATGATCTCGAGATCATACAGGAAGTTGGCCCATTTTT ADCK4 aarF domain containing kinase 4 TRCN0000007333 CCGGGAGCGGATTGTGCAGACCTTACTCGAGTAAGGTCTGCACAATCCGCTCTTTTT ADCK4 aarF domain containing kinase 4 TRCN0000007334 CCGGCAGGCTTTGAAACCAAGGCATCTCGAGATGCCTTGGTTTCAAAGCCTGTTTTT ADCK4 aarF domain containing kinase 4 TRCN0000197003 CCGGGCAGATGCTGAGAGTTCTTGACTCGAGTCAAGAACTCTCAGCATCTGCTTTTTTG ADCK5 aarF domain containing kinase 5 TRCN0000199091 CCGGCTACTGGTGGTGCACCAATGTCTCGAGACATTGGTGCACCACCAGTAGTTTTTTG ADCK5 aarF domain containing kinase 5 TRCN0000021479 CCGGCGGCGGGGCCCTTTTCACCTTCTCGAGAAGGTGAAAAGGGCCCCGCCGTTTTT ADCK5 aarF domain containing kinase 5 TRCN0000021480 CCGGGCAGTGCATGACATAGCAGAACTCGAGTTCTGCTATGTCATGCACTGCTTTTT ADCK5 aarF domain containing kinase 5 TRCN0000021482 CCGGGCCTTTGCTGAGCAGATATTTCTCGAGAAATATCTGCTCAGCAAAGGCTTTTT ADCK5 aarF domain containing kinase 5 TRCN0000197074 CCGGGTTCTTCAGGAGAAACGTCAGCTCGAGCTGACGTTTCTCCTGAAGAACTTTTTTG ADRBK1 adrenergic, beta, receptor kinase 1 TRCN0000000557 CCGGATTATTGTGATTTCCCGTGGCCTCGAGGCCACGGGAAATCACAATAATTTTTT ADRBK1 adrenergic, beta, receptor kinase 1 TRCN0000000558 CCGGAGCGATAAGTTCACACGGTTTCTCGAGAAACCGTGTGAACTTATCGCTTTTTT ADRBK1 adrenergic, beta, receptor kinase 1 TRCN0000000559 CCGGGATCAAGAAGTACGAGAAGCTCTCGAGAGCTTCTCGTACTTCTTGATCTTTTT ADRBK1 adrenergic, beta, receptor kinase 1 TRCN0000197133 CCGGGCATCATGCATGGCTACATGTCTCGAGACATGTAGCCATGCATGATGCTTTTTTG ADRBK1 adrenergic, beta, receptor kinase 1 TRCN0000199115 CCGGCCTCGGCTCCTGCTGCACCAACTCGAGTTGGTGCAGCAGGAGCCGAGGTTTTTTG ADRBK2 adrenergic, beta, receptor kinase 2 TRCN0000002034 CCGGCAGTAAATGCAGACACAGATACTCGAGTATCTGTGTCTGCATTTACTGTTTTT ADRBK2 adrenergic, beta, receptor kinase 2 TRCN0000002035 CCGGGAGTTCAGTGTGCATAGGATTCTCGAGAATCCTATGCACACTGAACTCTTTTT ADRBK2 adrenergic, beta, receptor kinase 2 TRCN0000002036 CCGGTGGAAGAAAGAGTTGAACGAACTCGAGTTCGTTCAACTCTTTCTTCCATTTTT ADRBK2 adrenergic, beta, receptor kinase 2 TRCN0000002037 CCGGCAGCCCTTTCAGACAACATAACTCGAGTTATGTTGTCTGAAAGGGCTGTTTTT ADRBK2 adrenergic, beta, receptor kinase 2 TRCN0000010678 CCGGGCACTTCGCAACTGACTTCTTCTCGAGAAGAAGTCAGTTGCGAAGTGCTTTTT AKT1 v-akt murine thymoma viral oncogene homolog 1 TRCN0000010171 CCGGCTATGGCGCTGAGATTGTGTCCTCGAGGACACAATCTCAGCGCCATAGTTTTT AKT1 v-akt murine thymoma viral oncogene homolog 1 TRCN0000010174 CCGGGGACTACCTGCACTCGGAGAACTCGAGTTCTCCGAGTGCAGGTAGTCCTTTTT AKT1 v-akt murine thymoma viral oncogene homolog 1 TRCN0000039794 CCGGGATCCTCAAGAAGGAAGTCATCTCGAGATGACTTCCTTCTTGAGGATCTTTTTG AKT1 v-akt murine thymoma viral oncogene homolog 1 TRCN0000039796 CCGGGCATCGCTTCTTTGCCGGTATCTCGAGATACCGGCAAAGAAGCGATGCTTTTTG AKT1 v-akt murine thymoma viral oncogene homolog 1 TRCN0000039797 CCGGCGCGTGACCATGAACGAGTTTCTCGAGAAACTCGTTCATGGTCACGCGTTTTTG AKT2 v-akt murine thymoma viral oncogene homolog 2 TRCN0000000563 CCGGCCCTTAAACAACTTCTCCGTACTCGAGTACGGAGAAGTTGTTTAAGGGTTTTT AKT2 v-akt murine thymoma viral oncogene homolog 2 TRCN0000039968 CCGGACAAGGTACTTCGATGATGAACTCGAGTTCATCATCGAAGTACCTTGTTTTTTG AKT2 v-akt murine thymoma viral oncogene homolog 2 TRCN0000039969 CCGGCCTGCGAAAGGAAGTCATCATCTCGAGATGATGACTTCCTTTCGCAGGTTTTTG AKT2 v-akt murine thymoma viral oncogene homolog 2 TRCN0000199106 CCGGCGTTCCTCACTGCGCTGAAGTCTCGAGACTTCAGCGCAGTGAGGAACGTTTTTTG AKT2 v-akt murine thymoma viral oncogene homolog 2 TRCN0000199171 CCGGCGCCATGAAGATCCTGCGAAACTCGAGTTTCGCAGGATCTTCATGGCGTTTTTTG v-akt murine thymoma viral oncogene homolog 3 AKT3 TRCN0000001612 CCGGGCTGCTACTGTCTTACTATTACTCGAGTAATAGTAAGACAGTAGCAGCTTTTT (protein kinase B, gamma) v-akt murine thymoma viral oncogene homolog 3 AKT3 TRCN0000001613 CCGGGCCTCTACAACCCATCATAAACTCGAGTTTATGATGGGTTGTAGAGGCTTTTT (protein kinase B, gamma) v-akt murine thymoma viral oncogene homolog 3 AKT3 TRCN0000001615 CCGGGAAAGGGAAGAATGGACAGAACTCGAGTTCTGTCCATTCTTCCCTTTCTTTTT (protein kinase B, gamma) v-akt murine thymoma viral oncogene homolog 3 AKT3 TRCN0000001616 CCGGAGAAACCTCAAGATGTGGATTCTCGAGAATCCACATCTTGAGGTTTCTTTTTT (protein kinase B, gamma) v-akt murine thymoma viral oncogene homolog 3 AKT3 TRCN0000010185 CCGGGCCTCTACAACCCATCATAAACTCGAGTTTATGATGGGTTGTAGAGGCTTTTT (protein kinase B, gamma) ALK anaplastic lymphoma receptor tyrosine kinase TRCN0000000786 CCGGACCCAAATCAAGAAACCTGTTCTCGAGAACAGGTTTCTTGATTTGGGTTTTTT ALK anaplastic lymphoma receptor tyrosine kinase TRCN0000000784 CCGGGTGATAAATACAAGGCCCAGACTCGAGTCTGGGCCTTGTATTTATCACTTTTT ALK anaplastic lymphoma receptor tyrosine kinase TRCN0000000785 CCGGGAGCTGGTCATTACGAGGATACTCGAGTATCCTCGTAATGACCAGCTCTTTTT ALK anaplastic lymphoma kinase (Ki-1) TRCN0000196366 CCGGGTATACTTCCTTATGCTTCTTCTCGAGAAGAAGCATAAGGAAGTATACTTTTTTG ALK anaplastic lymphoma kinase (Ki-1) TRCN0000199017 CCGGCTTCGCTGACTGCCAATATGACTCGAGTCATATTGGCAGTCAGCGAAGTTTTTTG ALPK1 alpha-kinase 1 TRCN0000021474 CCGGGCATGTGTTGTTTAAGCCATTCTCGAGAATGGCTTAAACAACACATGCTTTTT ALPK1 alpha-kinase 1 TRCN0000021477 CCGGGCCCAGGTGAAGGAACATTTACTCGAGTAAATGTTCCTTCACCTGGGCTTTTT ALPK1 alpha-kinase 1 TRCN0000021478 CCGGCCATCCACAATACTACTGATTCTCGAGAATCAGTAGTATTGTGGATGGTTTTT ALPK1 alpha-kinase 1 TRCN0000195267 CCGGCAAGAGGAATTGATCAGTATCCTCGAGGATACTGATCAATTCCTCTTGTTTTTTG ALPK1 alpha-kinase 1 TRCN0000196495 CCGGGCCAATGATTTGCAAGAGGAACTCGAGTTCCTCTTGCAAATCATTGGCTTTTTTG ALPK2 alpha-kinase 2 TRCN0000021391 CCGGGCGAAGACCTTGGCATTTATTCTCGAGAATAAATGCCAAGGTCTTCGCTTTTT ALPK2 alpha-kinase 2 TRCN0000194883 CCGGCCAACAACATTAACTGCTAATCTCGAGATTAGCAGTTAATGTTGTTGGTTTTTTG ALPK2 alpha-kinase 2 TRCN0000197061 CCGGGCAGACTTTAGGAGCTATGAACTCGAGTTCATAGCTCCTAAAGTCTGCTTTTTTG ALPK3 alpha-kinase 3 TRCN0000021524 CCGGCCCTCCTTGAAGTTTACACTTCTCGAGAAGTGTAAACTTCAAGGAGGGTTTTT ALPK3 alphakinase 3 TRCN0000196551 CCGGGAAGTGTATTTCTCCTTGAAGCTCGAGCTTCAAGGAGAAATACACTTCTTTTTTG AMHR2 anti-Mullerian hormone receptor, type II TRCN0000001956 CCGGTCCGACGAGCTGATATTTACTCTCGAGAGTAAATATCAGCTCGTCGGATTTTT AMHR2 anti-Mullerian hormone receptor, type II TRCN0000001957 CCGGACAGCGAAAGAACTACAGAGTCTCGAGACTCTGTAGTTCTTTCGCTGTTTTTT

157 Supplement

AMHR2 anti-Mullerian hormone receptor, type II TRCN0000001958 CCGGCTACAGCGAAAGAACTACAGACTCGAGTCTGTAGTTCTTTCGCTGTAGTTTTT AMHR2 anti-Mullerian hormone receptor, type II TRCN0000195737 CCGGCCAGAAGACTGTACTTCAATTCTCGAGAATTGAAGTACAGTCTTCTGGTTTTTTG AMHR2 anti-Mullerian hormone receptor, type II TRCN0000199683 CCGGGAATGTGCTCATTCGGGAAGACTCGAGTCTTCCCGAATGAGCACATTCTTTTTTG AMHR2 anti-Mullerian hormone receptor, type II TRCN0000199717 CCGGGACAAGACTCTGGACCTACAGCTCGAGCTGTAGGTCCAGAGTCTTGTCTTTTTTG ANKK1 ankyrin repeat and kinase domain containing 1 TRCN0000010691 CCGGCCTCCTAGAACATCACGCAAACTCGAGTTTGCGTGATGTTCTAGGAGGTTTTT ANKK1 ankyrin repeat and kinase domain containing 1 TRCN0000002302 CCGGCCTGGGTATTGTGATGGAGTTCTCGAGAACTCCATCACAATACCCAGGTTTTT ANKK1 ankyrin repeat and kinase domain containing 1 TRCN0000002303 CCGGGCACAGAATAACTTTGAGAATCTCGAGATTCTCAAAGTTATTCTGTGCTTTTT ANKK1 ankyrin repeat and kinase domain containing 1 TRCN0000195696 CCGGCGCCAGCTCTGATGTGAATTACTCGAGTAATTCACATCAGAGCTGGCGTTTTTTG ANKK1 ankyrin repeat and kinase domain containing 1 TRCN0000196471 CCGGGAAACCATACTCAGGGTTCAACTCGAGTTGAACCCTGAGTATGGTTTCTTTTTTG ARAF v-raf murine sarcoma 3611 viral oncogene homolog TRCN0000000567 CCGGCCAGCCAATCAATGTTCGTCTCTCGAGAGACGAACATTGATTGGCTGGTTTTT ARAF v-raf murine sarcoma 3611 viral oncogene homolog TRCN0000000569 CCGGGTCTAACAACATCTTCCTACACTCGAGTGTAGGAAGATGTTGTTAGACTTTTT ARAF v-raf murine sarcoma 3611 viral oncogene homolog TRCN0000000571 CCGGGACTCATCAAGGGACGAAAGACTCGAGTCTTTCGTCCCTTGATGAGTCTTTTT ARAF v-raf murine sarcoma 3611 viral oncogene homolog TRCN0000199116 CCGGCCAACAGTTCTACCACAGTGTCTCGAGACACTGTGGTAGAACTGTTGGTTTTTTG ARAF v-raf murine sarcoma 3611 viral oncogene homolog TRCN0000199244 CCGGCCCTGTCTCCTCCATCATTTGCTCGAGCAAATGATGGAGGAGACAGGGTTTTTTG ATM ataxia telangiectasia mutated TRCN0000039948 CCGGCCTTTCATTCAGCCTTTAGAACTCGAGTTCTAAAGGCTGAATGAAAGGTTTTTG ATM ataxia telangiectasia mutated TRCN0000039951 CCGGGCCTCCAATTCTTCACAGTAACTCGAGTTACTGTGAAGAATTGGAGGCTTTTTG ATM ataxia telangiectasia mutated TRCN0000194861 CCGGCCAAGGTCTATGATATGCTTACTCGAGTAAGCATATCATAGACCTTGGTTTTTTG ATM ataxia telangiectasia mutated TRCN0000010299 CCGGTGATGGTCTTAAGGAACATCTCTCGAGAGATGTTCCTTAAGACCATCATTTTTG ATM ataxia telangiectasia mutated TRCN0000038654 CCGGCCTGCCAACATACTTTAAGTACTCGAGTACTTAAAGTATGTTGGCAGGTTTTTG ATR ataxia telangiectasia and Rad3 related TRCN0000010300 CCGGAAAGAGGCTCCTACCAACGACTCGAGTCGTTGGTAGGAGCCTCTTTCTTTTTG ATR ataxia telangiectasia and Rad3 related TRCN0000010301 CCGGAATGGAGTAAACCAGTGAAACTCGAGTTTCACTGGTTTACTCCATTCTTTTTG ATR ataxia telangiectasia and Rad3 related TRCN0000010302 CCGGAATGCATTTGGTATGAATCTGCTCGAGCAGATTCATACCAAATGCATTTTTTTG ATR ataxia telangiectasia and Rad3 related TRCN0000039613 CCGGCTGTGGTTGTATCTGTTCAATCTCGAGATTGAACAGATACAACCACAGTTTTTG ATR ataxia telangiectasia and Rad3 related TRCN0000039614 CCGGCCGGATACTTACAGATGTAAACTCGAGTTTACATCTGTAAGTATCCGGTTTTTG AURKA aurora kinase A TRCN0000000655 CCGGACGAGAATTGTGCTACTTATACTCGAGTATAAGTAGCACAATTCTCGTTTTTT AURKA aurora kinase A TRCN0000000656 CCGGCCTGTCTTACTGTCATTCGAACTCGAGTTCGAATGACAGTAAGACAGGTTTTT AURKA aurora kinase A TRCN0000000657 CCGGGAGTCTACCTAATTCTGGAATCTCGAGATTCCAGAATTAGGTAGACTCTTTTT AURKA aurora kinase A TRCN0000010533 CCGGCACATACCAAGAGACCTACAACTCGAGTTGTAGGTCTCTTGGTATGTGTTTTT AURKA serine/threonine kinase 6 TRCN0000195549 CCGGCGCATTCCTTTGCAAGCACAACTCGAGTTGTGCTTGCAAAGGAATGCGTTTTTTG AURKB aurora kinase B TRCN0000000776 CCGGCTACCTCCTCCTTTGTTTAATCTCGAGATTAAACAAAGGAGGAGGTAGTTTTT AURKB aurora kinase B TRCN0000000777 CCGGCCTGCGTCTCTACAACTATTTCTCGAGAAATAGTTGTAGAGACGCAGGTTTTT AURKB aurora kinase B TRCN0000000779 CCGGGAAGAGCTGCACATTTGACGACTCGAGTCGTCAAATGTGCAGCTCTTCTTTTT AURKB aurora kinase B TRCN0000195436 CCGGCATCGTCAAGGTGGACCTAAACTCGAGTTTAGGTCCACCTTGACGATGTTTTTTG AURKB aurora kinase B TRCN0000199198 CCGGCAGCGAGTCCTCCGGAAAGAGCTCGAGCTCTTTCCGGAGGACTCGCTGTTTTTTG AURKC aurora kinase C TRCN0000010694 CCGGTGAGGTGAAGATTGCAGATTTCTCGAGAAATCTGCAATCTTCACCTCATTTTT AURKC aurora kinase C TRCN0000002333 CCGGCTCTGCCACCTCATTTGTCTTCTCGAGAAGACAAATGAGGTGGCAGAGTTTTT AURKC aurora kinase C TRCN0000002334 CCGGCTGCCATGACAAGAAAGTGATCTCGAGATCACTTTCTTGTCATGGCAGTTTTT AURKC aurora kinase C TRCN0000002335 CCGGCCTGCGCCTGTATAACTATTTCTCGAGAAATAGTTATACAGGCGCAGGTTTTT AURKC aurora kinase C TRCN0000195382 CCGGCCATTTCATTGTGGCCCTGAACTCGAGTTCAGGGCCACAATGAAATGGTTTTTTG AXL AXL receptor tyrosine kinase TRCN0000000572 CCGGCTTTAGGTTCTTTGCTGCATTCTCGAGAATGCAGCAAAGAACCTAAAGTTTTT AXL AXL receptor tyrosine kinase TRCN0000000573 CCGGGCGGTCTGCATGAAGGAATTTCTCGAGAAATTCCTTCATGCAGACCGCTTTTT AXL AXL receptor tyrosine kinase TRCN0000000576 CCGGGCTGTGAAGACGATGAAGATTCTCGAGAATCTTCATCGTCTTCACAGCTTTTT AXL AXL receptor tyrosine kinase TRCN0000001037 CCGGCTTTAGGTTCTTTGCTGCATTCTCGAGAATGCAGCAAAGAACCTAAAGTTTTT AXL AXL receptor tyrosine kinase TRCN0000001038 CCGGGCGGTCTGCATGAAGGAATTTCTCGAGAAATTCCTTCATGCAGACCGCTTTTT BCKDK branched chain ketoacid dehydrogenase kinase TRCN0000010192 CCGGAGAAGCCCTCAGTCCGCCTAACTCGAGTTAGGCGGACTGAGGGCTTCTTTTTT BCKDK branched chain ketoacid dehydrogenase kinase TRCN0000196380 CCGGGATCTGATCATCAGGATCTCACTCGAGTGAGATCCTGATGATCAGATCTTTTTTG BCKDK branched chain ketoacid dehydrogenase kinase TRCN0000199101 CCGGCCAGCACCAGTTCCGTCATTCCTCGAGGAATGACGGAACTGGTGCTGGTTTTTTG BCKDK branched chain ketoacid dehydrogenase kinase TRCN0000199200 CCGGCGTCCGCTACTTCTTGGACAACTCGAGTTGTCCAAGAAGTAGCGGACGTTTTTTG BCKDK branched chain ketoacid dehydrogenase kinase TRCN0000010183 CCGGTCAGGACCCATGCACGGCTTTCTCGAGAAAGCCGTGCATGGGTCCTGATTTTT BCR breakpoint cluster region TRCN0000000789 CCGGCAAGAGTTACACGTTCCTGATCTCGAGATCAGGAACGTGTAACTCTTGTTTTT BCR breakpoint cluster region TRCN0000000790 CCGGCTGACCAACTCGTGTGTGAAACTCGAGTTTCACACACGAGTTGGTCAGTTTTT BCR breakpoint cluster region TRCN0000000791 CCGGCGAGGAATTTGAGATAGAGCTCTCGAGAGCTCTATCTCAAATTCCTCGTTTTT BCR breakpoint cluster region TRCN0000000792 CCGGGTTCCTGATCTCCTCTGACTACTCGAGTAGTCAGAGGAGATCAGGAACTTTTT BCR breakpoint cluster region TRCN0000000793 CCGGAGAGCCAGAAGCAACAAAGATCTCGAGATCTTTGTTGCTTCTGGCTCTTTTTT BLK B lymphoid tyrosine kinase TRCN0000010083 CCGGAGATGAAGGGAGCAGATTGTCCTCGAGGACAATCTGCTCCCTTCATCTTTTTT BLK B lymphoid tyrosine kinase TRCN0000010086 CCGGGCCGATCAAAGAGAAGGACAACTCGAGTTGTCCTTCTCTTTGATCGGCTTTTT BLK B lymphoid tyrosine kinase TRCN0000010087 CCGGCCAGGTCACTCGTCACAGGAACTCGAGTTCCTGTGACGAGTGACCTGGTTTTT BLK B lymphoid tyrosine kinase TRCN0000194709 CCGGCTGATGGAAGTTGTCACTTATCTCGAGATAAGTGACAACTTCCATCAGTTTTTTG BLK B lymphoid tyrosine kinase TRCN0000195414 CCGGCCTGGATGAAGACAAGCATTTCTCGAGAAATGCTTGTCTTCATCCAGGTTTTTTG BMP2K BMP2 inducible kinase TRCN0000000914 CCGGGCACTGGGATGTCTACTCTATCTCGAGATAGAGTAGACATCCCAGTGCTTTTT BMP2K BMP2 inducible kinase TRCN0000000915 CCGGGACTGTGCTGTTAATTCAATTCTCGAGAATTGAATTAACAGCACAGTCTTTTT BMP2K BMP2 inducible kinase TRCN0000000916 CCGGGATGGTGGGAACTATGTACTTCTCGAGAAGTACATAGTTCCCACCATCTTTTT

158 Supplement

BMP2K BMP2 inducible kinase TRCN0000000917 CCGGTCTTCTATTCCTTCAGCTCTTCTCGAGAAGAGCTGAAGGAATAGAAGATTTTT BMP2K BMP2 inducible kinase TRCN0000000913 CCGGGCTGCTTTGTTGTCCTGATATCTCGAGATATCAGGACAACAAAGCAGCTTTTT BMPR1A bone morphogenetic protein receptor, type IA TRCN0000000794 CCGGCGCCAATCTCATACAAGCCATCTCGAGATGGCTTGTATGAGATTGGCGTTTTT BMPR1A bone morphogenetic protein receptor, type IA TRCN0000000795 CCGGCGTGATTTGGAACAGGATGAACTCGAGTTCATCCTGTTCCAAATCACGTTTTT BMPR1A bone morphogenetic protein receptor, type IA TRCN0000000797 CCGGGATGAATGTCTACGAGCAGTTCTCGAGAACTGCTCGTAGACATTCATCTTTTT BMPR1A bone morphogenetic protein receptor, type IA TRCN0000000798 CCGGGTCCAGATGATGCTATTAATACTCGAGTATTAATAGCATCATCTGGACTTTTT BMPR1A bone morphogenetic protein receptor, type IA TRCN0000194749 CCGGCTCACAGCATTGAGAATTAAGCTCGAGCTTAATTCTCAATGCTGTGAGTTTTTTG BMPR1B bone morphogenetic protein receptor, type IB TRCN0000000451 CCGGGACATCAAATAAGCATCCACACTCGAGTGTGGATGCTTATTTGATGTCTTTTT BMPR1B bone morphogenetic protein receptor, type IB TRCN0000000453 CCGGCCTCGATACAGCATTGGGTTACTCGAGTAACCCAATGCTGTATCGAGGTTTTT BMPR1B bone morphogenetic protein receptor, type IB TRCN0000000454 CCGGGACGAGAGCTTGAACAGAAATCTCGAGATTTCTGTTCAAGCTCTCGTCTTTTT BMPR1B bone morphogenetic protein receptor, type IB TRCN0000000455 CCGGTCAGGAGGTATAGTGGAAGAACTCGAGTTCTTCCACTATACCTCCTGATTTTT BMPR1B bone morphogenetic protein receptor, type IB TRCN0000194864 CCGGCTCATCAAAGAAGATCAATTGCTCGAGCAATTGATCTTCTTTGATGAGTTTTTTG bone morphogenetic protein receptor, type II BMPR2 TRCN0000000456 CCGGGCCTATGGAGTGAAATTATTTCTCGAGAAATAATTTCACTCCATAGGCTTTTT (serine/threonine kinase) bone morphogenetic protein receptor, type II BMPR2 TRCN0000195156 CCGGCCTAACTGTATACCAGAATTACTCGAGTAATTCTGGTATACAGTTAGGTTTTTTG (serine/threonine kinase) bone morphogenetic protein receptor, type II BMPR2 TRCN0000000457 CCGGGCCCGCTTTATAGTTGGAGATCTCGAGATCTCCAACTATAAAGCGGGCTTTTT (serine/threonine kinase) bone morphogenetic protein receptor, type II BMPR2 TRCN0000000458 CCGGCGCAGAATCAAGAACGGCTATCTCGAGATAGCCGTTCTTGATTCTGCGTTTTT (serine/threonine kinase) bone morphogenetic protein receptor, type II BMPR2 TRCN0000195509 CCGGCCCAAGAAATGTTGCAGAATCCTCGAGGATTCTGCAACATTTCTTGGGTTTTTTG (serine/threonine kinase) BMX BMX non-receptor tyrosine kinase TRCN0000006359 CCGGGAGTGCTGATAAGAATGAATACTCGAGTATTCATTCTTATCAGCACTCTTTTT BMX BMX non-receptor tyrosine kinase TRCN0000006360 CCGGCGTGCATACAAATGCTGAGAACTCGAGTTCTCAGCATTTGTATGCACGTTTTT BMX BMX non-receptor tyrosine kinase TRCN0000006361 CCGGGCCCTATGACTTGTATGACAACTCGAGTTGTCATACAAGTCATAGGGCTTTTT BMX BMX non-receptor tyrosine kinase TRCN0000194950 CCGGCCCATATACATAGTGACTGAACTCGAGTTCAGTCACTATGTATATGGGTTTTTTG BMX BMX non-receptor tyrosine kinase TRCN0000196445 CCGGGTGTTCTCTGTATTGTCTATTCTCGAGAATAGACAATACAGAGAACACTTTTTTG BRAF v-raf murine sarcoma viral oncogene homolog B1 TRCN0000006290 CCGGCCGCTGTCAAACATGTGGTTACTCGAGTAACCACATGTTTGACAGCGGTTTTT BRAF v-raf murine sarcoma viral oncogene homolog B1 TRCN0000195066 CCGGCAGCTTTCAGTCAGATGTATACTCGAGTATACATCTGACTGAAAGCTGTTTTTTG BRAF v-raf murine sarcoma viral oncogene homolog B1 TRCN0000195609 CCGGCTCAGTAAGGTACGGAGTAACCTCGAGGTTACTCCGTACCTTACTGAGTTTTTTG BRAF v-raf murine sarcoma viral oncogene homolog B1 TRCN0000196844 CCGGGTCATCAGAATGCAAGATAAACTCGAGTTTATCTTGCATTCTGATGACTTTTTTG BRAF v-raf murine sarcoma viral oncogene homolog B1 TRCN0000196918 CCGGGAACATATAGAGGCCCTATTGCTCGAGCAATAGGGCCTCTATATGTTCTTTTTTG BRD2 bromodomain containing 2 TRCN0000006308 CCGGCCCTTTGCTGTGACACTTCTTCTCGAGAAGAAGTGTCACAGCAAAGGGTTTTT BRD2 bromodomain containing 2 TRCN0000006309 CCGGGCCCTCTTTACGTGATTCAAACTCGAGTTTGAATCACGTAAAGAGGGCTTTTT BRD2 bromodomain containing 2 TRCN0000006310 CCGGCCCTGCCTACAGGTTATGATTCTCGAGAATCATAACCTGTAGGCAGGGTTTTT BRD2 bromodomain containing 2 TRCN0000006311 CCGGCCTATGGACATGGGTACTATTCTCGAGAATAGTACCCATGTCCATAGGTTTTT BRD2 bromodomain containing 2 TRCN0000006312 CCGGCCTACCACTGTCCTCAACATTCTCGAGAATGTTGAGGACAGTGGTAGGTTTTT BRD3 bromodomain containing 3 TRCN0000021374 CCGGCCAAGGAAATGTCTCGGATATCTCGAGATATCCGAGACATTTCCTTGGTTTTT BRD3 bromodomain containing 3 TRCN0000021375 CCGGCCCAAGAGGAAGTTGAATTATCTCGAGATAATTCAACTTCCTCTTGGGTTTTT BRD3 bromodomain containing 3 TRCN0000021376 CCGGGCTGATGTTCTCGAATTGCTACTCGAGTAGCAATTCGAGAACATCAGCTTTTT BRD3 bromodomain containing 3 TRCN0000021378 CCGGGAGATATGTCAAGTCTTGTTTCTCGAGAAACAAGACTTGACATATCTCTTTTT BRD3 bromodomain containing 3 TRCN0000195541 CCGGCAAATTGAACCTGCCGGATTACTCGAGTAATCCGGCAGGTTCAATTTGTTTTTTG BRD4 bromodomain containing 4 TRCN0000021428 CCGGCCAGAGTGATCTATTGTCAATCTCGAGATTGACAATAGATCACTCTGGTTTTT BRD4 bromodomain containing 4 TRCN0000196576 CCGGGCCAAATGTCTACACAGTATACTCGAGTATACTGTGTAGACATTTGGCTTTTTTG BRD4 bromodomain containing 4 TRCN0000199427 CCGGCAGTGACAGTTCGACTGATGACTCGAGTCATCAGTCGAACTGTCACTGTTTTTTG BRD4 bromodomain containing 4 TRCN0000199459 CCGGGCCTATGTCCTATGAGGAGAACTCGAGTTCTCCTCATAGGACATAGGCTTTTTTG BRD4 bromodomain containing 4 TRCN0000021424 CCGGCCGCCAAATGTCTACACAGTACTCGAGTACTGTGTAGACATTTGGCGGTTTTT BRDT bromodomain, testis-specific TRCN0000006303 CCGGCTCAGTTTTTAAATTAACCATCTCGAGATGGTTAATTTAAAAACTGAGTTTTT BRDT bromodomain, testis-specific TRCN0000195124 CCGGCACCACCAATTAGCATTTAATCTCGAGATTAAATGCTAATTGGTGGTGTTTTTTG BRDT bromodomain, testis-specific TRCN0000196703 CCGGGAAACTACAGTTGCCTGATTACTCGAGTAATCAGGCAACTGTAGTTTCTTTTTTG BRDT bromodomain, testis-specific TRCN0000006304 CCGGCCGATGGATCTTGGAACTATTCTCGAGAATAGTTCCAAGATCCATCGGTTTTT BRDT bromodomain, testis-specific TRCN0000006305 CCGGCCTATGAACTATGATGAGAAACTCGAGTTTCTCATCATAGTTCATAGGTTTTT BRSK1 BR serine/threonine kinase 1 TRCN0000002397 CCGGCAGAAACATCCTTGGTACCTACTCGAGTAGGTACCAAGGATGTTTCTGTTTTT BRSK1 BR serine/threonine kinase 1 TRCN0000002396 CCGGAGCTATTCGACTACCTGGTAACTCGAGTTACCAGGTAGTCGAATAGCTTTTTT BRSK1 BR serine/threonine kinase 1 TRCN0000002398 CCGGCAGCATCAAAGCAGACATCGTCTCGAGACGATGTCTGCTTTGATGCTGTTTTT BRSK1 BR serine/threonine kinase 1 TRCN0000002399 CCGGCCCAACTGTGAATCTGTAAATCTCGAGATTTACAGATTCACAGTTGGGTTTTT BRSK1 BR serine/threonine kinase 1 TRCN0000002400 CCGGCCCACTTCATTCCTCCAGATTCTCGAGAATCTGGAGGAATGAAGTGGGTTTTT BRSK2 BR serine/threonine kinase 2 TRCN0000000735 CCGGCAGTGTTATTTATTTGCCGTTCTCGAGAACGGCAAATAAATAACACTGTTTTT BRSK2 BR serine/threonine kinase 2 TRCN0000000736 CCGGCACTAACTGTATGGAAATGATCTCGAGATCATTTCCATACAGTTAGTGTTTTT BRSK2 BR serine/threonine kinase 2 TRCN0000000737 CCGGGAACCAGGAGAAGATGATTTACTCGAGTAAATCATCTTCTCCTGGTTCTTTTT BRSK2 BR serine/threonine kinase 2 TRCN0000000738 CCGGGCTCAACTCCATCAAGAACAGCTCGAGCTGTTCTTGATGGAGTTGAGCTTTTT BRSK2 BR serine/threonine kinase 2 TRCN0000000739 CCGGCTGGACGAGAAGAACAACATCCTCGAGGATGTTGTTCTTCTCGTCCAGTTTTT BTK Bruton agammaglobulinemia tyrosine kinase TRCN0000000358 CCGGGTGGACCGAATTTGGCAAGAACTCGAGTTCTTGCCAAATTCGGTCCACTTTTT BTK Bruton agammaglobulinemia tyrosine kinase TRCN0000000359 CCGGCCCAACTGAAGAACTAAGGAACTCGAGTTCCTTAGTTCTTCAGTTGGGTTTTT BTK Bruton agammaglobulinemia tyrosine kinase TRCN0000000360 CCGGCCAATGAATGCAAATGATCTACTCGAGTAGATCATTTGCATTCATTGGTTTTT

159 Supplement

BTK Bruton agammaglobulinemia tyrosine kinase TRCN0000000361 CCGGGAAGCAGAAGACTCCATAGAACTCGAGTTCTATGGAGTCTTCTGCTTCTTTTT BTK Bruton agammaglobulinemia tyrosine kinase TRCN0000009935 CCGGAGGAGGTTTCATTGTCAGAGACTCGAGTCTCTGACAATGAAACCTCCTTTTTT budding uninhibited by benzimidazoles 1 homolog BUB1 TRCN0000000800 CCGGCGAGGTTAATCCAGCACGTATCTCGAGATACGTGCTGGATTAACCTCGTTTTT (yeast) budding uninhibited by benzimidazoles 1 homolog BUB1 TRCN0000000801 CCGGACCAGTGAGTTCCTATCCAAACTCGAGTTTGGATAGGAACTCACTGGTTTTTT (yeast) budding uninhibited by benzimidazoles 1 homolog BUB1 TRCN0000010307 CCGGTACAACAGTGACCTCCATCAACTCGAGTTGATGGAGGTCACTGTTGTATTTTTG (yeast) budding uninhibited by benzimidazoles 1 homolog BUB1 TRCN0000010308 CCGGCATGGAACTACCAGATCGATTCTCGAGAATCGATCTGGTAGTTCCATGTTTTTG (yeast) budding uninhibited by benzimidazoles 1 homolog BUB1 TRCN0000010309 CCGGTAAATATGAATCTGCTCACTTCTCGAGAAGTGAGCAGATTCATATTTATTTTTG (yeast) budding uninhibited by benzimidazoles 1 homolog BUB1B TRCN0000000461 CCGGCTGAAACTGTATGTGCTGTAACTCGAGTTACAGCACATACAGTTTCAGTTTTT beta (yeast) budding uninhibited by benzimidazoles 1 homolog BUB1B TRCN0000000462 CCGGGCGTTTATGCAATGAGCCTTTCTCGAGAAAGGCTCATTGCATAAACGCTTTTT beta (yeast) budding uninhibited by benzimidazoles 1 homolog BUB1B TRCN0000000463 CCGGCCAGTGTACCTTTCTCCATTTCTCGAGAAATGGAGAAAGGTACACTGGTTTTT beta (yeast) budding uninhibited by benzimidazoles 1 homolog BUB1B TRCN0000000464 CCGGGAGACAACTAAACTGCAAATTCTCGAGAATTTGCAGTTTAGTTGTCTCTTTTT beta (yeast) budding uninhibited by benzimidazoles 1 homolog BUB1B TRCN0000000465 CCGGCCTCAGAAAGCATCACCTCAACTCGAGTTGAGGTGATGCTTTCTGAGGTTTTT beta (yeast) C9orf96 chromosome 9 open reading frame 96 TRCN0000199357 CCGGCCTGCGTCCATCACCGACATGCTCGAGCATGTCGGTGATGGACGCAGGTTTTTTG C9orf96 chromosome 9 open reading frame 96 TRCN0000082448 CCGGCCTTCCAGGAACTGGTTTCTTCTCGAGAAGAAACCAGTTCCTGGAAGGTTTTTG C9orf96 chromosome 9 open reading frame 96 TRCN0000082449 CCGGCTCGGATCGAATAACGATAAACTCGAGTTTATCGTTATTCGATCCGAGTTTTTG C9orf96 chromosome 9 open reading frame 96 TRCN0000082450 CCGGGCTAATGACAGACAAAGCCAACTCGAGTTGGCTTTGTCTGTCATTAGCTTTTTG C9orf96 chromosome 9 open reading frame 96 TRCN0000082451 CCGGGCATGTGATAAAGCAGGTGGACTCGAGTCCACCTGCTTTATCACATGCTTTTTG CAMK1 calcium/calmodulin-dependent protein kinase I TRCN0000000676 CCGGCTACCACTCCTCACTGCATTTCTCGAGAAATGCAGTGAGGAGTGGTAGTTTTT CAMK1 calcium/calmodulin-dependent protein kinase I TRCN0000000677 CCGGCGGAGGACATTAGAGACATCTCTCGAGAGATGTCTCTAATGTCCTCCGTTTTT CAMK1 calcium/calmodulin-dependent protein kinase I TRCN0000000679 CCGGGCTGGATGCTGTGAAATACCTCTCGAGAGGTATTTCACAGCATCCAGCTTTTT CAMK1 calcium/calmodulin-dependent protein kinase I TRCN0000009995 CCGGGAAGGCCGAGTACGAGTTTGACTCGAGTCAAACTCGTACTCGGCCTTCTTTTT CAMK1 calcium/calmodulin-dependent protein kinase I TRCN0000010001 CCGGGGCGGAGGACATTAGAGACATCTCGAGATGTCTCTAATGTCCTCCGCCTTTTT CAMK1D calcium/calmodulin-dependent protein kinase ID TRCN0000001752 CCGGTGCTGTGAAGTGTATCCCTAACTCGAGTTAGGGATACACTTCACAGCATTTTT CAMK1D calcium/calmodulin-dependent protein kinase ID TRCN0000001753 CCGGAGAATGAGATAGCCGTCCTGACTCGAGTCAGGACGGCTATCTCATTCTTTTTT CAMK1D calcium/calmodulin-dependent protein kinase ID TRCN0000195715 CCGGCAGATCCTCAAGGCGGAATATCTCGAGATATTCCGCCTTGAGGATCTGTTTTTTG CAMK1D calcium/calmodulin-dependent protein kinase ID TRCN0000197125 CCGGGACTTCATTCGGAACCTGATGCTCGAGCATCAGGTTCCGAATGAAGTCTTTTTTG CAMK1D calcium/calmodulin-dependent protein kinase ID TRCN0000001754 CCGGAGGCGGAATATGAGTTTGACTCTCGAGAGTCAAACTCATATTCCGCCTTTTTT CAMK1G calcium/calmodulin-dependent protein kinase IG TRCN0000001452 CCGGATATTCAACTCCTCTGCTCTTCTCGAGAAGAGCAGAGGAGTTGAATATTTTTT CAMK1G calcium/calmodulin-dependent protein kinase IG TRCN0000001453 CCGGCCTCCAGATCCAGAAGAACTTCTCGAGAAGTTCTTCTGGATCTGGAGGTTTTT CAMK1G calcium/calmodulin-dependent protein kinase IG TRCN0000001454 CCGGGTGAAATACCTACATGAGAATCTCGAGATTCTCATGTAGGTATTTCACTTTTT CAMK1G calcium/calmodulin-dependent protein kinase IG TRCN0000001455 CCGGGACTTTATTTGCCACTTGCTTCTCGAGAAGCAAGTGGCAAATAAAGTCTTTTT CAMK1G calcium/calmodulin-dependent protein kinase IG TRCN0000001456 CCGGGAAGATCAAGGAGGGCTACTACTCGAGTAGTAGCCCTCCTTGATCTTCTTTTT CAMK2A calcium/calmodulin-dependent protein kinase II alpha TRCN0000010283 CCGGAGAGCGATGGTGTGAAGGAATCTCGAGATTCCTTCACACCATCGCTCTTTTTT CAMK2A calcium/calmodulin-dependent protein kinase II alpha TRCN0000010284 CCGGGTGCGGAAACAGGAAATTATACTCGAGTATAATTTCCTGTTTCCGCACTTTTT CAMK2A calcium/calmodulin-dependent protein kinase II alpha TRCN0000010285 CCGGGGGACACCACTACCTGATCTTCTCGAGAAGATCAGGTAGTGGTGTCCCTTTTT CAMK2A calcium/calmodulin-dependent protein kinase II alpha TRCN0000010286 CCGGGACCATTAACCCATCCAAACGCTCGAGCGTTTGGATGGGTTAATGGTCTTTTT CAMK2A calcium/calmodulin-dependent protein kinase II alpha TRCN0000194685 CCGGCAGGATTTCATCTCACCATATCTCGAGATATGGTGAGATGAAATCCTGTTTTTTG CAMK2B calcium/calmodulin-dependent protein kinase II beta TRCN0000000466 CCGGGACCAGATGTGATTTGTTAAACTCGAGTTTAACAAATCACATCTGGTCTTTTT CAMK2B calcium/calmodulin-dependent protein kinase II beta TRCN0000000467 CCGGGATCATTAAGACCACGGAGCACTCGAGTGCTCCGTGGTCTTAATGATCTTTTT CAMK2B calcium/calmodulin-dependent protein kinase II beta TRCN0000000469 CCGGACAAGAAAGCAGATGGAGTCACTCGAGTGACTCCATCTGCTTTCTTGTTTTTT CAMK2B calcium/calmodulin-dependent protein kinase II beta TRCN0000000470 CCGGATCTCTGACATCCTGAACTCTCTCGAGAGAGTTCAGGATGTCAGAGATTTTTT calcium/calmodulindependent protein kinase (CaM CAMK2B TRCN0000195670 CCGGCCGGAAGCAGGAGATCATTAACTCGAGTTAATGATCTCCTGCTTCCGGTTTTTTG kinase) II beta CAMK2D calcium/calmodulin-dependent protein kinase II delta TRCN0000000471 CCGGCTTCTGCATTCTCTGTTCTCACTCGAGTGAGAACAGAGAATGCAGAAGTTTTT CAMK2D calcium/calmodulin-dependent protein kinase II delta TRCN0000000474 CCGGCAGATGGAGTAAAGGAGTCAACTCGAGTTGACTCCTTTACTCCATCTGTTTTT CAMK2D calcium/calmodulin-dependent protein kinase II delta TRCN0000000475 CCGGTGTGGTGTCATTCTCTATATTCTCGAGAATATAGAGAATGACACCACATTTTT CAMK2D calcium/calmodulin-dependent protein kinase II delta TRCN0000195041 CCGGCCTGAAGCTTTGGGTAATTTACTCGAGTAAATTACCCAAAGCTTCAGGTTTTTTG CAMK2D calcium/calmodulin-dependent protein kinase II delta TRCN0000195619 CCGGCCATGGATCTGTCAACGTTCTCTCGAGAGAACGTTGACAGATCCATGGTTTTTTG calcium/calmodulin-dependent protein kinase II CAMK2G TRCN0000000476 CCGGCGTTGCTGTACTGTCTTGTTTCTCGAGAAACAAGACAGTACAGCAACGTTTTT gamma calcium/calmodulin-dependent protein kinase II CAMK2G TRCN0000000478 CCGGAGAACAGCAAGCCTATCCATACTCGAGTATGGATAGGCTTGCTGTTCTTTTTT gamma calcium/calmodulin-dependent protein kinase II CAMK2G TRCN0000000480 CCGGGATCACCAGAAACTAGAACGTCTCGAGACGTTCTAGTTTCTGGTGATCTTTTT gamma calcium/calmodulin-dependent protein kinase II CAMK2G TRCN0000000477 CCGGACCTCGTGTTTGACCTTGTTACTCGAGTAACAAGGTCAAACACGAGGTTTTTT gamma calcium/calmodulin-dependent protein kinase II CAMK2G TRCN0000194892 CCGGCCTGTTTGTTTGAGGTTTAAACTCGAGTTTAAACCTCAAACAAACAGGTTTTTTG gamma CAMK4 calcium/calmodulin-dependent protein kinase IV TRCN0000000578 CCGGGCCTCTCACATCCAAACATTACTCGAGTAATGTTTGGATGTGAGAGGCTTTTT CAMK4 calcium/calmodulin-dependent protein kinase IV TRCN0000000579 CCGGAGAAAGTTAAAGGTGCAGATACTCGAGTATCTGCACCTTTAACTTTCTTTTTT CAMK4 calcium/calmodulin-dependent protein kinase IV TRCN0000000581 CCGGCAACGAGGACATGAAAGCTATCTCGAGATAGCTTTCATGTCCTCGTTGTTTTT CAMK4 calcium/calmodulin-dependent protein kinase IV TRCN0000009960 CCGGTCGTAAGAACTGAGATAGGAGCTCGAGCTCCTATCTCAGTTCTTACGATTTTT

160 Supplement

CAMK4 calcium/calmodulin-dependent protein kinase IV TRCN0000009961 CCGGTGGTCCTAGAACTCGTCACAGCTCGAGCTGTGACGAGTTCTAGGACCATTTTT calcium/calmodulin-dependent protein kinase kinase CAMKK1 TRCN0000001980 CCGGGACAGACACTATGCAATGAAACTCGAGTTTCATTGCATAGTGTCTGTCTTTTT 1, alpha calcium/calmodulin-dependent protein kinase kinase CAMKK1 TRCN0000001981 CCGGCTGGCCTACAACGAAAGTGAACTCGAGTTCACTTTCGTTGTAGGCCAGTTTTT 1, alpha calcium/calmodulin-dependent protein kinase kinase CAMKK1 TRCN0000001982 CCGGACAAGAATCCCGAGACGAGAACTCGAGTTCTCGTCTCGGGATTCTTGTTTTTT 1, alpha calcium/calmodulin-dependent protein kinase kinase CAMKK1 TRCN0000001983 CCGGCACGTTGTACTGCTTTGTCTACTCGAGTAGACAAAGCAGTACAACGTGTTTTT 1, alpha calcium/calmodulin-dependent protein kinase kinase CAMKK1 TRCN0000001984 CCGGAGTGCCCATTCATCGACGATTCTCGAGAATCGTCGATGAATGGGCACTTTTTT 1, alpha calcium/calmodulin-dependent protein kinase kinase CAMKK1 TRCN0000199160 CCGGCCACGTGAATGTGGTCAAACTCTCGAGAGTTTGACCACATTCACGTGGTTTTTTG 1, alpha calcium/calmodulin-dependent protein kinase kinase CAMKK2 TRCN0000002299 CCGGGTGAAGACCATGATACGTAAACTCGAGTTTACGTATCATGGTCTTCACTTTTT 2, beta calcium/calmodulin-dependent protein kinase kinase CAMKK2 TRCN0000002301 CCGGCGACCCTTTCTACTATGCATTCTCGAGAATGCATAGTAGAAAGGGTCGTTTTT 2, beta calcium/calmodulin-dependent protein kinase kinase CAMKK2 TRCN0000002297 CCGGCGAGCGGATCATGTGTTTACACTCGAGTGTAAACACATGATCCGCTCGTTTTT 2, beta calcium/calmodulin-dependent protein kinase kinase CAMKK2 TRCN0000002298 CCGGCCGTTTCTACTTCCAGGATCTCTCGAGAGATCCTGGAAGTAGAAACGGTTTTT 2, beta calcium/calmodulin-dependent protein kinase kinase CAMKK2 TRCN0000002300 CCGGAGTCAAACACATTCCCAGCTTCTCGAGAAGCTGGGAATGTGTTTGACTTTTTT 2, beta CAMKV CaM kinase-like vesicle-associated TRCN0000010253 CCGGGCAAAGAGTGATAATGTGGCCCTCGAGGGCCACATTATCACTCTTTGCTTTTT CAMKV CaM kinase-like vesicle-associated TRCN0000010254 CCGGGCGGAAAGCTGCCAAGAACGACTCGAGTCGTTCTTGGCAGCTTTCCGCTTTTT CAMKV CaM kinase-like vesicle-associated TRCN0000010255 CCGGCGGCTGAAGAACTCGAAGATTCTCGAGAATCTTCGAGTTCTTCAGCCGTTTTT CAMKV hypothetical protein MGC8407 TRCN0000194988 CCGGCCCTGTTATTTGTGTTATTTCCTCGAGGAAATAACACAAATAACAGGGTTTTTTG CAMKV hypothetical protein MGC8407 TRCN0000196332 CCGGGATGAGGAAGTAGGGTTAAACCTCGAGGTTTAACCCTACTTCCTCATCTTTTTTG calcium/calmodulin-dependent serine protein kinase CASK TRCN0000000692 CCGGCCCTGAGAATAACGACGCAAACTCGAGTTTGCGTCGTTATTCTCAGGGTTTTT (MAGUK family) calcium/calmodulin-dependent serine protein kinase CASK TRCN0000000694 CCGGGCAAAGGAACTAAAGCGTATTCTCGAGAATACGCTTTAGTTCCTTTGCTTTTT (MAGUK family) calcium/calmodulin-dependent serine protein kinase CASK TRCN0000195029 CCGGCGACGATGTATCAACAGAGAACTCGAGTTCTCTGTTGATACATCGTCGTTTTTTG (MAGUK family) calcium/calmodulin-dependent serine protein kinase CASK TRCN0000195030 CCGGCCCTGAAGAGTTACCAGATTTCTCGAGAAATCTGGTAACTCTTCAGGGTTTTTTG (MAGUK family) calcium/calmodulin-dependent serine protein kinase CASK TRCN0000195064 CCGGCCGAATAGATAGGAGGAGAAACTCGAGTTTCTCCTCCTATCTATTCGGTTTTTTG (MAGUK family) CDC2L2 cell division cycle 2-like 2 (PITSLRE proteins) TRCN0000006992 CCGGCGTATAGAAGAGAAGACTCAACTCGAGTTGAGTCTTCTCTTCTATACGTTTTT CDC2L2 cell division cycle 2-like 2 (PITSLRE proteins) TRCN0000006993 CCGGGCTCCCAGTAGTCAAGAAGATCTCGAGATCTTCTTGACTACTGGGAGCTTTTT CDC2L2 cell division cycle 2-like 2 (PITSLRE proteins) TRCN0000006995 CCGGCATCCCAACATTGTCACCGTTCTCGAGAACGGTGACAATGTTGGGATGTTTTT CDC2L2 cell division cycle 2-like 2 (PITSLRE proteins) TRCN0000197027 CCGGGCAGCAACATGGACAAGATCTCTCGAGAGATCTTGTCCATGTTGCTGCTTTTTTG CDC42BPA CDC42 binding protein kinase alpha (DMPK-like) TRCN0000001332 CCGGCGCTCAGTCTATGTTCCCAAACTCGAGTTTGGGAACATAGACTGAGCGTTTTT CDC42BPA CDC42 binding protein kinase alpha (DMPK-like) TRCN0000001334 CCGGGCTCAGTCAGTATTCCATCTACTCGAGTAGATGGAATACTGACTGAGCTTTTT CDC42BPA CDC42 binding protein kinase alpha (DMPK-like) TRCN0000000659 CCGGCCGCAGATAAATGTAGAAATACTCGAGTATTTCTACATTTATCTGCGGTTTTT CDC42BPA CDC42 binding protein kinase alpha (DMPK-like) TRCN0000000660 CCGGGCGATTACATAGAGAAGACTTCTCGAGAAGTCTTCTCTATGTAATCGCTTTTT CDC42BPA CDC42 binding protein kinase alpha (DMPK-like) TRCN0000195557 CCGGCCGATGCTCTGGATCAATTTGCTCGAGCAAATTGATCCAGAGCATCGGTTTTTTG CDC42BPA CDC42 binding protein kinase alpha (DMPK-like) TRCN0000195596 CCGGCCAGGCTAGTGAGCGATTAAACTCGAGTTTAATCGCTCACTAGCCTGGTTTTTTG CDC42BPB CDC42 binding protein kinase beta (DMPK-like) TRCN0000000853 CCGGTCACCCTTTGTACCAGATGTTCTCGAGAACATCTGGTACAAAGGGTGATTTTT CDC42BPB CDC42 binding protein kinase beta (DMPK-like) TRCN0000000854 CCGGGCAGTCCAACACATTAACCAACTCGAGTTGGTTAATGTGTTGGACTGCTTTTT CDC42BPB CDC42 binding protein kinase beta (DMPK-like) TRCN0000000855 CCGGCAGCAATTCAAACCGAGATAACTCGAGTTATCTCGGTTTGAATTGCTGTTTTT CDC42BPB CDC42 binding protein kinase beta (DMPK-like) TRCN0000010559 CCGGGATTACTATGTGGGTGGTGATCTCGAGATCACCACCCACATAGTAATCTTTTT CDC42BPB CDC42 binding protein kinase beta (DMPK-like) TRCN0000195057 CCGGCCACAGAAAGTTCAATGAGATCTCGAGATCTCATTGAACTTTCTGTGGTTTTTTG CDC42BPG CDC42 binding protein kinase gamma (DMPK-like) TRCN0000021469 CCGGGCCTTTCTAAGCCATTGGGAACTCGAGTTCCCAATGGCTTAGAAAGGCTTTTT CDC42BPG CDC42 binding protein kinase gamma (DMPK-like) TRCN0000021470 CCGGCCTACCAACTTCAACCACCTACTCGAGTAGGTGGTTGAAGTTGGTAGGTTTTT CDC42BPG CDC42 binding protein kinase gamma (DMPK-like) TRCN0000021471 CCGGCCCTTCGTATCAAAGGTGAAACTCGAGTTTCACCTTTGATACGAAGGGTTTTT CDC42BPG CDC42 binding protein kinase gamma (DMPK-like) TRCN0000021472 CCGGCACGCATCTTTAGGGTGACAACTCGAGTTGTCACCCTAAAGATGCGTGTTTTT CDC42BPG CDC42 binding protein kinase gamma (DMPK-like) TRCN0000021473 CCGGGTACACACTCAAGGAGGCTTACTCGAGTAAGCCTCCTTGAGTGTGTACTTTTT CDC42BPG CDC42 binding protein kinase gamma (DMPK-like) TRCN0000199657 CCGGGCTGGGTGAATGATGAGAAGGCTCGAGCCTTCTCATCATTCACCCAGCTTTTTTG CDC7 cell division cycle 7 homolog (S. cerevisiae) TRCN0000003168 CCGGGCCACAGCACAGTTACAAGTACTCGAGTACTTGTAACTGTGCTGTGGCTTTTT CDC7 cell division cycle 7 homolog (S. cerevisiae) TRCN0000003171 CCGGCCTAATCTGTTTGGTAAGTATCTCGAGATACTTACCAAACAGATTAGGTTTTT CDC7 CDC7 cell division cycle 7 (S. cerevisiae) TRCN0000196970 CCGGGCTGACAGATTTCCCATTTAGCTCGAGCTAAATGGGAAATCTGTCAGCTTTTTTG CDC7 cell division cycle 7 homolog (S. cerevisiae) TRCN0000003169 CCGGCGTGATGTTAAGCCCAGCAATCTCGAGATTGCTGGGCTTAACATCACGTTTTT CDC7 cell division cycle 7 homolog (S. cerevisiae) TRCN0000003170 CCGGCCAGGACAATACTCAGGGAATCTCGAGATTCCCTGAGTATTGTCCTGGTTTTT CDK1 cyclin-dependent kinase 1 TRCN0000000582 CCGGGCTGTACTTCGTCTTCTAATTCTCGAGAATTAGAAGACGAAGTACAGCTTTTT CDK1 cyclin-dependent kinase 1 TRCN0000000583 CCGGGTGGAATCTTTACAGGACTATCTCGAGATAGTCCTGTAAAGATTCCACTTTTT CDK1 cyclin-dependent kinase 1 TRCN0000000585 CCGGTGGCTTGGATTTGCTCTCGAACTCGAGTTCGAGAGCAAATCCAAGCCATTTTT CDK1 cell division cycle 2, G1 to S and G2 to M TRCN0000196602 CCGGGTTTCCATATGTTATGTCAACCTCGAGGTTGACATAACATATGGAAACTTTTTTG CDK1 cell division cycle 2, G1 to S and G2 to M TRCN0000196603 CCGGGATTCAGAAATTGATCAACTCCTCGAGGAGTTGATCAATTTCTGAATCTTTTTTG CDK10 cyclin-dependent kinase 10 TRCN0000000687 CCGGGCTGCACTTCCTGTTCATGTACTCGAGTACATGAACAGGAAGTGCAGCTTTTT CDK10 cyclin-dependent kinase 10 TRCN0000000689 CCGGCTACAACAACCTGAAGCACAACTCGAGTTGTGCTTCAGGTTGTTGTAGTTTTT CDK10 cyclin-dependent kinase 10 TRCN0000001821 CCGGCCTGTTCATGTACGACCCTAACTCGAGTTAGGGTCGTACATGAACAGGTTTTT

161 Supplement

CDK10 cyclin-dependent kinase 10 TRCN0000001822 CCGGGCTGCACTTCCTGTTCATGTACTCGAGTACATGAACAGGAAGTGCAGCTTTTT CDK10 cyclin-dependent kinase 10 TRCN0000010653 CCGGCCGCTGTCTTTGAGTTGTGGTCTCGAGACCACAACTCAAAGACAGCGGTTTTT CDK12 cyclin-dependent kinase 12 TRCN0000001798 CCGGGCACTGAAAGAGGAGATTGTTCTCGAGAACAATCTCCTCTTTCAGTGCTTTTT CDK12 cyclin-dependent kinase 12 TRCN0000001795 CCGGGCTCGGCTCTATAACTCTGAACTCGAGTTCAGAGTTATAGAGCCGAGCTTTTT CDK12 cyclin-dependent kinase 12 TRCN0000001796 CCGGGCTGCTTAACATCCACTCCAACTCGAGTTGGAGTGGATGTTAAGCAGCTTTTT CDK12 cyclin-dependent kinase 12 TRCN0000001799 CCGGCCATTGAGCATCTTGAACATACTCGAGTATGTTCAAGATGCTCAATGGTTTTT CDK12 cyclin-dependent kinase 12 TRCN0000196423 CCGGGAAGTAGAAGTCCTGCATATTCTCGAGAATATGCAGGACTTCTACTTCTTTTTTG CDK13 cyclin-dependent kinase 13 TRCN0000000704 CCGGCGATGTCTTCTTGCTGATTTACTCGAGTAAATCAGCAAGAAGACATCGTTTTT CDK13 cyclin-dependent kinase 13 TRCN0000194677 CCGGCGATTGTACATCTTCACAAATCTCGAGATTTGTGAAGATGTACAATCGTTTTTTG CDK13 cyclin-dependent kinase 13 TRCN0000194804 CCGGCGACGTAGTTTCATTGGAAATCTCGAGATTTCCAATGAAACTACGTCGTTTTTTG CDK13 cyclin-dependent kinase 13 TRCN0000195065 CCGGCTGAGGAAGATCTAGATTATCCTCGAGGATAATCTAGATCTTCCTCAGTTTTTTG CDK13 cyclin-dependent kinase 13 TRCN0000196896 CCGGGCTGATAGCTTACGAGGAAATCTCGAGATTTCCTCGTAAGCTATCAGCTTTTTTG CDK14 cyclin-dependent kinase 14 TRCN0000002366 CCGGGAGTTCATTCTTTACCACATTCTCGAGAATGTGGTAAAGAATGAACTCTTTTT CDK14 cyclin-dependent kinase 14 TRCN0000002367 CCGGGCAAAGAGTCACCTAAAGTTACTCGAGTAACTTTAGGTGACTCTTTGCTTTTT CDK14 cyclin-dependent kinase 14 TRCN0000002368 CCGGCTCGCCAACAAGTCCCAAATTCTCGAGAATTTGGGACTTGTTGGCGAGTTTTT CDK14 cyclin-dependent kinase 14 TRCN0000002369 CCGGGTAGGTTGCATCTTTGTTGAACTCGAGTTCAACAAAGATGCAACCTACTTTTT CDK14 cyclin-dependent kinase 14 TRCN0000002370 CCGGCCACCCATACAGGAAATCCAACTCGAGTTGGATTTCCTGTATGGGTGGTTTTT CDK15 cyclin-dependent kinase 15 TRCN0000002097 CCGGCTACCTAACTACAATCCAGAACTCGAGTTCTGGATTGTAGTTAGGTAGTTTTT CDK15 cyclin-dependent kinase 15 TRCN0000002098 CCGGAGGCTCTTATGCGACAGTTTACTCGAGTAAACTGTCGCATAAGAGCCTTTTTT CDK15 cyclin-dependent kinase 15 TRCN0000002099 CCGGCAAATCTAACTCCATACTGAACTCGAGTTCAGTATGGAGTTAGATTTGTTTTT CDK15 cyclin-dependent kinase 15 TRCN0000002100 CCGGAGCAGAATAAATGGACAACTACTCGAGTAGTTGTCCATTTATTCTGCTTTTTT CDK15 cyclin-dependent kinase 15 TRCN0000196498 CCGGGCTTACTAAGAAGCTTCAAATCTCGAGATTTGAAGCTTCTTAGTAAGCTTTTTTG CDK16 cyclin-dependent kinase 16 TRCN0000010249 CCGGCGAGGAGTTCAAGACATACAACTCGAGTTGTATGTCTTGAACTCCTCGTTTTT CDK16 cyclin-dependent kinase 16 TRCN0000197222 CCGGGCTCTCATCACTCCTTCACTTCTCGAGAAGTGAAGGAGTGATGAGAGCTTTTTTG CDK16 cyclin-dependent kinase 16 TRCN0000197254 CCGGGCCTATCTGAGATTGGCTTTGCTCGAGCAAAGCCAATCTCAGATAGGCTTTTTTG CDK16 cyclin-dependent kinase 16 TRCN0000010250 CCGGCGAGGCATAGACAAGACCAATCTCGAGATTGGTCTTGTCTATGCCTCGTTTTT CDK16 cyclin-dependent kinase 16 TRCN0000010251 CCGGGACCTACATTAAGCTGGACAACTCGAGTTGTCCAGCTTAATGTAGGTCTTTTT CDK17 cyclin-dependent kinase 17 TRCN0000194654 CCGGCCAGAAAGTGTATCAATATTCCTCGAGGAATATTGATACACTTTCTGGTTTTTTG CDK17 cyclin-dependent kinase 17 TRCN0000195214 CCGGCATGTGTACTTTCGAAGTCTGCTCGAGCAGACTTCGAAAGTACACATGTTTTTTG CDK17 cyclin-dependent kinase 17 TRCN0000196448 CCGGGATGAATCATTGTCTGAATTGCTCGAGCAATTCAGACAATGATTCATCTTTTTTG CDK17 cyclin-dependent kinase 17 TRCN0000006241 CCGGGCGGAATCATTGCTGCTAAATCTCGAGATTTAGCAGCAATGATTCCGCTTTTT CDK17 cyclin-dependent kinase 17 TRCN0000006242 CCGGCGGATCTCAATGGAGGATTTACTCGAGTAAATCCTCCATTGAGATCCGTTTTT CDK18 cyclin-dependent kinase 18 TRCN0000006333 CCGGGCCTTAAATTGGCAGGTGGTACTCGAGTACCACCTGCCAATTTAAGGCTTTTT CDK18 cyclin-dependent kinase 18 TRCN0000006335 CCGGGAAACTGGAAACATACGTGAACTCGAGTTCACGTATGTTTCCAGTTTCTTTTT CDK18 cyclin-dependent kinase 18 TRCN0000006334 CCGGGCCCACAAAGACTTACTCCAACTCGAGTTGGAGTAAGTCTTTGTGGGCTTTTT CDK18 cyclin-dependent kinase 18 TRCN0000006336 CCGGCGCACTGAGACCATTGAAGAACTCGAGTTCTTCAATGGTCTCAGTGCGTTTTT CDK18 cyclin-dependent kinase 18 TRCN0000006337 CCGGGCGCAGCAAACTGACGGAGAACTCGAGTTCTCCGTCAGTTTGCTGCGCTTTTT CDK19 cyclin-dependent kinase 19 TRCN0000003140 CCGGGCTTGTAGAGAGATTGCACTTCTCGAGAAGTGCAATCTCTCTACAAGCTTTTT CDK19 cyclin-dependent kinase 19 TRCN0000003141 CCGGGATATTAGAAAGATGCCAGAACTCGAGTTCTGGCATCTTTCTAATATCTTTTT CDK19 cyclin-dependent kinase 19 TRCN0000003144 CCGGAGGACTGATAGCTCTTCTTTACTCGAGTAAAGAAGAGCTATCAGTCCTTTTTT CDK19 cyclin-dependent kinase 19 TRCN0000195069 CCGGCGTTCGTATTTATCTAGTTTCCTCGAGGAAACTAGATAAATACGAACGTTTTTTG CDK19 cyclin-dependent kinase 19 TRCN0000196528 CCGGGTATGGCTGCTGTTTGATTATCTCGAGATAATCAAACAGCAGCCATACTTTTTTG CDK2 cyclin-dependent kinase 2 TRCN0000000587 CCGGGCCCTCTGAACTTGCCTTAAACTCGAGTTTAAGGCAAGTTCAGAGGGCTTTTT CDK2 cyclin-dependent kinase 2 TRCN0000000588 CCGGGCCTGATTACAAGCCAAGTTTCTCGAGAAACTTGGCTTGTAATCAGGCTTTTT CDK2 cyclin-dependent kinase 2 TRCN0000000590 CCGGCTATGCCTGATTACAAGCCAACTCGAGTTGGCTTGTAATCAGGCATAGTTTTT CDK2 cyclin-dependent kinase 2 TRCN0000000591 CCGGCTCCTGGGCTGCAAATATTATCTCGAGATAATATTTGCAGCCCAGGAGTTTTT CDK2 cyclin-dependent kinase 2 TRCN0000010469 CCGGCCATCAAGCTAGCAGACTTTCTCGAGAAAGTCTGCTAGCTTGATGGCTTTTTG CDK20 cyclin-dependent kinase 20 TRCN0000002215 CCGGTCTTGAGGAGTCGCTGTTGAACTCGAGTTCAACAGCGACTCCTCAAGATTTTT CDK20 cyclin-dependent kinase 20 TRCN0000002216 CCGGAGAACGATATTGAACAGCTTTCTCGAGAAAGCTGTTCAATATCGTTCTTTTTT CDK20 cyclin-dependent kinase 20 TRCN0000002218 CCGGTGCCGGACTACAACAAGATCTCTCGAGAGATCTTGTTGTAGTCCGGCATTTTT CDK20 cyclin-dependent kinase 20 TRCN0000199104 CCGGCCTGTGTACTTCACATCACTGCTCGAGCAGTGATGTGAAGTACACAGGTTTTTTG CDK20 cyclin-dependent kinase 20 TRCN0000199297 CCGGCTGGGTCAATTCCTTCTCTACCTCGAGGTAGAGAAGGAATTGACCCAGTTTTTTG CDK3 cyclin-dependent kinase 3 TRCN0000000481 CCGGGAGAGCAAAGCACTAAGGAATCTCGAGATTCCTTAGTGCTTTGCTCTCTTTTT CDK3 cyclin-dependent kinase 3 TRCN0000000482 CCGGGCTCTTTCGTATCTTTCGTATCTCGAGATACGAAAGATACGAAAGAGCTTTTT CDK3 cyclin-dependent kinase 3 TRCN0000000484 CCGGGCAAGTTCTATACCACAGCTGCTCGAGCAGCTGTGGTATAGAACTTGCTTTTT CDK3 cyclin-dependent kinase 3 TRCN0000010525 CCGGAGGAAGCTCTATCTGGTGTTTCTCGAGAAACACCAGATAGAGCTTCCTTTTTT CDK3 cyclin-dependent kinase 3 TRCN0000199128 CCGGCCCTGTTTCCTGGTGACTCTGCTCGAGCAGAGTCACCAGGAAACAGGGTTTTTTG CDK4 cyclin-dependent kinase 4 TRCN0000000362 CCGGCCTTCCCATTTCTCTACACTACTCGAGTAGTGTAGAGAAATGGGAAGGTTTTT CDK4 cyclin-dependent kinase 4 TRCN0000000363 CCGGCCTAGATTTCCTTCATGCCAACTCGAGTTGGCATGAAGGAAATCTAGGTTTTT CDK4 cyclin-dependent kinase 4 TRCN0000000364 CCGGGAAATTGGTGTCGGTGCCTATCTCGAGATAGGCACCGACACCAATTTCTTTTT CDK4 cyclin-dependent kinase 4 TRCN0000000365 CCGGAGGACATATCTGGACAAGGCACTCGAGTGCCTTGTCCAGATATGTCCTTTTTT CDK4 cyclin-dependent kinase 4 TRCN0000009876 CCGGCTTTATCTCTGAGGCTATGGACTCGAGTCCATAGCCTCAGAGATAAAGTTTTTG

162 Supplement

CDK5 cyclin-dependent kinase 5 TRCN0000021465 CCGGTCTGAAGTGTAACCCTGTCCACTCGAGTGGACAGGGTTACACTTCAGATTTTT CDK5 cyclin-dependent kinase 5 TRCN0000021466 CCGGTGTCCAGCGTATCTCAGCAGACTCGAGTCTGCTGAGATACGCTGGACATTTTT CDK5 cyclin-dependent kinase 5 TRCN0000021467 CCGGATTCCCGTCCGCTGTTACTCACTCGAGTGAGTAACAGCGGACGGGAATTTTTT CDK5 cyclin-dependent kinase 5 TRCN0000194974 CCGGCCTGAGATTGTAAAGTCATTCCTCGAGGAATGACTTTACAATCTCAGGTTTTTTG CDK5 cyclin-dependent kinase 5 TRCN0000195513 CCGGCAGAACCTTCTGAAGTGTAACCTCGAGGTTACACTTCAGAAGGTTCTGTTTTTTG CDK6 cyclin-dependent kinase 6 TRCN0000009877 CCGGAGTAGTGCATCGCGATCTAACTCGAGTTAGATCGCGATGCACTACTCTTTTTG CDK6 cyclin-dependent kinase 6 TRCN0000039746 CCGGCTTCTGAAGTGTTTGACATTTCTCGAGAAATGTCAAACACTTCAGAAGTTTTTG CDK6 cyclin-dependent kinase 6 TRCN0000055435 CCGGTCTGGAGTGTTGGCTGCATATCTCGAGATATGCAGCCAACACTCCAGATTTTT CDK6 cyclin-dependent kinase 6 TRCN0000194866 CCGGCAGATGTTGATCAACTAGGAACTCGAGTTCCTAGTTGATCAACATCTGTTTTTTG CDK6 cyclin-dependent kinase 6 TRCN0000194893 CCGGCATGAGATGTTCCTATCTTAACTCGAGTTAAGATAGGAACATCTCATGTTTTTTG CDK7 cyclin-dependent kinase 7 TRCN0000000592 CCGGGCTGTAGAAGTGAGTTTGTAACTCGAGTTACAAACTCACTTCTACAGCTTTTT CDK7 cyclin-dependent kinase 7 TRCN0000000593 CCGGGCAGGAGACGACTTACTAGATCTCGAGATCTAGTAAGTCGTCTCCTGCTTTTT CDK7 cyclin-dependent kinase 7 TRCN0000000594 CCGGTCAGAAGCTAAAGATGGTATACTCGAGTATACCATCTTTAGCTTCTGATTTTT CDK7 cyclin-dependent kinase 7 TRCN0000000595 CCGGGTGGGCTGTTGGCTGTATATTCTCGAGAATATACAGCCAACAGCCCACTTTTT CDK7 cyclin-dependent kinase 7 TRCN0000000596 CCGGCATTTAAGAGTTTCCCTGGAACTCGAGTTCCAGGGAAACTCTTAAATGTTTTT CDK8 cyclin-dependent kinase 8 TRCN0000000489 CCGGATGTCCAGTAGCCAAGTTCCACTCGAGTGGAACTTGGCTACTGGACATTTTTT CDK8 cyclin-dependent kinase 8 TRCN0000000490 CCGGGCAGGGCAATAACCACACTAACTCGAGTTAGTGTGGTTATTGCCCTGCTTTTT CDK8 cyclin-dependent kinase 8 TRCN0000000491 CCGGCCTCTGGCATATAATCAAGTTCTCGAGAACTTGATTATATGCCAGAGGTTTTT CDK8 cyclin-dependent kinase 8 TRCN0000000492 CCGGCAAGGCATTATACCAAAGCTACTCGAGTAGCTTTGGTATAATGCCTTGTTTTT CDK8 cyclin-dependent kinase 8 TRCN0000000493 CCGGCACTTCCTACATCAGACGTTTCTCGAGAAACGTCTGATGTAGGAAGTGTTTTT CDK9 cyclin-dependent kinase 9 TRCN0000000494 CCGGGCACAGTTTGGTCCGTTAGAACTCGAGTTCTAACGGACCAAACTGTGCTTTTT CDK9 cyclin-dependent kinase 9 TRCN0000000497 CCGGCTACTACATCCACAGAAACAACTCGAGTTGTTTCTGTGGATGTAGTAGTTTTT CDK9 cyclin-dependent kinase 9 TRCN0000000498 CCGGTGATTGAGATTTGTCGAACCACTCGAGTGGTTCGACAAATCTCAATCATTTTT CDK9 cyclin-dependent kinase 9 TRCN0000196455 CCGGGAAGTTTCCAAATACGAGAAGCTCGAGCTTCTCGTATTTGGAAACTTCTTTTTTG CDK9 cyclin-dependent kinase 9 TRCN0000199187 CCGGCCAAACGTGGACAACTATGAGCTCGAGCTCATAGTTGTCCACGTTTGGTTTTTTG CDKL1 cyclin-dependent kinase-like 1 (CDC2-related kinase) TRCN0000006069 CCGGCCAGCAAGTGTTTAGCACGAACTCGAGTTCGTGCTAAACACTTGCTGGTTTTT CDKL1 cyclin-dependent kinase-like 1 (CDC2-related kinase) TRCN0000006070 CCGGGCCATCAAGAAGTTTCTGGAACTCGAGTTCCAGAAACTTCTTGATGGCTTTTT CDKL1 cyclin-dependent kinase-like 1 (CDC2-related kinase) TRCN0000006071 CCGGCACGAAACATTCCGTGATTAACTCGAGTTAATCACGGAATGTTTCGTGTTTTT CDKL1 cyclin-dependent kinase-like 1 (CDC2-related kinase) TRCN0000006072 CCGGCCTGAAGATATGGAACCACTTCTCGAGAAGTGGTTCCATATCTTCAGGTTTTT CDKL1 cyclin-dependent kinase-like 1 (CDC2-related kinase) TRCN0000006073 CCGGCCGGTGGATGTTTGGGCAATTCTCGAGAATTGCCCAAACATCCACCGGTTTTT CDKL2 cyclin-dependent kinase-like 2 (CDC2-related kinase) TRCN0000000724 CCGGGAACTGGATGATGCTCTTGCACTCGAGTGCAAGAGCATCATCCAGTTCTTTTT CDKL2 cyclin-dependent kinase-like 2 (CDC2-related kinase) TRCN0000000726 CCGGGAGTTATGGAATGGTGATGAACTCGAGTTCATCACCATTCCATAACTCTTTTT CDKL2 cyclin-dependent kinase-like 2 (CDC2-related kinase) TRCN0000000728 CCGGTGCGAGAAATCAAGTTACTAACTCGAGTTAGTAACTTGATTTCTCGCATTTTT CDKL2 cyclin-dependent kinase-like 2 (CDC2-related kinase) TRCN0000000725 CCGGCAGTAGGACAAGCCACAACAACTCGAGTTGTTGTGGCTTGTCCTACTGTTTTT CDKL2 cyclin-dependent kinase-like 2 (CDC2-related kinase) TRCN0000000727 CCGGCCATCAGGCATTTATAACATTCTCGAGAATGTTATAAATGCCTGATGGTTTTT CDKL3 cyclin-dependent kinase-like 3 TRCN0000002376 CCGGCACACAGTATTAGATGAGTTACTCGAGTAACTCATCTAATACTGTGTGTTTTT CDKL3 cyclin-dependent kinase-like 3 TRCN0000002377 CCGGGCCACCCATCAATCTAACTAACTCGAGTTAGTTAGATTGATGGGTGGCTTTTT CDKL3 cyclin-dependent kinase-like 3 TRCN0000002378 CCGGGTCTGTATGTAAACTGAACTTCTCGAGAAGTTCAGTTTACATACAGACTTTTT CDKL3 cyclin-dependent kinase-like 3 TRCN0000002379 CCGGACTAACTGTAATGGCTTGAAACTCGAGTTTCAAGCCATTACAGTTAGTTTTTT CDKL3 cyclin-dependent kinase-like 3 TRCN0000002380 CCGGCCATCAATCTAACTAACAGTACTCGAGTACTGTTAGTTAGATTGATGGTTTTT CDKL4 cyclin-dependent kinase-like 4 TRCN0000021519 CCGGGCTATAAAAATAATTCCTTTTCTCGAGAAAAGGAATTATTTTTATAGCTTTTT CDKL4 cyclin-dependent kinase-like 4 TRCN0000021520 CCGGCCAAGACATCAATCAATCTTTCTCGAGAAAGATTGATTGATGTCTTGGTTTTT CDKL4 cyclin-dependent kinase-like 4 TRCN0000021521 CCGGCCGATTATGTAGCTACGAGATCTCGAGATCTCGTAGCTACATAATCGGTTTTT CDKL4 cyclin-dependent kinase-like 4 TRCN0000021522 CCGGCTGAAGATGATCCTGTTGTTACTCGAGTAACAACAGGATCATCTTCAGTTTTT CDKL4 cyclin-dependent kinase-like 4 TRCN0000021523 CCGGGTATGGTTCTTCAGTCGATATCTCGAGATATCGACTGAAGAACCATACTTTTT CDKL5 cyclin-dependent kinase-like 5 TRCN0000002011 CCGGACATCTCTCTTCGGCCTCAAACTCGAGTTTGAGGCCGAAGAGAGATGTTTTTT CDKL5 cyclin-dependent kinase-like 5 TRCN0000002012 CCGGGTGGAGTTGAAGGAAGCATTTCTCGAGAAATGCTTCCTTCAACTCCACTTTTT CDKL5 cyclin-dependent kinase-like 5 TRCN0000002013 CCGGCTACATCTATCAGCTAATCAACTCGAGTTGATTAGCTGATAGATGTAGTTTTT CDKL5 cyclin-dependent kinase-like 5 TRCN0000002014 CCGGGGAAGAACCAATTAACACCAACTCGAGTTGGTGTTAATTGGTTCTTCCTTTTT CDKL5 cyclin-dependent kinase-like 5 TRCN0000002015 CCGGCGACAGAACAACAAGGAGAATCTCGAGATTCTCCTTGTTGTTCTGTCGTTTTT CHEK1 CHK1 checkpoint homolog (S. pombe) TRCN0000000499 CCGGCTGCAAATAGTAGTTCCTGAACTCGAGTTCAGGAACTACTATTTGCAGTTTTT CHEK1 CHK1 checkpoint homolog (S. pombe) TRCN0000000500 CCGGCGCAGTGAAGATTGTAGATATCTCGAGATATCTACAATCTTCACTGCGTTTTT CHEK1 CHK1 checkpoint homolog (S. pombe) TRCN0000000502 CCGGGTGGTTTATCTGCATGGTATTCTCGAGAATACCATGCAGATAAACCACTTTTT CHEK1 CHK1 checkpoint homolog (S. pombe) TRCN0000009942 CCGGGTAAACAGTGCTTCTAGTGAACTCGAGTTCACTAGAAGCACTGTTTACTTTTT CHEK1 CHK1 checkpoint homolog (S. pombe) TRCN0000009946 CCGGGACAAATCTTATCAATGCCTGCTCGAGCAGGCATTGATAAGATTTGTCTTTTT CHEK2 CHK2 checkpoint homolog (S. pombe) TRCN0000010210 CCGGTACATAGAAGATCACAGTGGCCTCGAGGCCACTGTGATCTTCTATGTATTTTT CHEK2 CHK2 checkpoint homolog (S. pombe) TRCN0000039945 CCGGCGCCGTCCTTTGAATAACAATCTCGAGATTGTTATTCAAAGGACGGCGTTTTTG CHEK2 CHK2 checkpoint homolog (S. pombe) TRCN0000010209 CCGGGAACAGATAAATACCGAACATCTCGAGATGTTCGGTATTTATCTGTTCTTTTT CHEK2 CHK2 checkpoint homolog (S. pombe) TRCN0000010211 CCGGTGTAAGAAAGTAGCCATAAAGCTCGAGCTTTATGGCTACTTTCTTACATTTTT CHEK2 CHK2 checkpoint homolog (S. pombe) TRCN0000010212 CCGGAGCTAAATCATCCTTGCATCACTCGAGTGATGCAAGGATGATTTAGCTTTTTT CHUK conserved helix-loop-helix ubiquitous kinase TRCN0000000507 CCGGGCAAATGAGGAACAGGGCAATCTCGAGATTGCCCTGTTCCTCATTTGCTTTTT CHUK conserved helix-loop-helix ubiquitous kinase TRCN0000000508 CCGGGCGTGCCATTGATCTATATAACTCGAGTTATATAGATCAATGGCACGCTTTTT

163 Supplement

CHUK conserved helixloophelix ubiquitous kinase TRCN0000194782 CCGGCCAGATACTTTCTTTACTAAGCTCGAGCTTAGTAAAGAAAGTATCTGGTTTTTTG CHUK conserved helixloophelix ubiquitous kinase TRCN0000196924 CCGGGCTGCTCACAAGTTCTATTTCCTCGAGGAAATAGAACTTGTGAGCAGCTTTTTTG CHUK conserved helixloophelix ubiquitous kinase TRCN0000199496 CCGGGCAGATGACGTATGGGATATCCTCGAGGATATCCCATACGTCATCTGCTTTTTTG CIT citron (rho-interacting, serine/threonine kinase 21) TRCN0000006314 CCGGGCCAATAAACTTGCAGCAAATCTCGAGATTTGCTGCAAGTTTATTGGCTTTTT CIT citron (rho-interacting, serine/threonine kinase 21) TRCN0000006315 CCGGGCGTCCTCATACCAGGATAAACTCGAGTTTATCCTGGTATGAGGACGCTTTTT CIT citron (rho-interacting, serine/threonine kinase 21) TRCN0000006316 CCGGCGGAAGTATTCCGACACCATACTCGAGTATGGTGTCGGAATACTTCCGTTTTT CIT citron (rho-interacting, serine/threonine kinase 21) TRCN0000006313 CCGGCCCTCCTATTAGAGTACGAAACTCGAGTTTCGTACTCTAATAGGAGGGTTTTT CIT citron (rho-interacting, serine/threonine kinase 21) TRCN0000006317 CCGGGCTGATCTACTGAAGACAGAACTCGAGTTCTGTCTTCAGTAGATCAGCTTTTT CLK1 CDC-like kinase 1 TRCN0000000755 CCGGGCTGCAAATACAATCACTCTACTCGAGTAGAGTGATTGTATTTGCAGCTTTTT CLK1 CDC-like kinase 1 TRCN0000000758 CCGGGATATGCAAGTCTGTGAATTTCTCGAGAAATTCACAGACTTGCATATCTTTTT CLK1 CDC-like kinase 1 TRCN0000000754 CCGGTGGTTCATTAAGTACATAGCTCTCGAGAGCTATGTACTTAATGAACCATTTTT CLK1 CDC-like kinase 1 TRCN0000000756 CCGGGCTCGCTCAGAAATACAAGTTCTCGAGAACTTGTATTTCTGAGCGAGCTTTTT CLK1 CDC-like kinase 1 TRCN0000000757 CCGGGATATGTTTCAAGAGCCTGTACTCGAGTACAGGCTCTTGAAACATATCTTTTT CLK2 CDC-like kinase 2 TRCN0000195230 CCGGCTATCGGCATTCCTATGAATACTCGAGTATTCATAGGAATGCCGATAGTTTTTTG CLK2 CDC-like kinase 2 TRCN0000197205 CCGGGCTCTTCGATCTGATTGAAAGCTCGAGCTTTCAATCAGATCGAAGAGCTTTTTTG CLK2 CDC-like kinase 2 TRCN0000199189 CCGGCGAGCCAGAGTTCACTCCTTCCTCGAGGAAGGAGTGAACTCTGGCTCGTTTTTTG CLK2 CDC-like kinase 2 TRCN0000000750 CCGGCTTCCTCCTGGCTCTCTATATCTCGAGATATAGAGAGCCAGGAGGAAGTTTTT CLK2 CDC-like kinase 2 TRCN0000000751 CCGGGAGATCAACGTGCTAGAGAAACTCGAGTTTCTCTAGCACGTTGATCTCTTTTT CLK2 CDC-like kinase 2 TRCN0000196747 CCGGGCCTTGTACATAATACTATTCCTCGAGGAATAGTATTATGTACAAGGCTTTTTTG CLK3 CDC-like kinase 3 TRCN0000000745 CCGGGCTAGAAATCAACGTGCTCAACTCGAGTTGAGCACGTTGATTTCTAGCTTTTT CLK3 CDC-like kinase 3 TRCN0000000746 CCGGCCGTACCAGGAAGCAGAAATACTCGAGTATTTCTGCTTCCTGGTACGGTTTTT CLK3 CDC-like kinase 3 TRCN0000000747 CCGGCCTGTGTGTCTTGATGTCTGACTCGAGTCAGACATCAAGACACACAGGTTTTT CLK3 CDC-like kinase 3 TRCN0000000748 CCGGACTACTATGGACCTTCACGTTCTCGAGAACGTGAAGGTCCATAGTAGTTTTTT CLK3 CDC-like kinase 3 TRCN0000000749 CCGGCATTGGCTGCATTCTCTTTGACTCGAGTCAAAGAGAATGCAGCCAATGTTTTT CLK4 CDC-like kinase 4 TRCN0000001350 CCGGGTGTCCAGTGATAAATGTGATCTCGAGATCACATTTATCACTGGACACTTTTT CLK4 CDC-like kinase 4 TRCN0000001353 CCGGCGATGTGTCCAGATGCTAGAACTCGAGTTCTAGCATCTGGACACATCGTTTTT CLK4 CDC-like kinase 4 TRCN0000001351 CCGGGCATCCTTTCTTTGACTTATTCTCGAGAATAAGTCAAAGAAAGGATGCTTTTT CLK4 CDC-like kinase 4 TRCN0000001352 CCGGCTGGCAATGATGGAACGAATACTCGAGTATTCGTTCCATCATTGCCAGTTTTT CLK4 CDC-like kinase 4 TRCN0000010605 CCGGTGACGAATACAGGAATGACTACTCGAGTAGTCATTCCTGTATTCGTCATTTTT CSF1R colony stimulating factor 1 receptor TRCN0000010645 CCGGAGCTCGCAATCCCTCAACAATCTCGAGATTGTTGAGGGATTGCGAGCTTTTTT CSF1R colony stimulating factor 1 receptor TRCN0000001590 CCGGGACTGACTTTATGCCTATGAACTCGAGTTCATAGGCATAAAGTCAGTCTTTTT CSF1R colony stimulating factor 1 receptor TRCN0000001591 CCGGCTGCTGACTGTTGAGACCTTACTCGAGTAAGGTCTCAACAGTCAGCAGTTTTT CSF1R colony stimulating factor 1 receptor TRCN0000001592 CCGGCGACTATAAGAACATCCACCTCTCGAGAGGTGGATGTTCTTATAGTCGTTTTT CSF1R colony stimulating factor 1 receptor TRCN0000010644 CCGGCCAACAACGCTACCTTCCAAACTCGAGTTTGGAAGGTAGCGTTGTTGGTTTTT CSK c-src tyrosine kinase TRCN0000000803 CCGGAGAAAGAAAGTACCCAGCAAACTCGAGTTTGCTGGGTACTTTCTTTCTTTTTT CSK c-src tyrosine kinase TRCN0000000804 CCGGCGAGGAGGTGTACTTTGAGAACTCGAGTTCTCAAAGTACACCTCCTCGTTTTT CSK c-src tyrosine kinase TRCN0000000805 CCGGTGTCTCCTCAAGTTCTCGCTACTCGAGTAGCGAGAACTTGAGGAGACATTTTT CSK c-src tyrosine kinase TRCN0000000806 CCGGGAGAAGGGCTACAAGATGGATCTCGAGATCCATCTTGTAGCCCTTCTCTTTTT CSK c-src tyrosine kinase TRCN0000000807 CCGGTGCATTAAGAACGACGCCACTCTCGAGAGTGGCGTCGTTCTTAATGCATTTTT CSNK1A1 casein kinase 1, alpha 1 TRCN0000006042 CCGGGCAGAATTTGCGATGTACTTACTCGAGTAAGTACATCGCAAATTCTGCTTTTT CSNK1A1 casein kinase 1, alpha 1 TRCN0000006044 CCGGCATCTATTTGGCGATCAACATCTCGAGATGTTGATCGCCAAATAGATGTTTTT CSNK1A1 casein kinase 1, alpha 1 TRCN0000006045 CCGGGAATTCATTGTCGGAGGGAAACTCGAGTTTCCCTCCGACAATGAATTCTTTTT CSNK1A1 casein kinase 1, alpha 1 TRCN0000194651 CCGGCCTTGCTGACTCACTATTAAACTCGAGTTTAATAGTGAGTCAGCAAGGTTTTTTG CSNK1A1 casein kinase 1, alpha 1 TRCN0000196287 CCGGGCAAGCTCTATAAGATTCTTCCTCGAGGAAGAATCTTATAGAGCTTGCTTTTTTG CSNK1A1L casein kinase 1, alpha 1-like TRCN0000007024 CCGGCCCAAAGTGTAGCCTCTGTAACTCGAGTTACAGAGGCTACACTTTGGGTTTTT CSNK1A1L casein kinase 1, alpha 1-like TRCN0000007025 CCGGGAGAGCAAACTCTACACGATTCTCGAGAATCGTGTAGAGTTTGCTCTCTTTTT CSNK1A1L casein kinase 1, alpha 1-like TRCN0000007028 CCGGGCTGGAATCTCAGAAGGTCAACTCGAGTTGACCTTCTGAGATTCCAGCTTTTT CSNK1A1L casein kinase 1, alpha 1-like TRCN0000195022 CCGGCAGAATTGAATACGTGCATACCTCGAGGTATGCACGTATTCAATTCTGTTTTTTG CSNK1A1L casein kinase 1, alpha 1-like TRCN0000195180 CCGGCTATATCATGTTCTCGGTATTCTCGAGAATACCGAGAACATGATATAGTTTTTTG CSNK1D casein kinase 1, delta TRCN0000000598 CCGGCGAAAGGATTAGCGAGAAGAACTCGAGTTCTTCTCGCTAATCCTTTCGTTTTT CSNK1D casein kinase 1, delta TRCN0000000599 CCGGCCAAGAGACAGAAATACGAAACTCGAGTTTCGTATTTCTGTCTCTTGGTTTTT CSNK1D casein kinase 1, delta TRCN0000001552 CCGGCCAAGAGACAGAAATACGAAACTCGAGTTTCGTATTTCTGTCTCTTGGTTTTT CSNK1D casein kinase 1, delta TRCN0000001553 CCGGCGAAGTGTTGTGTAAAGGCTACTCGAGTAGCCTTTACACAACACTTCGTTTTT CSNK1D casein kinase 1, delta TRCN0000000600 CCGGCGAAGTGTTGTGTAAAGGCTACTCGAGTAGCCTTTACACAACACTTCGTTTTT CSNK1E casein kinase 1, epsilon TRCN0000000602 CCGGCCAGTGTTTGCTTAGTGTCTTCTCGAGAAGACACTAAGCAAACACTGGTTTTT CSNK1E casein kinase 1, epsilon TRCN0000000603 CCGGCTCTTACCTACGTCAGCTCTTCTCGAGAAGAGCTGACGTAGGTAAGAGTTTTT CSNK1E casein kinase 1, epsilon TRCN0000000604 CCGGTCAGCGAGAAGAAGATGTCAACTCGAGTTGACATCTTCTTCTCGCTGATTTTT CSNK1E casein kinase 1, epsilon TRCN0000001834 CCGGTCAGCGAGAAGAAGATGTCAACTCGAGTTGACATCTTCTTCTCGCTGATTTTT CSNK1E casein kinase 1, epsilon TRCN0000001835 CCGGCCAGTGTTTGCTTAGTGTCTTCTCGAGAAGACACTAAGCAAACACTGGTTTTT CSNK1G1 casein kinase 1, gamma 1 TRCN0000010607 CCGGCCTTTGACTATGCCTATGATTCTCGAGAATCATAGGCATAGTCAAAGGTTTTT CSNK1G1 casein kinase 1, gamma 1 TRCN0000010608 CCGGTGACCGAACATTTACTTTGAACTCGAGTTCAAAGTAAATGTTCGGTCATTTTT CSNK1G1 casein kinase 1, gamma 1 TRCN0000010609 CCGGGATGGCAACCTACCTTCGATACTCGAGTATCGAAGGTAGGTTGCCATCTTTTT

164 Supplement

CSNK1G1 casein kinase 1, gamma 1 TRCN0000197037 CCGGGAACCTCATTTACCGAGATGTCTCGAGACATCTCGGTAAATGAGGTTCTTTTTTG CSNK1G1 casein kinase 1, gamma 1 TRCN0000010606 CCGGTCAGAATAGTAGCAGATGTAACTCGAGTTACATCTGCTACTATTCTGATTTTT CSNK1G2 casein kinase 1, gamma 2 TRCN0000038669 CCGGCCCTCCAAGAGCATTAACTATCTCGAGATAGTTAATGCTCTTGGAGGGTTTTTG CSNK1G2 casein kinase 1, gamma 2 TRCN0000038670 CCGGGCACACCAAGAGCCTAATCTACTCGAGTAGATTAGGCTCTTGGTGTGCTTTTTG CSNK1G2 casein kinase 1, gamma 2 TRCN0000038671 CCGGCGCCTAGGAAAGAATCTCTATCTCGAGATAGAGATTCTTTCCTAGGCGTTTTTG CSNK1G2 casein kinase 1, gamma 2 TRCN0000038672 CCGGCTGTTTCTTCAAGAGGAGAAACTCGAGTTTCTCCTCTTGAAGAAACAGTTTTTG CSNK1G2 casein kinase 1, gamma 2 TRCN0000038673 CCGGAGTGGCTTCGTGTTCGACTATCTCGAGATAGTCGAACACGAAGCCACTTTTTTG CSNK1G3 casein kinase 1, gamma 3 TRCN0000000808 CCGGCACCGAAACTTACTGCTGAATCTCGAGATTCAGCAGTAAGTTTCGGTGTTTTT CSNK1G3 casein kinase 1, gamma 3 TRCN0000000809 CCGGCCGGAGACAAAGAAACACATACTCGAGTATGTGTTTCTTTGTCTCCGGTTTTT CSNK1G3 casein kinase 1, gamma 3 TRCN0000000811 CCGGACTTCTTAATAGGACGACCAACTCGAGTTGGTCGTCCTATTAAGAAGTTTTTT CSNK1G3 casein kinase 1, gamma 3 TRCN0000010550 CCGGCCCAGCAAGTTATTCACATTACTCGAGTAATGTGAATAACTTGCTGGGTTTTT CSNK1G3 casein kinase 1, gamma 3 TRCN0000196897 CCGGGCTAGATATATGAGCATAAACCTCGAGGTTTATGCTCATATATCTAGCTTTTTTG CSNK2A1 casein kinase 2, alpha 1 polypeptide TRCN0000000606 CCGGGCTGCATTTAGGTGGAGACTTCTCGAGAAGTCTCCACCTAAATGCAGCTTTTT CSNK2A1 casein kinase 2, alpha 1 polypeptide TRCN0000000607 CCGGCGTAAACAACACAGACTTCAACTCGAGTTGAAGTCTGTGTTGTTTACGTTTTT CSNK2A1 casein kinase 2, alpha 1 polypeptide TRCN0000000608 CCGGCAAGAATATAATGTCCGAGTTCTCGAGAACTCGGACATTATATTCTTGTTTTT CSNK2A1 casein kinase 2, alpha 1 polypeptide TRCN0000000609 CCGGAGAATTTGAGAGGAGGTCCCACTCGAGTGGGACCTCCTCTCAAATTCTTTTTT CSNK2A1 casein kinase 2, alpha 1 polypeptide TRCN0000000610 CCGGCCAAGAATATAATGTCCGAGTCTCGAGACTCGGACATTATATTCTTGGTTTTT CSNK2A2 casein kinase 2, alpha prime polypeptide TRCN0000000614 CCGGCTGGGACAACATTCACGGAAACTCGAGTTTCCGTGAATGTTGTCCCAGTTTTT CSNK2A2 casein kinase 2, alpha prime polypeptide TRCN0000194896 CCGGCCTCACAATGTCATGATAGATCTCGAGATCTATCATGACATTGTGAGGTTTTTTG CSNK2A2 casein kinase 2, alpha prime polypeptide TRCN0000000611 CCGGGCGGCAGTTACATATTATTATCTCGAGATAATAATATGTAACTGCCGCTTTTT CSNK2A2 casein kinase 2, alpha prime polypeptide TRCN0000000612 CCGGCCTCGTGGACTATCAGATGTACTCGAGTACATCTGATAGTCCACGAGGTTTTT CSNK2A2 casein kinase 2, alpha prime polypeptide TRCN0000000613 CCGGCGTGGTGGAACAAATATCATTCTCGAGAATGATATTTGTTCCACCACGTTTTT DAPK1 death-associated protein kinase 1 TRCN0000000982 CCGGCTGTCCTGAGAAGCATGTAATCTCGAGATTACATGCTTCTCAGGACAGTTTTT DAPK1 death-associated protein kinase 1 TRCN0000000983 CCGGCCACGTCGATACCTTGAAATTCTCGAGAATTTCAAGGTATCGACGTGGTTTTT DAPK1 death-associated protein kinase 1 TRCN0000000984 CCGGCGGCACCTCTTACAATTCCATCTCGAGATGGAATTGTAAGAGGTGCCGTTTTT DAPK1 death-associated protein kinase 1 TRCN0000000985 CCGGCGACATCCAGAACGCTTATTTCTCGAGAAATAAGCGTTCTGGATGTCGTTTTT DAPK1 death-associated protein kinase 1 TRCN0000194694 CCGGCCTTGCTTCTTACTGATAATTCTCGAGAATTATCAGTAAGAAGCAAGGTTTTTTG DAPK2 death-associated protein kinase 2 TRCN0000001719 CCGGTCATCACCTACATCCTCTTAACTCGAGTTAAGAGGATGTAGGTGATGATTTTT DAPK2 death-associated protein kinase 2 TRCN0000001722 CCGGTGCTCCAGAAATTGTGAACTACTCGAGTAGTTCACAATTTCTGGAGCATTTTT DAPK2 death-associated protein kinase 2 TRCN0000196486 CCGGGAAGATGGAGTTGAATTTAAGCTCGAGCTTAAATTCAACTCCATCTTCTTTTTTG DAPK2 death-associated protein kinase 2 TRCN0000199968 CCGGCCTGAGCACTTTGCAAGAGAGCTCGAGCTCTCTTGCAAAGTGCTCAGGTTTTTTG DAPK2 death-associated protein kinase 2 TRCN0000001718 CCGGTACCTGATGCTTGGCTTCTTTCTCGAGAAAGAAGCCAAGCATCAGGTATTTTT DAPK3 death-associated protein kinase 3 TRCN0000000519 CCGGCAACCCACGAATCAAGCTCATCTCGAGATGAGCTTGATTCGTGGGTTGTTTTT DAPK3 death-associated protein kinase 3 TRCN0000000520 CCGGCATCGCACACTTTGACCTGAACTCGAGTTCAGGTCAAAGTGTGCGATGTTTTT DAPK3 death-associated protein kinase 3 TRCN0000009958 CCGGCCCAAGCGGAGAATGACCATTCTCGAGAATGGTCATTCTCCGCTTGGGTTTTT DAPK3 death-associated protein kinase 3 TRCN0000000522 CCGGGAAGGAGTACACCATCAAGTCCTCGAGGACTTGATGGTGTACTCCTTCTTTTT DAPK3 death-associated protein kinase 3 TRCN0000009944 CCGGCAAGCAAGTAGCCTCCGAGATCTCGAGATCTCGGAGGCTACTTGCTTGTTTTT DCLK1 doublecortin-like kinase 1 TRCN0000002144 CCGGAGCTACAATAACAGAACGATACTCGAGTATCGTTCTGTTATTGTAGCTTTTTT DCLK1 doublecortin-like kinase 1 TRCN0000002145 CCGGGAACTGTATCTTGTCATGGAACTCGAGTTCCATGACAAGATACAGTTCTTTTT DCLK1 doublecortin-like kinase 1 TRCN0000002146 CCGGCAGGTATCTTTGTAGCGGTTTCTCGAGAAACCGCTACAAAGATACCTGTTTTT DCLK1 doublecortin-like kinase 1 TRCN0000002147 CCGGGCGCCATCAAATACCTGCATACTCGAGTATGCAGGTATTTGATGGCGCTTTTT DCLK1 doublecortin-like kinase 1 TRCN0000194785 CCGGCCATTACTTCCACTAACAAATCTCGAGATTTGTTAGTGGAAGTAATGGTTTTTTG DCLK2 doublecortin-like kinase 2 TRCN0000001970 CCGGGCAGCCAACTTTCTACTCCTACTCGAGTAGGAGTAGAAAGTTGGCTGCTTTTT DCLK2 doublecortin-like kinase 2 TRCN0000001971 CCGGGCCGAGTGAAACATCCCAATACTCGAGTATTGGGATGTTTCACTCGGCTTTTT DCLK2 doublecortin-like kinase 2 TRCN0000001974 CCGGCCAGGAGAATGTGCAACTTTACTCGAGTAAAGTTGCACATTCTCCTGGTTTTT DCLK2 doublecortin-like kinase 2 TRCN0000001972 CCGGTCAGTCAAATGCTTCAGGTAACTCGAGTTACCTGAAGCATTTGACTGATTTTT DCLK2 doublecortin-like kinase 2 TRCN0000001973 CCGGGCAAATCACCAGCTTCAGTTACTCGAGTAACTGAAGCTGGTGATTTGCTTTTT DCLK3 doublecortin-like kinase 3 TRCN0000021554 CCGGCCCAGCAGAAATTCAAGCATACTCGAGTATGCTTGAATTTCTGCTGGGTTTTT DCLK3 doublecortin-like kinase 3 TRCN0000021555 CCGGCCCGAAATTCTTTCTGAGAAACTCGAGTTTCTCAGAAAGAATTTCGGGTTTTT DCLK3 doublecortin-like kinase 3 TRCN0000021556 CCGGCCTCGGGTGAAATTATCAGATCTCGAGATCTGATAATTTCACCCGAGGTTTTT DCLK3 doublecortin-like kinase 3 TRCN0000021558 CCGGCCGTGTGAGGAAACTGTTTAACTCGAGTTAAACAGTTTCCTCACACGGTTTTT DCLK3 doublecortin-like kinase 3 TRCN0000021557 CCGGGCCTATGCGATGAAGATCATTCTCGAGAATGATCTTCATCGCATAGGCTTTTT DDR1 discoidin domain receptor tyrosine kinase 1 TRCN0000000617 CCGGGTATTTATCTGAGGCCGTGTACTCGAGTACACGGCCTCAGATAAATACTTTTT DDR1 discoidin domain receptor tyrosine kinase 1 TRCN0000000618 CCGGCTGGTAGCTGTCAAGATCTTACTCGAGTAAGATCTTGACAGCTACCAGTTTTT DDR1 discoidin domain receptor tyrosine kinase 1 TRCN0000121082 CCGGCCTATACGTTTCTGTGGAGTACTCGAGTACTCCACAGAAACGTATAGGTTTTTG DDR1 discoidin domain receptor tyrosine kinase 1 TRCN0000121083 CCGGCCTGGTTACTCTTCAGCGAAACTCGAGTTTCGCTGAAGAGTAACCAGGTTTTTG DDR1 discoidin domain receptor tyrosine kinase 1 TRCN0000121084 CCGGACTCCACCTATGACGGACATACTCGAGTATGTCCGTCATAGGTGGAGTTTTTTG DDR2 discoidin domain receptor tyrosine kinase 2 TRCN0000001417 CCGGGCCAACAAGAATGCCAGGAATCTCGAGATTCCTGGCATTCTTGTTGGCTTTTT DDR2 discoidin domain receptor tyrosine kinase 2 TRCN0000001418 CCGGGCCAGATTTGTCCGGTTCATTCTCGAGAATGAACCGGACAAATCTGGCTTTTT DDR2 discoidin domain receptor tyrosine kinase 2 TRCN0000001419 CCGGGCCAAGTGATTCTAGCATGTTCTCGAGAACATGCTAGAATCACTTGGCTTTTT DDR2 discoidin domain receptor tyrosine kinase 2 TRCN0000001420 CCGGGCTGACATAGTGAACCTCCAACTCGAGTTGGAGGTTCACTATGTCAGCTTTTT DDR2 discoidin domain receptor tyrosine kinase 2 TRCN0000001421 CCGGCTCAGGTTAATCCAGCTATATCTCGAGATATAGCTGGATTAACCTGAGTTTTT

165 Supplement

DMPK dystrophia myotonica-protein kinase TRCN0000000813 CCGGTCGAGACTTCATTCAGCGGTTCTCGAGAACCGCTGAATGAAGTCTCGATTTTT DMPK dystrophia myotonica-protein kinase TRCN0000000814 CCGGCCTGGTCATGGAGTATTACGTCTCGAGACGTAATACTCCATGACCAGGTTTTT DMPK dystrophia myotonica-protein kinase TRCN0000000815 CCGGCCCTTTACACCGGATTTCGAACTCGAGTTCGAAATCCGGTGTAAAGGGTTTTT DMPK dystrophia myotonica-protein kinase TRCN0000000816 CCGGAGCGGTAGTGAAGATGAAGCACTCGAGTGCTTCATCTTCACTACCGCTTTTTT DMPK dystrophia myotonica-protein kinase TRCN0000199032 CCGGCCACCGACACATGCAACTTCGCTCGAGCGAAGTTGCATGTGTCGGTGGTTTTTTG DSTYK dual serine/threonine and tyrosine protein kinase TRCN0000037509 CCGGCGTGCCAAGATCACTGACTTACTCGAGTAAGTCAGTGATCTTGGCACGTTTTTG DSTYK dual serine/threonine and tyrosine protein kinase TRCN0000037513 CCGGCCAGAACGTCTTCCTGTGTTTCTCGAGAAACACAGGAAGACGTTCTGGTTTTTG DSTYK dual serine/threonine and tyrosine protein kinase TRCN0000194775 CCGGCATGAAAGAATGACCCTTATTCTCGAGAATAAGGGTCATTCTTTCATGTTTTTTG DSTYK dual serine/threonine and tyrosine protein kinase TRCN0000195331 CCGGCCAACCCAATGCGAAGTATTTCTCGAGAAATACTTCGCATTGGGTTGGTTTTTTG DSTYK dual serine/threonine and tyrosine protein kinase TRCN0000195393 CCGGCCGCTTTATCGCCAGCTAATTCTCGAGAATTAGCTGGCGATAAAGCGGTTTTTTG dual-specificity tyrosine-(Y)-phosphorylation DYRK1A TRCN0000000524 CCGGGCTGCTAATACCTTGGACTTTCTCGAGAAAGTCCAAGGTATTAGCAGCTTTTT regulated kinase 1A dual-specificity tyrosine-(Y)-phosphorylation DYRK1A TRCN0000000525 CCGGCAGTATATTCAGAGTCGCTTTCTCGAGAAAGCGACTCTGAATATACTGTTTTT regulated kinase 1A dual-specificity tyrosine-(Y)-phosphorylation DYRK1A TRCN0000000526 CCGGCGGAAGGTTTACAATGATGGTCTCGAGACCATCATTGTAAACCTTCCGTTTTT regulated kinase 1A dual-specificity tyrosine-(Y)-phosphorylation DYRK1A TRCN0000000527 CCGGCTTTGGACAGAATGGAGCTATCTCGAGATAGCTCCATTCTGTCCAAAGTTTTT regulated kinase 1A dual-specificity tyrosine-(Y)-phosphorylation DYRK1A TRCN0000010611 CCGGGCTGCTAATACCTTGGACTTTCTCGAGAAAGTCCAAGGTATTAGCAGCTTTTT regulated kinase 1A dual-specificity tyrosine-(Y)-phosphorylation DYRK1B TRCN0000002139 CCGGGACCTACAAGCACATCAATGACTCGAGTCATTGATGTGCTTGTAGGTCTTTTT regulated kinase 1B dual-specificity tyrosine-(Y)-phosphorylation DYRK1B TRCN0000002141 CCGGCACGGAGATGAAGTACTATATCTCGAGATATAGTACTTCATCTCCGTGTTTTT regulated kinase 1B dual-specificity tyrosine-(Y)-phosphorylation DYRK1B TRCN0000002142 CCGGTGACGACAACCATGACTACATCTCGAGATGTAGTCATGGTTGTCGTCATTTTT regulated kinase 1B dual-specificity tyrosine-(Y)-phosphorylation DYRK1B TRCN0000002143 CCGGGAAGGACGAAAGAACTCAGGACTCGAGTCCTGAGTTCTTTCGTCCTTCTTTTT regulated kinase 1B dual-specificity tyrosine-(Y)-phosphorylation DYRK1B TRCN0000195657 CCGGCCATGGTTATGATGACGACAACTCGAGTTGTCGTCATCATAACCATGGTTTTTTG regulated kinase 1B dual-specificity tyrosine-(Y)-phosphorylation DYRK2 TRCN0000000650 CCGGCCTGGGAAACTATCAACTCTTCTCGAGAAGAGTTGATAGTTTCCCAGGTTTTT regulated kinase 2 dual-specificity tyrosine-(Y)-phosphorylation DYRK2 TRCN0000000651 CCGGGCAGGGTAGAAGCGGTATTAACTCGAGTTAATACCGCTTCTACCCTGCTTTTT regulated kinase 2 dual-specificity tyrosine-(Y)-phosphorylation DYRK2 TRCN0000000652 CCGGGAGGACTAATTTGGCGCAGATCTCGAGATCTGCGCCAAATTAGTCCTCTTTTT regulated kinase 2 dual-specificity tyrosine-(Y)-phosphorylation DYRK2 TRCN0000000653 CCGGGCAGGACAAGGATAACACAATCTCGAGATTGTGTTATCCTTGTCCTGCTTTTT regulated kinase 2 dual-specificity tyrosine-(Y)-phosphorylation DYRK2 TRCN0000000654 CCGGCTGAACAAGCAATGAAGCAATCTCGAGATTGCTTCATTGCTTGTTCAGTTTTT regulated kinase 2 dual-specificity tyrosine-(Y)-phosphorylation DYRK3 TRCN0000000647 CCGGGCCAGGGTCTATGATCACAAACTCGAGTTTGTGATCATAGACCCTGGCTTTTT regulated kinase 3 dual-specificity tyrosine-(Y)-phosphorylation DYRK3 TRCN0000194768 CCGGCAGAAACCAATGGTAGTATACCTCGAGGTATACTACCATTGGTTTCTGTTTTTTG regulated kinase 3 dual-specificity tyrosine-(Y)-phosphorylation DYRK3 TRCN0000196853 CCGGGAATAGCCAATAAGCTTAAAGCTCGAGCTTTAAGCTTATTGGCTATTCTTTTTTG regulated kinase 3 dual-specificity tyrosine-(Y)-phosphorylation DYRK3 TRCN0000197273 CCGGGTCAGGGAAACGGGTAGTTAACTCGAGTTAACTACCCGTTTCCCTGACTTTTTTG regulated kinase 3 dual-specificity tyrosine-(Y)-phosphorylation DYRK3 TRCN0000199947 CCGGGCAAGCCCATTGGTGGATGTTCTCGAGAACATCCACCAATGGGCTTGCTTTTTTG regulated kinase 3 dual-specificity tyrosine-(Y)-phosphorylation DYRK4 TRCN0000000712 CCGGGTACATCCAAAGCCGGTTCTACTCGAGTAGAACCGGCTTTGGATGTACTTTTT regulated kinase 4 dual-specificity tyrosine-(Y)-phosphorylation DYRK4 TRCN0000195624 CCGGCCTCAAGCATGCTTGGATTCACTCGAGTGAATCCAAGCATGCTTGAGGTTTTTTG regulated kinase 4 dual-specificity tyrosine-(Y)-phosphorylation DYRK4 TRCN0000000710 CCGGACCAGTGATTTGTATTAAGACCTCGAGGTCTTAATACAAATCACTGGTTTTTT regulated kinase 4 dual-specificity tyrosine-(Y)-phosphorylation DYRK4 TRCN0000000711 CCGGGACAAAGACAACACCTACAATCTCGAGATTGTAGGTGTTGTCTTTGTCTTTTT regulated kinase 4 dual-specificity tyrosine-(Y)-phosphorylation DYRK4 TRCN0000000713 CCGGCAAGCCTCTGTTAAAGTCATTCTCGAGAATGACTTTAACAGAGGCTTGTTTTT regulated kinase 4 EEF2K eukaryotic elongation factor-2 kinase TRCN0000006221 CCGGCCCATAAATGACAGTGACTTTCTCGAGAAAGTCACTGTCATTTATGGGTTTTT EEF2K eukaryotic elongation factor-2 kinase TRCN0000006222 CCGGCCACTCATACAGTAATCGGAACTCGAGTTCCGATTACTGTATGAGTGGTTTTT EEF2K eukaryotic elongation factor-2 kinase TRCN0000006223 CCGGCGATGAGGAAGGTTACTTCATCTCGAGATGAAGTAACCTTCCTCATCGTTTTT EEF2K eukaryotic elongation factor2 kinase TRCN0000195347 CCGGCCAGACAATGGCGATTGTTATCTCGAGATAACAATCGCCATTGTCTGGTTTTTTG EEF2K eukaryotic elongation factor2 kinase TRCN0000197071 CCGGGCTTGAAGAAGCAGCCTAATGCTCGAGCATTAGGCTGCTTCTTCAAGCTTTTTTG epidermal growth factor receptor (erythroblastic EGFR TRCN0000039633 CCGGGCTGAGAATGTGGAATACCTACTCGAGTAGGTATTCCACATTCTCAGCTTTTTG leukemia viral (v-erb-b) oncogene homolog, avian) epidermal growth factor receptor (erythroblastic EGFR TRCN0000039634 CCGGGCTGGATGATAGACGCAGATACTCGAGTATCTGCGTCTATCATCCAGCTTTTTG leukemia viral (v-erb-b) oncogene homolog, avian) epidermal growth factor receptor (erythroblastic EGFR TRCN0000039635 CCGGCCCGTCGCTATCAAGGAATTACTCGAGTAATTCCTTGATAGCGACGGGTTTTTG leukemia viral (v-erb-b) oncogene homolog, avian) epidermal growth factor receptor (erythroblastic EGFR TRCN0000121067 CCGGGCTGCTCTGAAATCTCCTTTACTCGAGTAAAGGAGATTTCAGAGCAGCTTTTTG leukemia viral (v-erb-b) oncogene homolog, avian) epidermal growth factor receptor (erythroblastic EGFR TRCN0000121068 CCGGGCCACAAAGCAGTGAATTTATCTCGAGATAAATTCACTGCTTTGTGGCTTTTTG leukemia viral (v-erb-b) oncogene homolog, avian) eukaryotic translation initiation factor 2-alpha kinase EIF2AK1 TRCN0000010232 CCGGGAGCTGCCATTGAGTTGCCATCTCGAGATGGCAACTCAATGGCAGCTCTTTTT 1 eukaryotic translation initiation factor 2-alpha kinase EIF2AK1 TRCN0000010229 CCGGGGATTGGATAGTCGAGAGAAACTCGAGTTTCTCTCGACTATCCAATCCTTTTT 1 eukaryotic translation initiation factor 2-alpha kinase EIF2AK1 TRCN0000010230 CCGGGAATTGGTAGAAGGTGTGTTTCTCGAGAAACACACCTTCTACCAATTCTTTTT 1 eukaryotic translation initiation factor 2-alpha kinase EIF2AK1 TRCN0000010231 CCGGAGCTACTTTGCCAGACGTTTACTCGAGTAAACGTCTGGCAAAGTAGCTTTTTT 1 eukaryotic translation initiation factor 2-alpha kinase EIF2AK1 TRCN0000010233 CCGGGTACACCACCAATTTAGTCATCTCGAGATGACTAAATTGGTGGTGTACTTTTT 1

166 Supplement

eukaryotic translation initiation factor 2-alpha kinase EIF2AK2 TRCN0000001379 CCGGTCCTGGCTCATCTCTTTATTCCTCGAGGAATAAAGAGATGAGCCAGGATTTTT 2 eukaryotic translation initiation factor 2-alpha kinase EIF2AK2 TRCN0000001381 CCGGGCTGTTGGGATGGATTTGATTCTCGAGAATCAAATCCATCCCAACAGCTTTTT 2 eukaryotic translation initiation factor 2-alpha kinase EIF2AK2 TRCN0000001382 CCGGTCGACCTAACACATCTGAAATCTCGAGATTTCAGATGTGTTAGGTCGATTTTT 2 eukaryotic translation initiation factor 2-alpha kinase EIF2AK2 TRCN0000196400 CCGGGCTGAACTTCTTCATGTATGTCTCGAGACATACATGAAGAAGTTCAGCTTTTTTG 2 eukaryotic translation initiation factor 2-alpha kinase EIF2AK2 TRCN0000197012 CCGGGAGGCGAGAAACTAGACAAAGCTCGAGCTTTGTCTAGTTTCTCGCCTCTTTTTTG 2 eukaryotic translation initiation factor 2-alpha kinase EIF2AK3 TRCN0000001399 CCGGCCGTAGTAAGAAATGGATCATCTCGAGATGATCCATTTCTTACTACGGTTTTT 3 eukaryotic translation initiation factor 2-alpha kinase EIF2AK3 TRCN0000001400 CCGGGCACACAGATTACAGTCAGATCTCGAGATCTGACTGTAATCTGTGTGCTTTTT 3 eukaryotic translation initiation factor 2-alpha kinase EIF2AK3 TRCN0000001401 CCGGCCTCAAGCCATCCAACATATTCTCGAGAATATGTTGGATGGCTTGAGGTTTTT 3 eukaryotic translation initiation factor 2-alpha kinase EIF2AK3 TRCN0000001402 CCGGGCTTTGGAATCTGTCACTAATCTCGAGATTAGTGACAGATTCCAAAGCTTTTT 3 eukaryotic translation initiation factor 2-alpha kinase EIF2AK3 TRCN0000195161 CCGGCCCAAACTGATTATAGGTAACCTCGAGGTTACCTATAATCAGTTTGGGTTTTTTG 3 eukaryotic translation initiation factor 2 alpha kinase EIF2AK4 TRCN0000078649 CCGGCCAGATGTAGTTCCTGAAATACTCGAGTATTTCAGGAACTACATCTGGTTTTTG 4 eukaryotic translation initiation factor 2 alpha kinase EIF2AK4 TRCN0000078651 CCGGCCAAAGGTCTATCAAATGAAACTCGAGTTTCATTTGATAGACCTTTGGTTTTTG 4 eukaryotic translation initiation factor 2 alpha kinase EIF2AK4 TRCN0000078648 CCGGCGATGCAGCAACTTCATTGTTCTCGAGAACAATGAAGTTGCTGCATCGTTTTTG 4 eukaryotic translation initiation factor 2 alpha kinase EIF2AK4 TRCN0000078650 CCGGCCAACTTTGAAAGAAGTTCAACTCGAGTTGAACTTCTTTCAAAGTTGGTTTTTG 4 eukaryotic translation initiation factor 2 alpha kinase EIF2AK4 TRCN0000078652 CCGGGCCTAACTGGTGAAGAAGTATCTCGAGATACTTCTTCACCAGTTAGGCTTTTTG 4 EPHA1 EPH receptor A1 TRCN0000006398 CCGGACTAGGCTATCGGTGCTGCTTCTCGAGAAGCAGCACCGATAGCCTAGTTTTTT EPHA1 EPH receptor A1 TRCN0000006401 CCGGCGCCAAGGAAGTTACTCTGATCTCGAGATCAGAGTAACTTCCTTGGCGTTTTT EPHA1 EPH receptor A1 TRCN0000006399 CCGGGCCAGAAACATCTTGGTGAATCTCGAGATTCACCAAGATGTTTCTGGCTTTTT EPHA1 EPH receptor A1 TRCN0000006400 CCGGCCGATCATGATCATCACAGAACTCGAGTTCTGTGATGATCATGATCGGTTTTT EPHA1 EPH receptor A1 TRCN0000006402 CCGGCCTTATGCCAACTACACCTTTCTCGAGAAAGGTGTAGTTGGCATAAGGTTTTT EPHA10 EPH receptor A10 TRCN0000021384 CCGGCCTGGCCTAAAGGAAGTCATTCTCGAGAATGACTTCCTTTAGGCCAGGTTTTT EPHA10 EPH receptor A10 TRCN0000021387 CCGGCTTCTGCGAAGGTATCCAGTTCTCGAGAACTGGATACCTTCGCAGAAGTTTTT EPHA10 EPH receptor A10 TRCN0000021385 CCGGGAGGAAGTTATCCTCCTGGATCTCGAGATCCAGGAGGATAACTTCCTCTTTTT EPHA10 EPH receptor A10 TRCN0000021386 CCGGTGGACTGCACTGCCAAGTAATCTCGAGATTACTTGGCAGTGCAGTCCATTTTT EPHA10 EPH receptor A10 TRCN0000021388 CCGGCCTGGGTGAGCGCAAGATGAACTCGAGTTCATCTTGCGCTCACCCAGGTTTTT EPHA2 EPH receptor A2 TRCN0000006403 CCGGCGGACAGACATATAGGATATTCTCGAGAATATCCTATATGTCTGTCCGTTTTT EPHA2 EPH receptor A2 TRCN0000006405 CCGGCCATCAAGATGCAGCAGTATACTCGAGTATACTGCTGCATCTTGATGGTTTTT EPHA2 EPH receptor A2 TRCN0000006406 CCGGGCGTATCTTCATTGAGCTCAACTCGAGTTGAGCTCAATGAAGATACGCTTTTT EPHA2 EPH receptor A2 TRCN0000006407 CCGGCTCCAAATACAAGCCCATGATCTCGAGATCATGGGCTTGTATTTGGAGTTTTT EPHA2 EPH receptor A2 TRCN0000195734 CCGGGATAAGTTTCTATTCTGTCAGCTCGAGCTGACAGAATAGAAACTTATCTTTTTTG EPHA3 EPH receptor A3 TRCN0000006408 CCGGGCTCTATTGATACTCTTTCTACTCGAGTAGAAAGAGTATCAATAGAGCTTTTT EPHA3 EPH receptor A3 TRCN0000006409 CCGGGCCGCAAGTTTGAGTTTGAAACTCGAGTTTCAAACTCAAACTTGCGGCTTTTT EPHA3 EPH receptor A3 TRCN0000006410 CCGGCCTTCCAATGAAGTCAATCTACTCGAGTAGATTGACTTCATTGGAAGGTTTTT EPHA3 EPH receptor A3 TRCN0000194718 CCGGCCTGACACTATATACGTATTCCTCGAGGAATACGTATATAGTGTCAGGTTTTTTG EPHA3 EPH receptor A3 TRCN0000196830 CCGGGATGAAAGTTTCACTCAAATGCTCGAGCATTTGAGTGAAACTTTCATCTTTTTTG EPHA4 EPH receptor A4 TRCN0000220021 CCGGGATTGGCTCCAGGCCATTAAACTCGAGTTTAATGGCCTGGAGCCAATCTTTTTG EPHA4 EPH receptor A4 TRCN0000010153 CCGGCCAAGCAGCACCATCATCCATCTCGAGATGGATGATGGTGCTGCTTGGTTTTT EPHA4 EPH receptor A4 TRCN0000010161 CCGGGCCAGGAACACAGATATCAAACTCGAGTTTGATATCTGTGTTCCTGGCTTTTT EPHA4 EPH receptor A4 TRCN0000010164 CCGGGGGTCTGGGATGAAGTATTTACTCGAGTAAATACTTCATCCCAGACCCTTTTT EPHA4 EPH receptor A4 TRCN0000010165 CCGGTCAGTCCGTGTGTTCTATAAACTCGAGTTTATAGAACACACGGACTGATTTTT EPHA5 EPH receptor A5 TRCN0000006413 CCGGTGAATGATTCTGCACTTTGTACTCGAGTACAAAGTGCAGAATCATTCATTTTT EPHA5 EPH receptor A5 TRCN0000006415 CCGGGCTGGCAGAAAGAGCGAAATACTCGAGTATTTCGCTCTTTCTGCCAGCTTTTT EPHA5 EPH receptor A5 TRCN0000006416 CCGGGCCAGGAGTAAGAACTTACATCTCGAGATGTAAGTTCTTACTCCTGGCTTTTT EPHA5 EPH receptor A5 TRCN0000006417 CCGGGCTCACACAAACTATACCTTTCTCGAGAAAGGTATAGTTTGTGTGAGCTTTTT EPHA5 EPH receptor A5 TRCN0000006414 CCGGCGGCAGTATGTGTCTGTAAATCTCGAGATTTACAGACACATACTGCCGTTTTT EPHA6 EPH receptor A6 TRCN0000001767 CCGGCTGACCTCTTCCAAACTCTAACTCGAGTTAGAGTTTGGAAGAGGTCAGTTTTT EPHA6 EPH receptor A6 TRCN0000001768 CCGGGCTCGGAATATACTGGTCAATCTCGAGATTGACCAGTATATTCCGAGCTTTTT EPHA6 EPH receptor A6 TRCN0000001769 CCGGGTTTGTGAATTGGCTTGACTTCTCGAGAAGTCAAGCCAATTCACAAACTTTTT EPHA6 EPH receptor A6 TRCN0000001770 CCGGCGTCATCCTCACTTTATTCTTCTCGAGAAGAATAAAGTGAGGATGACGTTTTT EPHA6 EPH receptor A6 TRCN0000001771 CCGGGCAGCAGAACAAGGACAGATTCTCGAGAATCTGTCCTTGTTCTGCTGCTTTTT EPHA7 EPH receptor A7 TRCN0000006418 CCGGCGGTCATAATTGGTCTTGTTTCTCGAGAAACAAGACCAATTATGACCGTTTTT EPHA7 EPH receptor A7 TRCN0000006421 CCGGTGGTCCATTATTGAGAACTTACTCGAGTAAGTTCTCAATAATGGACCATTTTT EPHA7 EPH receptor A7 TRCN0000195051 CCGGCGATGTGACCTACAGAATATTCTCGAGAATATTCTGTAGGTCACATCGTTTTTTG EPHA7 EPH receptor A7 TRCN0000196477 CCGGGAAACCAGTCATGATAGTAATCTCGAGATTACTATCATGACTGGTTTCTTTTTTG EPHA7 EPH receptor A7 TRCN0000197070 CCGGGTCTACTTCAGCCTCCATTAACTCGAGTTAATGGAGGCTGAAGTAGACTTTTTTG EPHA8 EPH receptor A8 TRCN0000196492 CCGGGAGTATGAGATCAAGTACTACCTCGAGGTAGTACTTGATCTCATACTCTTTTTTG EPHA8 EPH receptor A8 TRCN0000001345 CCGGCGAGCTGTTCTTCCTTCCTATCTCGAGATAGGAAGGAAGAACAGCTCGTTTTT

167 Supplement

EPHA8 EPH receptor A8 TRCN0000001346 CCGGGACGAGGAGAAGATGCACTATCTCGAGATAGTGCATCTTCTCCTCGTCTTTTT EPHA8 EPH receptor A8 TRCN0000001347 CCGGGCGAAGTGAATTTGCTGGACACTCGAGTGTCCAGCAAATTCACTTCGCTTTTT EPHA8 EPH receptor A8 TRCN0000001348 CCGGCTATAAGAAGTGCCCTGCCATCTCGAGATGGCAGGGCACTTCTTATAGTTTTT EPHB1 EPH receptor B1 TRCN0000000817 CCGGCACTCGTTTCCCTTTGCTCATCTCGAGATGAGCAAAGGGAAACGAGTGTTTTT EPHB1 EPH receptor B1 TRCN0000000818 CCGGGCCTCTTACTCGGAATGGTTTCTCGAGAAACCATTCCGAGTAAGAGGCTTTTT EPHB1 EPH receptor B1 TRCN0000000819 CCGGGCTGCGATGGAAGAAACGTTACTCGAGTAACGTTTCTTCCATCGCAGCTTTTT EPHB1 EPH receptor B1 TRCN0000000821 CCGGCCTGGCTGAGATGAATTATGTCTCGAGACATAATTCATCTCAGCCAGGTTTTT EPHB1 EPH receptor B1 TRCN0000195710 CCGGCCTGAGAATAGGCATCACCTTCTCGAGAAGGTGATGCCTATTCTCAGGTTTTTTG EPHB2 EPH receptor B2 TRCN0000006423 CCGGGCTAGACAAGATGATCCGCAACTCGAGTTGCGGATCATCTTGTCTAGCTTTTT EPHB2 EPH receptor B2 TRCN0000006424 CCGGGCTGTGATTTCCAGTGTCAATCTCGAGATTGACACTGGAAATCACAGCTTTTT EPHB2 EPH receptor B2 TRCN0000006426 CCGGCGGGAGTTTGCCAAGGAAATTCTCGAGAATTTCCTTGGCAAACTCCCGTTTTT EPHB2 EPH receptor B2 TRCN0000196573 CCGGGAAGATCTACATCGATCCTTTCTCGAGAAAGGATCGATGTAGATCTTCTTTTTTG EPHB2 EPH receptor B2 TRCN0000199819 CCGGGCGTGTCTTCTACCGCAAGTGCTCGAGCACTTGCGGTAGAAGACACGCTTTTTTG EPHB3 EPH receptor B3 TRCN0000006427 CCGGCCCAAACCTCTTCATATTGAACTCGAGTTCAATATGAAGAGGTTTGGGTTTTT EPHB3 EPH receptor B3 TRCN0000006428 CCGGGCAGTACATTGCTCCTGGAATCTCGAGATTCCAGGAGCAATGTACTGCTTTTT EPHB3 EPH receptor B3 TRCN0000006430 CCGGCGAGATGAAGTACTTTGAGAACTCGAGTTCTCAAAGTACTTCATCTCGTTTTT EPHB3 EPH receptor B3 TRCN0000011020 CCGGCGTGGACATCTCATCCAGAAACTCGAGTTTCTGGATGAGATGTCCACGTTTTT EPHB3 EPH receptor B3 TRCN0000006429 CCGGCCTTCACGACAGTTGGTGATTCTCGAGAATCACCAACTGTCGTGAAGGTTTTT EPHB4 EPH receptor B4 TRCN0000001773 CCGGCAATGGGAGAGAAGCAGAATACTCGAGTATTCTGCTTCTCTCCCATTGTTTTT EPHB4 EPH receptor B4 TRCN0000001774 CCGGTGATCTGAAGTGGGTGACATTCTCGAGAATGTCACCCACTTCAGATCATTTTT EPHB4 EPH receptor B4 TRCN0000001772 CCGGGACTGTGAACCTGACTCGATTCTCGAGAATCGAGTCAGGTTCACAGTCTTTTT EPHB4 EPH receptor B4 TRCN0000010651 CCGGCTGGAGTTACGGGATTGTGATCTCGAGATCACAATCCCGTAACTCCAGTTTTT EPHB4 EPH receptor B4 TRCN0000195407 CCGGCGTCATGATTCTCACAGAGTTCTCGAGAACTCTGTGAGAATCATGACGTTTTTTG EPHB6 EPH receptor B6 TRCN0000002016 CCGGCTTTGGGATACTCATGTGGGACTCGAGTCCCACATGAGTATCCCAAAGTTTTT EPHB6 EPH receptor B6 TRCN0000002017 CCGGTATTTCCAGACACTTCCTCAACTCGAGTTGAGGAAGTGTCTGGAAATATTTTT EPHB6 EPH receptor B6 TRCN0000002018 CCGGCACATTCGACTCCACTTCTCTCTCGAGAGAGAAGTGGAGTCGAATGTGTTTTT EPHB6 EPH receptor B6 TRCN0000010677 CCGGATGTGGGAAGTGATGAGTTATCTCGAGATAACTCATCACTTCCCACATTTTTT EPHB6 EPH receptor B6 TRCN0000199164 CCGGCCCTGGACACTGGTCCGAGAACTCGAGTTCTCGGACCAGTGTCCAGGGTTTTTTG v-erb-b2 erythroblastic leukemia viral oncogene ERBB2 homolog 2, neuro/glioblastoma derived oncogene TRCN0000010341 CCGGCAGTTACCAGTGCCAATATCCCTCGAGGGATATTGGCACTGGTAACTGTTTTTG homolog (avian) v-erb-b2 erythroblastic leukemia viral oncogene ERBB2 homolog 2, neuro/glioblastoma derived oncogene TRCN0000010343 CCGGAAGTACACGATGCGGAGACTCTCGAGAGTCTCCGCATCGTGTACTTCTTTTTG homolog (avian) v-erb-b2 erythroblastic leukemia viral oncogene ERBB2 homolog 2, neuro/glioblastoma derived oncogene TRCN0000039878 CCGGTGTCAGTATCCAGGCTTTGTACTCGAGTACAAAGCCTGGATACTGACATTTTTG homolog (avian) v-erb-b2 erythroblastic leukemia viral oncogene ERBB2 homolog 2, neuro/glioblastoma derived oncogene TRCN0000039881 CCGGCAGTGCCAATATCCAGGAGTTCTCGAGAACTCCTGGATATTGGCACTGTTTTTG homolog (avian) verbb2 erythroblastic leukemia viral oncogene ERBB2 homolog 2, neuro/glioblastoma derived oncogene TRCN0000195369 CCGGCCCTAAGGGAGTGTCTAAGAACTCGAGTTCTTAGACACTCCCTTAGGGTTTTTTG homolog (avian) v-erb-b2 erythroblastic leukemia viral oncogene ERBB3 TRCN0000000621 CCGGCCTGACAAGATGGAAGTAGATCTCGAGATCTACTTCCATCTTGTCAGGTTTTT homolog 3 (avian) v-erb-b2 erythroblastic leukemia viral oncogene ERBB3 TRCN0000000623 CCGGCTGCCTTTGATAACCCTGATTCTCGAGAATCAGGGTTATCAAAGGCAGTTTTT homolog 3 (avian) v-erb-b2 erythroblastic leukemia viral oncogene ERBB3 TRCN0000009835 CCGGAGGTTAGGAGTAGATATTGACTCGAGTCAATATCTACTCCTAACCTCTTTTTG homolog 3 (avian) v-erb-b2 erythroblastic leukemia viral oncogene ERBB3 TRCN0000018327 CCGGTATATGAATCGGCAACGAGATCTCGAGATCTCGTTGCCGATTCATATATTTTTG homolog 3 (avian) v-erb-b2 erythroblastic leukemia viral oncogene ERBB3 TRCN0000040108 CCGGGCTCTGATACTTGTGCTCAATCTCGAGATTGAGCACAAGTATCAGAGCTTTTTG homolog 3 (avian) v-erb-a erythroblastic leukemia viral oncogene ERBB4 TRCN0000001411 CCGGGCGCAGGAAACATCTATATTACTCGAGTAATATAGATGTTTCCTGCGCTTTTT homolog 4 (avian) v-erb-a erythroblastic leukemia viral oncogene ERBB4 TRCN0000009836 CCGGATAACCAGCATTGAGCACAACTCGAGTTGTGCTCAATGCTGGTTATCTTTTTG homolog 4 (avian) v-erb-a erythroblastic leukemia viral oncogene ERBB4 TRCN0000018328 CCGGCAGACTACCTGCAGGAGTACACTCGAGTGTACTCCTGCAGGTAGTCTGTTTTTG homolog 4 (avian) v-erb-a erythroblastic leukemia viral oncogene ERBB4 TRCN0000039690 CCGGCCAGAGAAACTGAACGTCTTTCTCGAGAAAGACGTTCAGTTTCTCTGGTTTTTG homolog 4 (avian) v-erb-a erythroblastic leukemia viral oncogene ERBB4 TRCN0000001407 CCGGGCTAAGATAAAGACTGTGGAACTCGAGTTCCACAGTCTTTATCTTAGCTTTTT homolog 4 (avian) ERN1 endoplasmic reticulum to nucleus signaling 1 TRCN0000000529 CCGGCCCATCAACCTCTCTTCTGTACTCGAGTACAGAAGAGAGGTTGATGGGTTTTT ERN1 endoplasmic reticulum to nucleus signaling 1 TRCN0000000528 CCGGCTACTGGATAAACTTGCTTCACTCGAGTGAAGCAAGTTTATCCAGTAGTTTTT ERN1 endoplasmic reticulum to nucleus signaling 1 TRCN0000000530 CCGGGAGAAGATGATTGCGATGGATCTCGAGATCCATCGCAATCATCTTCTCTTTTT ERN1 endoplasmic reticulum to nucleus signaling 1 TRCN0000000532 CCGGGAAATACTCTACCAGCCTCTACTCGAGTAGAGGCTGGTAGAGTATTTCTTTTT ERN1 endoplasmic reticulum to nucleus signaling 1 TRCN0000195378 CCGGCCTGCTTAATGTCAGTCTACACTCGAGTGTAGACTGACATTAAGCAGGTTTTTTG ERN2 endoplasmic reticulum to nucleus signalling 2 TRCN0000147669 CCGGGAAGATTTCCTTCAATCCCAACTCGAGTTGGGATTGAAGGAAATCTTCTTTTTTG ERN2 endoplasmic reticulum to nucleus signalling 2 TRCN0000179143 CCGGGAAGGATGAAACTGGCTTCTACTCGAGTAGAAGCCAGTTTCATCCTTCTTTTTTG ERN2 endoplasmic reticulum to nucleus signalling 2 TRCN0000180418 CCGGGATCACTTGAGCTCAGGAGTTCTCGAGAACTCCTGAGCTCAAGTGATCTTTTTTG ERN2 endoplasmic reticulum to nucleus signalling 2 TRCN0000195136 CCGGCTGGCTTCTATGTCTCTAAAGCTCGAGCTTTAGAGACATAGAAGCCAGTTTTTTG ERN2 endoplasmic reticulum to nucleus signalling 2 TRCN0000195361 CCGGCGTCATCGAAGGACCAATGTACTCGAGTACATTGGTCCTTCGATGACGTTTTTTG

168 Supplement

FASTK Fas-activated serine/threonine kinase TRCN0000006318 CCGGCCTTGCAGTCTTACTTGGCTTCTCGAGAAGCCAAGTAAGACTGCAAGGTTTTT FASTK Fas-activated serine/threonine kinase TRCN0000006320 CCGGGAGTCAGCTCATCATCCGAAACTCGAGTTTCGGATGATGAGCTGACTCTTTTT FASTK Fas-activated serine/threonine kinase TRCN0000006321 CCGGCCATCACCCAACTCCATGCTTCTCGAGAAGCATGGAGTTGGGTGATGGTTTTT FASTK Fas-activated serine/threonine kinase TRCN0000006319 CCGGCCGCTGCAAGTACAGTCACAACTCGAGTTGTGACTGTACTTGCAGCGGTTTTT FASTK Fas-activated serine/threonine kinase TRCN0000006322 CCGGCAGCAGTTTATGCCCTGCCTTCTCGAGAAGGCAGGGCATAAACTGCTGTTTTT FER fer (fps/fes related) tyrosine kinase TRCN0000002347 CCGGCGGCTGCTAAAGAACAAGAAACTCGAGTTTCTTGTTCTTTAGCAGCCGTTTTT FER fer (fps/fes related) tyrosine kinase TRCN0000002348 CCGGGCCAAGGAACGATACGACAAACTCGAGTTTGTCGTATCGTTCCTTGGCTTTTT FER fer (fps/fes related) tyrosine kinase TRCN0000002349 CCGGCCACCTCCAGTAGTAAATTATCTCGAGATAATTTACTACTGGAGGTGGTTTTT FER fer (fps/fes related) tyrosine kinase TRCN0000002350 CCGGGAGAGCAAGTAGAAAGAGGATCTCGAGATCCTCTTTCTACTTGCTCTCTTTTT FER fer (fps/fes related) tyrosine kinase TRCN0000002351 CCGGCAGTATGTATTGGCGTTGAAACTCGAGTTTCAACGCCAATACATACTGTTTTT FES feline sarcoma oncogene TRCN0000195709 CCGGCAAGGCCAAGGACAAGTATGTCTCGAGACATACTTGTCCTTGGCCTTGTTTTTTG FES feline sarcoma oncogene TRCN0000000624 CCGGCAAGGCCAAGTTTCTACAGGACTCGAGTCCTGTAGAAACTTGGCCTTGTTTTT FES feline sarcoma oncogene TRCN0000000625 CCGGCATTCCTTTGCTCATCGACCACTCGAGTGGTCGATGAGCAAAGGAATGTTTTT FES feline sarcoma oncogene TRCN0000000626 CCGGCTTGGATAACCTGTACCGACTCTCGAGAGTCGGTACAGGTTATCCAAGTTTTT FES feline sarcoma oncogene TRCN0000000627 CCGGGAGAAGAATGTCCTGAAGATCCTCGAGGATCTTCAGGACATTCTTCTCTTTTT FGFR1 fibroblast growth factor receptor 1 TRCN0000000418 CCGGCGAGGCATTATTTGACCGGATCTCGAGATCCGGTCAAATAATGCCTCGTTTTT FGFR1 fibroblast growth factor receptor 1 TRCN0000000419 CCGGCAGAGGAGAAAGAAACAGATACTCGAGTATCTGTTTCTTTCTCCTCTGTTTTT FGFR1 fibroblast growth factor receptor 1 TRCN0000121102 CCGGCCCTCCCAGATGTTGGACCAACTCGAGTTGGTCCAACATCTGGGAGGGTTTTTG FGFR1 fibroblast growth factor receptor 1 TRCN0000121105 CCGGGCCAAGACAGTGAAGTTCAAACTCGAGTTTGAACTTCACTGTCTTGGCTTTTTG FGFR1 fibroblast growth factor receptor 1 TRCN0000121106 CCGGGAGATGGAGGTGCTTCACTTACTCGAGTAAGTGAAGCACCTCCATCTCTTTTTG FGFR2 fibroblast growth factor receptor 2 TRCN0000000366 CCGGGCACACACTTACAGAGCACAACTCGAGTTGTGCTCTGTAAGTGTGTGCTTTTT FGFR2 fibroblast growth factor receptor 2 TRCN0000000367 CCGGGCCACCAACCAAATACCAAATCTCGAGATTTGGTATTTGGTTGGTGGCTTTTT FGFR2 fibroblast growth factor receptor 2 TRCN0000000368 CCGGCCGAATGAAGAACACGACCAACTCGAGTTGGTCGTGTTCTTCATTCGGTTTTT FGFR2 fibroblast growth factor receptor 2 TRCN0000000369 CCGGCCCAACAATAGGACAGTGCTTCTCGAGAAGCACTGTCCTATTGTTGGGTTTTT FGFR2 fibroblast growth factor receptor 2 TRCN0000000370 CCGGGCCAACCTCTCGAACAGTATTCTCGAGAATACTGTTCGAGAGGTTGGCTTTTT FGFR3 fibroblast growth factor receptor 3 TRCN0000010521 CCGGTGAAAGACGATGCCACTGACACTCGAGTGTCAGTGGCATCGTCTTTCATTTTT FGFR3 fibroblast growth factor receptor 3 TRCN0000000371 CCGGGTTCCGATGTTATTAGATGTTCTCGAGAACATCTAATAACATCGGAACTTTTT FGFR3 fibroblast growth factor receptor 3 TRCN0000000372 CCGGTGCGTCGTGGAGAACAAGTTTCTCGAGAAACTTGTTCTCCACGACGCATTTTT FGFR3 fibroblast growth factor receptor 3 TRCN0000000373 CCGGCTCGACTACTACAAGAAGACACTCGAGTGTCTTCTTGTAGTAGTCGAGTTTTT FGFR3 fibroblast growth factor receptor 3 TRCN0000000374 CCGGGCACAACCTCGACTACTACAACTCGAGTTGTAGTAGTCGAGGTTGTGCTTTTT FGFR4 fibroblast growth factor receptor 4 TRCN0000000628 CCGGGCCGACACAAGAACATCATCACTCGAGTGATGATGTTCTTGTGTCGGCTTTTT FGFR4 fibroblast growth factor receptor 4 TRCN0000000629 CCGGCCTATGTGCAAGTCCTAAAGACTCGAGTCTTTAGGACTTGCACATAGGTTTTT FGFR4 fibroblast growth factor receptor 4 TRCN0000000630 CCGGAGACATCAATAGCTCAGAGGTCTCGAGACCTCTGAGCTATTGATGTCTTTTTT FGFR4 fibroblast growth factor receptor 4 TRCN0000010530 CCGGTCCATGATCGTCCTGCAGAATCTCGAGATTCTGCAGGACGATCATGGATTTTT FGFR4 fibroblast growth factor receptor 4 TRCN0000010531 CCGGATCTACCTCTCGACCCACTATCTCGAGATAGTGGGTCGAGAGGTAGATTTTTT Gardner-Rasheed feline sarcoma viral (v-fgr) FGR TRCN0000001593 CCGGCCAGGTTTGAGGGAGAAGTTTCTCGAGAAACTTCTCCCTCAAACCTGGTTTTT oncogene homolog Gardner-Rasheed feline sarcoma viral (v-fgr) FGR TRCN0000001594 CCGGCTTCCTTGATAGTGGCACCATCTCGAGATGGTGCCACTATCAAGGAAGTTTTT oncogene homolog Gardner-Rasheed feline sarcoma viral (v-fgr) FGR TRCN0000001595 CCGGGCATGAATAAACGGGAAGTGTCTCGAGACACTTCCCGTTTATTCATGCTTTTT oncogene homolog Gardner-Rasheed feline sarcoma viral (v-fgr) FGR TRCN0000001596 CCGGCACATCCTGAACAATACTGAACTCGAGTTCAGTATTGTTCAGGATGTGTTTTT oncogene homolog Gardner-Rasheed feline sarcoma viral (v-fgr) FGR TRCN0000001597 CCGGACCCTGTTCATTGCCCTGTATCTCGAGATACAGGGCAATGAACAGGGTTTTTT oncogene homolog FLJ23356 hypothetical protein FLJ23356 TRCN0000195311 CCGGCTTAGCCATGTGGTTCGTTGTCTCGAGACAACGAACCACATGGCTAAGTTTTTTG FLJ23356 hypothetical protein FLJ23356 TRCN0000196355 CCGGGATGATCTCATGCCCTCATATCTCGAGATATGAGGGCATGAGATCATCTTTTTTG FLJ23356 hypothetical protein FLJ23356 TRCN0000196554 CCGGGAATGGAAGTTACAGCATTCTCTCGAGAGAATGCTGTAACTTCCATTCTTTTTTG FLJ23356 hypothetical protein FLJ23356 TRCN0000196781 CCGGGTTACAGCATTCTACTCTGATCTCGAGATCAGAGTAGAATGCTGTAACTTTTTTG FLJ40852 hypothetical LOC285962 TRCN0000037474 CCGGGTTCTGATGATATAGGACCAACTCGAGTTGGTCCTATATCATCAGAACTTTTTG fms-related tyrosine kinase 1 (vascular endothelial FLT1 TRCN0000000631 CCGGCCCGTCTCTATACCAACCAAACTCGAGTTTGGTTGGTATAGAGACGGGTTTTT growth factor/vascular permeability factor receptor) fms-related tyrosine kinase 1 (vascular endothelial FLT1 TRCN0000000632 CCGGCCCGAATCTATCTTTGACAAACTCGAGTTTGTCAAAGATAGATTCGGGTTTTT growth factor/vascular permeability factor receptor) fms-related tyrosine kinase 1 (vascular endothelial FLT1 TRCN0000000633 CCGGCGCCGGAAGTTGTATGGTTAACTCGAGTTAACCATACAACTTCCGGCGTTTTT growth factor/vascular permeability factor receptor) fms-related tyrosine kinase 1 (vascular endothelial FLT1 TRCN0000000634 CCGGGAGAGACTTAAACTGGGCAAACTCGAGTTTGCCCAGTTTAAGTCTCTCTTTTT growth factor/vascular permeability factor receptor) fms-related tyrosine kinase 1 (vascular endothelial FLT1 TRCN0000194670 CCGGCGTAGAGATGTACAGTGAAATCTCGAGATTTCACTGTACATCTCTACGTTTTTTG growth factor/vascular permeability factor receptor) FLT3 fms-related tyrosine kinase 3 TRCN0000000773 CCGGGCTAACTTCTACAAACTGATTCTCGAGAATCAGTTTGTAGAAGTTAGCTTTTT FLT3 fms-related tyrosine kinase 3 TRCN0000000774 CCGGCCACTTTCCAATCACATCCAACTCGAGTTGGATGTGATTGGAAAGTGGTTTTT FLT3 fms-related tyrosine kinase 3 TRCN0000000775 CCGGCTGGAATTTAAGTCGTGTGTTCTCGAGAACACACGACTTAAATTCCAGTTTTT FLT3 fms-related tyrosine kinase 3 TRCN0000009887 CCGGAAGAAGCGATGTATCAGAATCTCGAGATTCTGATACATCGCTTCTTCTTTTTG FLT3 fms-related tyrosine kinase 3 TRCN0000009888 CCGGAATTGTGTACCTGAAGTACACTCGAGTGTACTTCAGGTACACAATTCTTTTTG FLT4 fms-related tyrosine kinase 4 TRCN0000000637 CCGGGATCGTGGAGTTCTGCAAGTACTCGAGTACTTGCAGAACTCCACGATCTTTTT FLT4 fms-related tyrosine kinase 4 TRCN0000000638 CCGGAGCAGATAGAGAGCAGGCATACTCGAGTATGCCTGCTCTCTATCTGCTTTTTT FLT4 fms-related tyrosine kinase 4 TRCN0000000636 CCGGGAGAGACTTTGAGCAGCCATTCTCGAGAATGGCTGCTCAAAGTCTCTCTTTTT

169 Supplement

FLT4 fms-related tyrosine kinase 4 TRCN0000000639 CCGGTCACCATCGAATCCAAGCCATCTCGAGATGGCTTGGATTCGATGGTGATTTTT FLT4 fms-related tyrosine kinase 4 TRCN0000000640 CCGGTGCGAATACCTGTCCTACGATCTCGAGATCGTAGGACAGGTATTCGCATTTTT FRK fyn-related kinase TRCN0000010095 CCGGGCTCCATTTGATTTGTCGTATCTCGAGATACGACAAATCAAATGGAGCTTTTT FRK fyn-related kinase TRCN0000010096 CCGGCAGTTTGGCGAAGTATGGGAACTCGAGTTCCCATACTTCGCCAAACTGTTTTT FRK fyn-related kinase TRCN0000010097 CCGGCGAAATAAAGCTGCCGGTGAACTCGAGTTCACCGGCAGCTTTATTTCGTTTTT FRK fynrelated kinase TRCN0000195605 CCGGCCAGGTTCAATGGATCCAAATCTCGAGATTTGGATCCATTGAACCTGGTTTTTTG FRK fyn-related kinase TRCN0000010098 CCGGGCCGTGGTTCTTTGGAGCAATCTCGAGATTGCTCCAAAGAACCACGGCTTTTT FYN FYN oncogene related to SRC, FGR, YES TRCN0000003097 CCGGGCGATCAGCAAACATTCTAGTCTCGAGACTAGAATGTTTGCTGATCGCTTTTT FYN FYN oncogene related to SRC, FGR, YES TRCN0000003099 CCGGGCCTATTCACTTTCTATCCGTCTCGAGACGGATAGAAAGTGAATAGGCTTTTT FYN FYN oncogene related to SRC, FGR, YES TRCN0000003101 CCGGGTGCCAACAATCCTAGTGCTTCTCGAGAAGCACTAGGATTGTTGGCACTTTTT FYN FYN oncogene related to SRC, FGR, YES TRCN0000003098 CCGGGACTCTTAAACCAGGCACAATCTCGAGATTGTGCCTGGTTTAAGAGTCTTTTT FYN FYN oncogene related to SRC, FGR, YES TRCN0000003100 CCGGCTTACCGATCTGTCTGTCAAACTCGAGTTTGACAGACAGATCGGTAAGTTTTT GAK cyclin G associated kinase TRCN0000002154 CCGGCCAGAATTGCAGTGATGTCATCTCGAGATGACATCACTGCAATTCTGGTTTTT GAK cyclin G associated kinase TRCN0000002158 CCGGAGCATTCCAAAGCCTCTGATTCTCGAGAATCAGAGGCTTTGGAATGCTTTTTT GAK cyclin G associated kinase TRCN0000195054 CCGGCCTCTGATTGTTGTTTCCTTTCTCGAGAAAGGAAACAACAATCAGAGGTTTTTTG GAK cyclin G associated kinase TRCN0000195055 CCGGCCAGAAATCATAGACTTGTATCTCGAGATACAAGTCTATGATTTCTGGTTTTTTG GAK cyclin G associated kinase TRCN0000196794 CCGGGAGAACTTGTTGCTTAGTAACCTCGAGGTTACTAAGCAACAAGTTCTCTTTTTTG GRK1 G protein-coupled receptor kinase 1 TRCN0000010624 CCGGCTCTGGCCTATGCGTTTGAAACTCGAGTTTCAAACGCATAGGCCAGAGTTTTT GRK1 G protein-coupled receptor kinase 1 TRCN0000001486 CCGGCGTGAAGTACCCTGATAAGTTCTCGAGAACTTATCAGGGTACTTCACGTTTTT GRK1 G protein-coupled receptor kinase 1 TRCN0000001487 CCGGCTGGAAAGACATCGAGGACTACTCGAGTAGTCCTCGATGTCTTTCCAGTTTTT GRK1 G protein-coupled receptor kinase 1 TRCN0000001488 CCGGCTACAACGTGAATGAGGAGAACTCGAGTTCTCCTCATTCACGTTGTAGTTTTT GRK1 G protein-coupled receptor kinase 1 TRCN0000001489 CCGGGACTATGACACGGCAGACAATCTCGAGATTGTCTGCCGTGTCATAGTCTTTTT GRK4 G protein-coupled receptor kinase 4 TRCN0000000986 CCGGGCCTACGCTTATGAAACCAAACTCGAGTTTGGTTTCATAAGCGTAGGCTTTTT GRK4 G protein-coupled receptor kinase 4 TRCN0000000987 CCGGAGGATGTTACTCACCAAGAATCTCGAGATTCTTGGTGAGTAACATCCTTTTTT GRK4 G protein-coupled receptor kinase 4 TRCN0000000988 CCGGACCCGTAACAAAGAACACATTCTCGAGAATGTGTTCTTTGTTACGGGTTTTTT GRK4 G protein-coupled receptor kinase 4 TRCN0000000989 CCGGGAATATGAAGTTGCCGATGATCTCGAGATCATCGGCAACTTCATATTCTTTTT GRK4 G protein-coupled receptor kinase 4 TRCN0000000990 CCGGCTTGGCTGTCTGATCTATGAACTCGAGTTCATAGATCAGACAGCCAAGTTTTT GRK5 G protein-coupled receptor kinase 5 TRCN0000000841 CCGGGAAGGAAATTATGACCAAGTACTCGAGTACTTGGTCATAATTTCCTTCTTTTT GRK5 G protein-coupled receptor kinase 5 TRCN0000000840 CCGGCGAAGGACCATAGACAGAGATCTCGAGATCTCTGTCTATGGTCCTTCGTTTTT GRK5 G protein-coupled receptor kinase 5 TRCN0000000842 CCGGACGAGATGATAGAAACAGAATCTCGAGATTCTGTTTCTATCATCTCGTTTTTT GRK5 G protein-coupled receptor kinase 5 TRCN0000010557 CCGGGTGAGACTTTGAGGGTGTATACTCGAGTATACACCCTCAAAGTCTCACTTTTT GRK5 G protein-coupled receptor kinase 5 TRCN0000195681 CCGGCCTTAGAAGTGGAAGTAGTGGCTCGAGCCACTACTTCCACTTCTAAGGTTTTTTG GRK6 G protein-coupled receptor kinase 6 TRCN0000001367 CCGGCCTCGACAGCATCTACTTCAACTCGAGTTGAAGTAGATGCTGTCGAGGTTTTT GRK6 G protein-coupled receptor kinase 6 TRCN0000001368 CCGGCAGCATCTACTTCAACCGTTTCTCGAGAAACGGTTGAAGTAGATGCTGTTTTT GRK6 G protein-coupled receptor kinase 6 TRCN0000001369 CCGGCAGTAGGTTTGTAGTGAGCTTCTCGAGAAGCTCACTACAAACCTACTGTTTTT GRK6 G protein-coupled receptor kinase 6 TRCN0000010618 CCGGGTGTTAGGGTAGCATGGGATTCTCGAGAATCCCATGCTACCCTAACACTTTTT GRK6 G protein-coupled receptor kinase 6 TRCN0000199727 CCGGGCGGCAGCTAACGCAGAATTTCTCGAGAAATTCTGCGTTAGCTGCCGCTTTTTTG GRK7 G protein-coupled receptor kinase 7 TRCN0000002406 CCGGCGGCTGACATAATCCTCGAATCTCGAGATTCGAGGATTATGTCAGCCGTTTTT GRK7 G protein-coupled receptor kinase 7 TRCN0000002407 CCGGTGGCGTGTGTTTGTTATTGTACTCGAGTACAATAACAAACACACGCCATTTTT GRK7 G protein-coupled receptor kinase 7 TRCN0000002408 CCGGGCATGGCAGGAAGAAATTATACTCGAGTATAATTTCTTCCTGCCATGCTTTTT GRK7 G protein-coupled receptor kinase 7 TRCN0000002409 CCGGGCCAAAGACATCGCTGAAATTCTCGAGAATTTCAGCGATGTCTTTGGCTTTTT GRK7 G protein-coupled receptor kinase 7 TRCN0000010696 CCGGCTGGGAAGATGTATGCCTGTACTCGAGTACAGGCATACATCTTCCCAGTTTTT GSG2 germ cell associated 2 (haspin) TRCN0000021529 CCGGGCTGATAACAAATGTTCTGAACTCGAGTTCAGAACATTTGTTATCAGCTTTTT GSG2 germ cell associated 2 (haspin) TRCN0000021531 CCGGCCACAGGACAATGCTGAACTTCTCGAGAAGTTCAGCATTGTCCTGTGGTTTTT GSG2 germ cell associated 2 (haspin) TRCN0000021532 CCGGCCTCCTCTATGTATTTGCTAACTCGAGTTAGCAAATACATAGAGGAGGTTTTT GSG2 germ cell associated 2 (haspin) TRCN0000021533 CCGGCCTGGGATCACTATAATTCAACTCGAGTTGAATTATAGTGATCCCAGGTTTTT GSG2 germ cell associated 2 (haspin) TRCN0000021530 CCGGCCCTCCTATCAGAATGTTCAACTCGAGTTGAACATTCTGATAGGAGGGTTTTT GSK3A glycogen synthase kinase 3 alpha TRCN0000038680 CCGGCCAGGACAAGAGGTTCAAGAACTCGAGTTCTTGAACCTCTTGTCCTGGTTTTTG GSK3A glycogen synthase kinase 3 alpha TRCN0000038681 CCGGGAGTTCAAGTTCCCTCAGATTCTCGAGAATCTGAGGGAACTTGAACTCTTTTTG GSK3A glycogen synthase kinase 3 alpha TRCN0000038682 CCGGGTTCAAGTTCCCTCAGATTAACTCGAGTTAATCTGAGGGAACTTGAACTTTTTG GSK3A glycogen synthase kinase 3 alpha TRCN0000038683 CCGGCACTGATTACACCTCATCCATCTCGAGATGGATGAGGTGTAATCAGTGTTTTTG GSK3A glycogen synthase kinase 3 alpha TRCN0000039763 CCGGAGTGGCTTACACGGACATCAACTCGAGTTGATGTCCGTGTAAGCCACTTTTTTG GSK3B glycogen synthase kinase 3 beta TRCN0000000822 CCGGCCCAAATGTCAAACTACCAAACTCGAGTTTGGTAGTTTGACATTTGGGTTTTT GSK3B glycogen synthase kinase 3 beta TRCN0000000823 CCGGCCGATTGCGTTATTTCTTCTACTCGAGTAGAAGAAATAACGCAATCGGTTTTT GSK3B glycogen synthase kinase 3 beta TRCN0000000824 CCGGCCAATGTTTCGTATATCTGTTCTCGAGAACAGATATACGAAACATTGGTTTTT GSK3B glycogen synthase kinase 3 beta TRCN0000010551 CCGGCACTGGTCACGTTTGGAAAGACTCGAGTCTTTCCAAACGTGACCAGTGTTTTT GSK3B glycogen synthase kinase 3 beta TRCN0000039564 CCGGCATGAAAGTTAGCAGAGACAACTCGAGTTGTCTCTGCTAACTTTCATGTTTTTG guanylate cyclase 2C (heat stable enterotoxin GUCY2C TRCN0000002019 CCGGAGGTATAAGGACTCACACAAACTCGAGTTTGTGTGAGTCCTTATACCTTTTTT receptor) guanylate cyclase 2C (heat stable enterotoxin GUCY2C TRCN0000002020 CCGGCCTGGAGCACTTCGTATGTTTCTCGAGAAACATACGAAGTGCTCCAGGTTTTT receptor) guanylate cyclase 2C (heat stable enterotoxin GUCY2C TRCN0000002021 CCGGCCAGGAATCTATCACCAACAACTCGAGTTGTTGGTGATAGATTCCTGGTTTTT receptor)

170 Supplement

guanylate cyclase 2C (heat stable enterotoxin GUCY2C TRCN0000002022 CCGGCAGCAGGGATAAGAAGCCAAACTCGAGTTTGGCTTCTTATCCCTGCTGTTTTT receptor) guanylate cyclase 2C (heat stable enterotoxin GUCY2C TRCN0000002023 CCGGCGACAGTGCAAATACGACAAACTCGAGTTTGTCGTATTTGCACTGTCGTTTTT receptor) guanylate cyclase 2C (heat stable enterotoxin GUCY2C TRCN0000196972 CCGGGAACCTTATTCCAGCAGTTGTCTCGAGACAACTGCTGGAATAAGGTTCTTTTTTG receptor) GUCY2D guanylate cyclase 2D, membrane (retina-specific) TRCN0000000375 CCGGGGTGGGTGAAATAAAGGCATACTCGAGTATGCCTTTATTTCACCCACCTTTTT GUCY2D guanylate cyclase 2D, membrane (retina-specific) TRCN0000000376 CCGGCGTCTTTAGCTTGGCCATCATCTCGAGATGATGGCCAAGCTAAAGACGTTTTT GUCY2D guanylate cyclase 2D, membrane (retina-specific) TRCN0000000377 CCGGCAACGATCTCTACACACTCTTCTCGAGAAGAGTGTGTAGAGATCGTTGTTTTT GUCY2D guanylate cyclase 2D, membrane (retina-specific) TRCN0000000378 CCGGCCGGAAGACGAACATCATTGACTCGAGTCAATGATGTTCGTCTTCCGGTTTTT GUCY2F guanylate cyclase 2F, retinal TRCN0000000533 CCGGAGGCAATGGGAAAGCTCACTTCTCGAGAAGTGAGCTTTCCCATTGCCTTTTTT GUCY2F guanylate cyclase 2F, retinal TRCN0000000535 CCGGAGTTTGTTCATGGGAGGCTAACTCGAGTTAGCCTCCCATGAACAAACTTTTTT GUCY2F guanylate cyclase 2F, retinal TRCN0000000536 CCGGGTACACACTCTTTGATGCAATCTCGAGATTGCATCAAAGAGTGTGTACTTTTT GUCY2F guanylate cyclase 2F, retinal TRCN0000000537 CCGGACCTACGTCTTTGTTCCTTATCTCGAGATAAGGAACAAAGACGTAGGTTTTTT GUCY2F guanylate cyclase 2F, retinal TRCN0000194894 CCGGCTTTGGAGGATGTAACGTTTACTCGAGTAAACGTTACATCCTCCAAAGTTTTTTG HCK hemopoietic cell kinase TRCN0000009969 CCGGCAACAGCAACACACCAGGAATCTCGAGATTCCTGGTGTGTTGCTGTTGTTTTT HCK hemopoietic cell kinase TRCN0000009967 CCGGGGTCAAACTTCATGCGGTGGTCTCGAGACCACCGCATGAAGTTTGACCTTTTT HCK hemopoietic cell kinase TRCN0000009968 CCGGCCAGGTCGGAGGCAATACATTCTCGAGAATGTATTGCCTCCGACCTGGTTTTT HCK hemopoietic cell kinase TRCN0000009970 CCGGATCATCGTGGTTGCCCTGTATCTCGAGATACAGGGCAACCACGATGATTTTTT HCK hemopoietic cell kinase TRCN0000009971 CCGGCAGGGAGATACCGTGAAACATCTCGAGATGTTTCACGGTATCTCCCTGTTTTT HIPK1 homeodomain interacting protein kinase 1 TRCN0000007161 CCGGCCAAGGAAATTGTGGCTATTACTCGAGTAATAGCCACAATTTCCTTGGTTTTT HIPK1 homeodomain interacting protein kinase 1 TRCN0000007162 CCGGCCAGTGTTCTAGCTTCCAGTTCTCGAGAACTGGAAGCTAGAACACTGGTTTTT HIPK1 homeodomain interacting protein kinase 1 TRCN0000007163 CCGGGCCCATGTTGTCAGACAACAACTCGAGTTGTTGTCTGACAACATGGGCTTTTT HIPK1 homeodomain interacting protein kinase 1 TRCN0000007165 CCGGGCAATCATGTTAAGTCTTGTTCTCGAGAACAAGACTTAACATGATTGCTTTTT HIPK1 homeodomain interacting protein kinase 1 TRCN0000007164 CCGGCCTGAAATTATTCTTGGGTTACTCGAGTAACCCAAGAATAATTTCAGGTTTTT HIPK2 homeodomain interacting protein kinase 2 TRCN0000010766 CCGGAGGGATTAAAGAGGGTGGGAACTCGAGTTCCCACCCTCTTTAATCCCTTTTTT HIPK2 homeodomain interacting protein kinase 2 TRCN0000003201 CCGGCGAGTCAGTATCCAGCCCAATCTCGAGATTGGGCTGGATACTGACTCGTTTTT HIPK2 homeodomain interacting protein kinase 2 TRCN0000003202 CCGGCCTGACCATGACCTTTAACAACTCGAGTTGTTAAAGGTCATGGTCAGGTTTTT HIPK2 homeodomain interacting protein kinase 2 TRCN0000003203 CCGGCGGGACAAAGACAACTAGGTTCTCGAGAACCTAGTTGTCTTTGTCCCGTTTTT HIPK2 homeodomain interacting protein kinase 2 TRCN0000003204 CCGGCCATACTAAACTACCCATCTACTCGAGTAGATGGGTAGTTTAGTATGGTTTTT HIPK3 homeodomain interacting protein kinase 3 TRCN0000003258 CCGGGAACATTAAGAAGTCAGGCATCTCGAGATGCCTGACTTCTTAATGTTCTTTTT HIPK3 homeodomain interacting protein kinase 3 TRCN0000199785 CCGGGCCATAGACATGTGGTCATTGCTCGAGCAATGACCACATGTCTATGGCTTTTTTG HIPK3 homeodomain interacting protein kinase 3 TRCN0000003254 CCGGCCTGCAAGAGACCGAATAGTACTCGAGTACTATTCGGTCTCTTGCAGGTTTTT HIPK3 homeodomain interacting protein kinase 3 TRCN0000003255 CCGGCTACTCTACTTCCATACCCATCTCGAGATGGGTATGGAAGTAGAGTAGTTTTT HIPK3 homeodomain interacting protein kinase 3 TRCN0000003256 CCGGGATATTTGTAAGTCCCACCTACTCGAGTAGGTGGGACTTACAAATATCTTTTT HSPB8 heat shock 22kDa protein 8 TRCN0000010218 CCGGCCCTTCCCAGACGACTTGACACTCGAGTGTCAAGTCGTCTGGGAAGGGTTTTT HSPB8 heat shock 22kDa protein 8 TRCN0000010219 CCGGCCTGGAAAGTGTGTGTGAATGCTCGAGCATTCACACACACTTTCCAGGTTTTT HSPB8 heat shock 22kDa protein 8 TRCN0000195561 CCGGCCGCATGGTTTGGTTAATGAACTCGAGTTCATTAACCAAACCATGCGGTTTTTTG HSPB8 heat shock 22kDa protein 8 TRCN0000196245 CCGGGATAGTGTAGTGGTAGATTTCCTCGAGGAAATCTACCACTACACTATCTTTTTTG HSPB8 heat shock 22kDa protein 8 TRCN0000196817 CCGGGCATTGTTTCTAAGAACTTCACTCGAGTGAAGTTCTTAGAAACAATGCTTTTTTG HUNK hormonally up-regulated Neu-associated kinase TRCN0000002267 CCGGAGGCTCGCTTATGACACAGATCTCGAGATCTGTGTCATAAGCGAGCCTTTTTT HUNK hormonally up-regulated Neu-associated kinase TRCN0000002268 CCGGCCCAATATCACTCAGCTCCTTCTCGAGAAGGAGCTGAGTGATATTGGGTTTTT HUNK hormonally up-regulated Neu-associated kinase TRCN0000002269 CCGGCTGTAATGTCACCTATCCCAACTCGAGTTGGGATAGGTGACATTACAGTTTTT HUNK hormonally up-regulated Neu-associated kinase TRCN0000002270 CCGGCAGAAGATGGTAGACAAAGAACTCGAGTTCTTTGTCTACCATCTTCTGTTTTT HUNK hormonally up-regulated Neu-associated kinase TRCN0000002271 CCGGCCTGTGTTCATCCTGTTGTTTCTCGAGAAACAACAGGATGAACACAGGTTTTT ICK intestinal cell (MAK-like) kinase TRCN0000006323 CCGGCCTACCATCAAGCCATTGTTTCTCGAGAAACAATGGCTTGATGGTAGGTTTTT ICK intestinal cell (MAK-like) kinase TRCN0000006326 CCGGGTCAGTAATCAGCAAAGTAAACTCGAGTTTACTTTGCTGATTACTGACTTTTT ICK intestinal cell (MAK-like) kinase TRCN0000006327 CCGGCCAGCTCATTAAAGAGAGAAACTCGAGTTTCTCTCTTTAATGAGCTGGTTTTT ICK intestinal cell (MAK-like) kinase TRCN0000006324 CCGGCCAGTGAAATTGACACAATATCTCGAGATATTGTGTCAATTTCACTGGTTTTT ICK intestinal cell (MAK-like) kinase TRCN0000006325 CCGGGCTTCTTTCATCGAGACTTAACTCGAGTTAAGTCTCGATGAAAGAAGCTTTTT IGF1R insulin-like growth factor 1 receptor TRCN0000000424 CCGGGCTGATGTGTACGTTCCTGATCTCGAGATCAGGAACGTACACATCAGCTTTTT IGF1R insulin-like growth factor 1 receptor TRCN0000000425 CCGGCCTTGGACGTTCTTTCAGCATCTCGAGATGCTGAAAGAACGTCCAAGGTTTTT IGF1R insulin-like growth factor 1 receptor TRCN0000000426 CCGGCCAAGCCTGAGCAAGATGATTCTCGAGAATCATCTTGCTCAGGCTTGGTTTTT IGF1R insulin-like growth factor 1 receptor TRCN0000039673 CCGGAACACATTTGGGATGTTCCTCCTCGAGGAGGAACATCCCAAATGTGTTTTTTTG IGF1R insulin-like growth factor 1 receptor TRCN0000039674 CCGGCGGCACAATTACTGCTCCAAACTCGAGTTTGGAGCAGTAATTGTGCCGTTTTTG inhibitor of kappa light polypeptide gene enhancer in IKBKB TRCN0000018915 CCGGGCACTGGGAAAGTATCTGAAACTCGAGTTTCAGATACTTTCCCAGTGCTTTTT B-cells, kinase beta inhibitor of kappa light polypeptide gene enhancer in IKBKB TRCN0000018916 CCGGCCAGCCAAGAAGAGTGAAGAACTCGAGTTCTTCACTCTTCTTGGCTGGTTTTT B-cells, kinase beta inhibitor of kappa light polypeptide gene enhancer in IKBKB TRCN0000018917 CCGGGCTGGTTCATATCTTGAACATCTCGAGATGTTCAAGATATGAACCAGCTTTTT B-cells, kinase beta inhibitor of kappa light polypeptide gene enhancer in IKBKB TRCN0000018918 CCGGCGGAAGTACCTGAACCAGTTTCTCGAGAAACTGGTTCAGGTACTTCCGTTTTT B-cells, kinase beta inhibitor of kappa light polypeptide gene enhancer in IKBKB TRCN0000018919 CCGGCCATGATGAATCTCCTCCGAACTCGAGTTCGGAGGAGATTCATCATGGTTTTT B-cells, kinase beta inhibitor of kappa light polypeptide gene enhancer in IKBKE TRCN0000010027 CCGGGAGCATTGGAGTGACCTTGTACTCGAGTACAAGGTCACTCCAATGCTCTTTTT B-cells, kinase epsilon

171 Supplement

inhibitor of kappa light polypeptide gene enhancer in IKBKE TRCN0000010034 CCGGCTTCGACCAGTTCTTTGCGGACTCGAGTCCGCAAAGAACTGGTCGAAGTTTTT B-cells, kinase epsilon inhibitor of kappa light polypeptide gene enhancer in IKBKE TRCN0000010035 CCGGTGCCCACAACACGATAGCCATCTCGAGATGGCTATCGTGTTGTGGGCATTTTT B-cells, kinase epsilon inhibitor of kappa light polypeptide gene enhancer in IKBKE TRCN0000010036 CCGGTGGGCAGGAGCTAATGTTTCGCTCGAGCGAAACATTAGCTCCTGCCCATTTTT B-cells, kinase epsilon inhibitor of kappa light polypeptide gene enhancer in IKBKE TRCN0000010037 CCGGGTCCTTAGTCACACACGGCAACTCGAGTTGCCGTGTGTGACTAAGGACTTTTT B-cells, kinase epsilon ILK integrin-linked kinase TRCN0000000968 CCGGTCAGAGCTTTGTCACTTGCCACTCGAGTGGCAAGTGACAAAGCTCTGATTTTT ILK integrin-linked kinase TRCN0000000972 CCGGTCCCACGACATGCACTCAATACTCGAGTATTGAGTGCATGTCGTGGGATTTTT ILK integrin-linked kinase TRCN0000194750 CCGGCGACCCAAATTTGACATGATTCTCGAGAATCATGTCAAATTTGGGTCGTTTTTTG ILK integrin-linked kinase TRCN0000195112 CCGGCCGTAGTGTAATGATTGATGACTCGAGTCATCAATCATTACACTACGGTTTTTTG ILK integrin-linked kinase TRCN0000199983 CCGGGCAATGACATTGTCGTGAAGGCTCGAGCCTTCACGACAATGTCATTGCTTTTTTG INSR insulin receptor TRCN0000000379 CCGGGCTCTGTTACTTGGCCACTATCTCGAGATAGTGGCCAAGTAACAGAGCTTTTT INSR insulin receptor TRCN0000000380 CCGGGTGCTGTATGAAGTGAGTTATCTCGAGATAACTCACTTCATACAGCACTTTTT INSR insulin receptor TRCN0000000381 CCGGCACTGATTACTTGCTGCTCTTCTCGAGAAGAGCAGCAAGTAATCAGTGTTTTT INSR insulin receptor TRCN0000000382 CCGGCAGTGTTGTGATTGGAAGTATCTCGAGATACTTCCAATCACAACACTGTTTTT INSR insulin receptor TRCN0000039700 CCGGGCCAAGAGTGACATCATTTATCTCGAGATAAATGATGTCACTCTTGGCTTTTTG INSRR insulin receptor-related receptor TRCN0000003187 CCGGCGCCCATCTTTCACACACATTCTCGAGAATGTGTGTGAAAGATGGGCGTTTTT INSRR insulin receptor-related receptor TRCN0000003188 CCGGCATCCTCAAGTACGAAATCAACTCGAGTTGATTTCGTACTTGAGGATGTTTTT INSRR insulin receptor-related receptor TRCN0000003189 CCGGCCTCTGCTTGGAACACATCTACTCGAGTAGATGTGTTCCAAGCAGAGGTTTTT INSRR insulin receptor-related receptor TRCN0000003190 CCGGCGACCTCTACCTCAATGACTACTCGAGTAGTCATTGAGGTAGAGGTCGTTTTT INSRR insulin receptor-related receptor TRCN0000010765 CCGGCCTTGGGATTTGGCCTGGATACTCGAGTATCCAGGCCAAATCCCAAGGTTTTT IRAK1 interleukin-1 receptor-associated kinase 1 TRCN0000000543 CCGGCCCTCCTACCTGCTTACAATTCTCGAGAATTGTAAGCAGGTAGGAGGGTTTTT IRAK1 interleukin-1 receptor-associated kinase 1 TRCN0000000544 CCGGGCCCGAAGAAAGTGATGAATTCTCGAGAATTCATCACTTTCTTCGGGCTTTTT IRAK1 interleukin-1 receptor-associated kinase 1 TRCN0000000545 CCGGCGGGCAATTCAGTTTCTACATCTCGAGATGTAGAAACTGAATTGCCCGTTTTT IRAK1 interleukin-1 receptor-associated kinase 1 TRCN0000000546 CCGGCATTGTGGACTTTGCTGGCTACTCGAGTAGCCAGCAAAGTCCACAATGTTTTT IRAK1 interleukin-1 receptor-associated kinase 1 TRCN0000121137 CCGGGCTGAAGTAGGAGGATCATTTCTCGAGAAATGATCCTCCTACTTCAGCTTTTTG IRAK2 interleukin-1 receptor-associated kinase 2 TRCN0000000549 CCGGACAGTTTCACAGCTTCATCTACTCGAGTAGATGAAGCTGTGAAACTGTTTTTT IRAK2 interleukin-1 receptor-associated kinase 2 TRCN0000196789 CCGGGACTTACTCCTCAGTGATATTCTCGAGAATATCACTGAGGAGTAAGTCTTTTTTG IRAK2 interleukin-1 receptor-associated kinase 2 TRCN0000000548 CCGGCTGCAATGGATAACAACCGAACTCGAGTTCGGTTGTTATCCATTGCAGTTTTT IRAK2 interleukin-1 receptor-associated kinase 2 TRCN0000010527 CCGGCTTCAGCACCTCCATTCCTAACTCGAGTTAGGAATGGAGGTGCTGAAGTTTTT IRAK2 interleukin-1 receptor-associated kinase 2 TRCN0000195520 CCGGCAGAAACTTCGTGGCAAATTGCTCGAGCAATTTGCCACGAAGTTTCTGTTTTTTG IRAK3 interleukin-1 receptor-associated kinase 3 TRCN0000000875 CCGGTGGGTGATGCAGATAAACAATCTCGAGATTGTTTATCTGCATCACCCATTTTT IRAK3 interleukin-1 receptor-associated kinase 3 TRCN0000000876 CCGGGCAGTGTAAGAAGCATTGGAACTCGAGTTCCAATGCTTCTTACACTGCTTTTT IRAK3 interleukin-1 receptor-associated kinase 3 TRCN0000000877 CCGGGAAGATGATGAAAGCCAGAATCTCGAGATTCTGGCTTTCATCATCTTCTTTTT IRAK3 interleukin-1 receptor-associated kinase 3 TRCN0000000878 CCGGCGGGCAAAGTTAAGACCATCACTCGAGTGATGGTCTTAACTTTGCCCGTTTTT IRAK3 interleukin-1 receptor-associated kinase 3 TRCN0000000879 CCGGCATCAGAGTTGTACCATAAATCTCGAGATTTATGGTACAACTCTGATGTTTTT IRAK4 interleukin-1 receptor-associated kinase 4 TRCN0000002065 CCGGCCCAGACATTAAGAAGGTTCACTCGAGTGAACCTTCTTAATGTCTGGGTTTTT IRAK4 interleukin-1 receptor-associated kinase 4 TRCN0000002064 CCGGCCTCTGCTTAGTATATGTTTACTCGAGTAAACATATACTAAGCAGAGGTTTTT IRAK4 interleukin-1 receptor-associated kinase 4 TRCN0000002066 CCGGGCCTGACCTAATCCAAGTGAACTCGAGTTCACTTGGATTAGGTCAGGCTTTTT IRAK4 interleukin-1 receptor-associated kinase 4 TRCN0000010679 CCGGGCTAATACACTACCTTCTAAACTCGAGTTTAGAAGGTAGTGTATTAGCTTTTT IRAK4 interleukin-1 receptor-associated kinase 4 TRCN0000195149 CCGGCCACTACTAATTTGCTGTAAACTCGAGTTTACAGCAAATTAGTAGTGGTTTTTTG ITK IL2-inducible T-cell kinase TRCN0000010021 CCGGCTCCACACACGTCTACCAGATCTCGAGATCTGGTAGACGTGTGTGGAGTTTTT ITK IL2-inducible T-cell kinase TRCN0000195263 CCGGCATCAACTATCACCAACATAACTCGAGTTATGTTGGTGATAGTTGATGTTTTTTG ITK IL2-inducible T-cell kinase TRCN0000196768 CCGGGTGAGAACAATCCCTGTATAACTCGAGTTATACAGGGATTGTTCTCACTTTTTTG ITK IL2-inducible T-cell kinase TRCN0000197104 CCGGGAAGACATCAGTACCGGATTTCTCGAGAAATCCGGTACTGATGTCTTCTTTTTTG ITK IL2-inducible T-cell kinase TRCN0000010020 CCGGTCAGTACACCAGTTCCACAGGCTCGAGCCTGTGGAACTGGTGTACTGATTTTT JAK1 Janus kinase 1 TRCN0000003102 CCGGGAGACTTCCATGTTACTGATTCTCGAGAATCAGTAACATGGAAGTCTCTTTTT JAK1 Janus kinase 1 TRCN0000003103 CCGGCATGCCGTATCTCTCCTCTTTCTCGAGAAAGAGGAGAGATACGGCATGTTTTT JAK1 Janus kinase 1 TRCN0000003104 CCGGCTGAGCTACTTGGAGGATAAACTCGAGTTTATCCTCCAAGTAGCTCAGTTTTT JAK1 Janus kinase 1 TRCN0000003105 CCGGCTTGGCTACCTTGGAAACTTTCTCGAGAAAGTTTCCAAGGTAGCCAAGTTTTT JAK1 Janus kinase 1 TRCN0000010760 CCGGTGCACAGAAGACGGAGGAAATCTCGAGATTTCCTCCGTCTTCTGTGCATTTTT JAK2 Janus kinase 2 TRCN0000003178 CCGGCCCTGACCCTAAATAATACATCTCGAGATGTATTATTTAGGGTCAGGGTTTTT JAK2 Janus kinase 2 TRCN0000003179 CCGGCACAGTTTGAAGAGAGACATTCTCGAGAATGTCTCTCTTCAAACTGTGTTTTT JAK2 Janus kinase 2 TRCN0000003180 CCGGGCTTTGTCTTTCGTGTCATTACTCGAGTAATGACACGAAAGACAAAGCTTTTT JAK2 Janus kinase 2 TRCN0000003181 CCGGGCAGAATTAGCAAACCTTATACTCGAGTATAAGGTTTGCTAATTCTGCTTTTT JAK2 Janus kinase 2 (a protein tyrosine kinase) TRCN0000196855 CCGGGCGGAATTTATGCGTATGATTCTCGAGAATCATACGCATAAATTCCGCTTTTTTG JAK3 Janus kinase 3 TRCN0000000384 CCGGCCAGGACAGACAACCAGATTTCTCGAGAAATCTGGTTGTCTGTCCTGGTTTTT JAK3 Janus kinase 3 TRCN0000000383 CCGGCAAAGAAGCAAGGAACCAAATCTCGAGATTTGGTTCCTTGCTTCTTTGTTTTT JAK3 Janus kinase 3 TRCN0000000385 CCGGTCCTGCTAAGAAACTCCAATTCTCGAGAATTGGAGTTTCTTAGCAGGATTTTT JAK3 Janus kinase 3 TRCN0000000386 CCGGCTCTTCACCTACTGCGACAAACTCGAGTTTGTCGCAGTAGGTGAAGAGTTTTT JAK3 Janus kinase 3 TRCN0000000387 CCGGCAGCGCCTATCTTTCTCCTTTCTCGAGAAAGGAGAAAGATAGGCGCTGTTTTT KALRN kalirin, RhoGEF kinase TRCN0000048208 CCGGCCCGGAAGAAAGAATTTATTACTCGAGTAATAAATTCTTTCTTCCGGGTTTTTG

172 Supplement

KALRN kalirin, RhoGEF kinase TRCN0000048211 CCGGGCTCAGAATACGTACACCAATCTCGAGATTGGTGTACGTATTCTGAGCTTTTTG KALRN kalirin, RhoGEF kinase TRCN0000048212 CCGGGCATATCATCTTTGGCAACATCTCGAGATGTTGCCAAAGATGATATGCTTTTTG KALRN kalirin, RhoGEF kinase TRCN0000048209 CCGGGCCATGAACAACATGACCTTTCTCGAGAAAGGTCATGTTGTTCATGGCTTTTTG KALRN kalirin, RhoGEF kinase TRCN0000048210 CCGGCCTGTCCAAAGGATCACCAAACTCGAGTTTGGTGATCCTTTGGACAGGTTTTTG kinase insert domain receptor (a type III receptor KDR TRCN0000001685 CCGGGCGGCACGAAATATCCTCTTACTCGAGTAAGAGGATATTTCGTGCCGCTTTTT tyrosine kinase) kinase insert domain receptor (a type III receptor KDR TRCN0000001686 CCGGAGGCTAATACAACTCTTCAAACTCGAGTTTGAAGAGTTGTATTAGCCTTTTTT tyrosine kinase) kinase insert domain receptor (a type III receptor KDR TRCN0000001687 CCGGGTGCTGTTTCTGACTCCTAATCTCGAGATTAGGAGTCAGAAACAGCACTTTTT tyrosine kinase) kinase insert domain receptor (a type III receptor KDR TRCN0000001688 CCGGCTTTACTATTCCCAGCTACATCTCGAGATGTAGCTGGGAATAGTAAAGTTTTT tyrosine kinase) kinase insert domain receptor (a type III receptor KDR TRCN0000001689 CCGGGTGGTCTCTCTGGTTGTGTATCTCGAGATACACAACCAGAGAGACCACTTTTT tyrosine kinase) KIAA1804 mixed lineage kinase 4 TRCN0000003209 CCGGGCAACTATTATCTCAGCCACTCTCGAGAGTGGCTGAGATAATAGTTGCTTTTT KIAA1804 mixed lineage kinase 4 TRCN0000003210 CCGGGCCTACATTGATCTACCTCTTCTCGAGAAGAGGTAGATCAATGTAGGCTTTTT KIAA1804 mixed lineage kinase 4 TRCN0000003211 CCGGCCTCCATCAGTAGCCCTTTATCTCGAGATAAAGGGCTACTGATGGAGGTTTTT KIAA1804 mixed lineage kinase 4 TRCN0000003212 CCGGCCCTCATATTCGTCCATCGTTCTCGAGAACGATGGACGAATATGAGGGTTTTT KIAA1804 mixed lineage kinase 4 TRCN0000003213 CCGGCGTCCATCGTTTGCCTTAATTCTCGAGAATTAAGGCAAACGATGGACGTTTTT v-kit Hardy-Zuckerman 4 feline sarcoma viral KIT TRCN0000195226 CCGGCCTTTGTGTTTCTATTGACTTCTCGAGAAGTCAATAGAAACACAAAGGTTTTTTG oncogene homolog v-kit Hardy-Zuckerman 4 feline sarcoma viral KIT TRCN0000000388 CCGGCCATAAGGTTTCGTTTCTGTACTCGAGTACAGAAACGAAACCTTATGGTTTTT oncogene homolog v-kit Hardy-Zuckerman 4 feline sarcoma viral KIT TRCN0000000389 CCGGGCGACGAGATTAGGCTGTTATCTCGAGATAACAGCCTAATCTCGTCGCTTTTT oncogene homolog v-kit Hardy-Zuckerman 4 feline sarcoma viral KIT TRCN0000000390 CCGGGCACCAACAAACACGGCTTAACTCGAGTTAAGCCGTGTTTGTTGGTGCTTTTT oncogene homolog v-kit Hardy-Zuckerman 4 feline sarcoma viral KIT TRCN0000000391 CCGGGCCGGTCGATTCTAAGTTCTACTCGAGTAGAACTTAGAATCGACCGGCTTTTT oncogene homolog KSR1 kinase suppressor of ras 1 TRCN0000006227 CCGGGCTCTTCAAGAAAGAGGTGATCTCGAGATCACCTCTTTCTTGAAGAGCTTTTT KSR1 kinase suppressor of ras 1 TRCN0000006230 CCGGGTGCCAGAAGAGCATGATATTCTCGAGAATATCATGCTCTTCTGGCACTTTTT KSR1 kinase suppressor of ras 1 TRCN0000006226 CCGGGCCTCCTTATTGCAGAAAGTTCTCGAGAACTTTCTGCAATAAGGAGGCTTTTT KSR1 kinase suppressor of ras 1 TRCN0000006229 CCGGGCTGCCTACTTCATTCATCATCTCGAGATGATGAATGAAGTAGGCAGCTTTTT KSR2 kinase suppressor of ras 2 TRCN0000007062 CCGGCCTCAAGTCAAAGAACGTCTTCTCGAGAAGACGTTCTTTGACTTGAGGTTTTT KSR2 kinase suppressor of ras 2 TRCN0000199136 CCGGCGTAGGCAGCTGCGAGAACATCTCGAGATGTTCTCGCAGCTGCCTACGTTTTTTG KSR2 kinase suppressor of ras 2 TRCN0000199619 CCGGGCCTCAGGAATGTCCACATGTCTCGAGACATGTGGACATTCCTGAGGCTTTTTTG KSR2 kinase suppressor of ras 2 TRCN0000007061 CCGGCCAGGCAGATTGCTCAAGAAACTCGAGTTTCTTGAGCAATCTGCCTGGTTTTT KSR2 kinase suppressor of ras 2 TRCN0000007063 CCGGGCAGAGGCAATAATCTGGCAACTCGAGTTGCCAGATTATTGCCTCTGCTTTTT LATS1 LATS, large tumor suppressor, homolog 1 (Drosophila) TRCN0000001776 CCGGGAAGATAAAGACACTAGGAATCTCGAGATTCCTAGTGTCTTTATCTTCTTTTT LATS1 LATS, large tumor suppressor, homolog 1 (Drosophila) TRCN0000001777 CCGGCACGGCAAGATAGCATGGATTCTCGAGAATCCATGCTATCTTGCCGTGTTTTT LATS1 LATS, large tumor suppressor, homolog 1 (Drosophila) TRCN0000001779 CCGGCAAGTCAGAAATCCACCCAAACTCGAGTTTGGGTGGATTTCTGACTTGTTTTT LATS1 LATS, large tumor suppressor, homolog 1 (Drosophila) TRCN0000001780 CCGGGAGAAATTAAGCCATCGTGTTCTCGAGAACACGATGGCTTAATTTCTCTTTTT LATS1 LATS, large tumor suppressor, homolog 1 (Drosophila) TRCN0000195739 CCGGCACACGATTCTAAGTACTATCCTCGAGGATAGTACTTAGAATCGTGTGTTTTTTG LATS2 LATS, large tumor suppressor, homolog 2 (Drosophila) TRCN0000000880 CCGGCCGTCGATTACTTCACTTGAACTCGAGTTCAAGTGAAGTAATCGACGGTTTTT LATS2 LATS, large tumor suppressor, homolog 2 (Drosophila) TRCN0000000881 CCGGGCCATGAAGACCCTAAGGAAACTCGAGTTTCCTTAGGGTCTTCATGGCTTTTT LATS2 LATS, large tumor suppressor, homolog 2 (Drosophila) TRCN0000000882 CCGGCCTCTGGGATGATGTGTCTAACTCGAGTTAGACACATCATCCCAGAGGTTTTT LATS2 LATS, large tumor suppressor, homolog 2 (Drosophila) TRCN0000000883 CCGGCAGGACCAAACAGTGACACTTCTCGAGAAGTGTCACTGTTTGGTCCTGTTTTT LATS2 LATS, large tumor suppressor, homolog 2 (Drosophila) TRCN0000000884 CCGGCTACTCGCCATACGCCTTTAACTCGAGTTAAAGGCGTATGGCGAGTAGTTTTT LCK lymphocyte-specific protein tyrosine kinase TRCN0000001598 CCGGGCACACATCAGGAGTTCAATACTCGAGTATTGAACTCCTGATGTGTGCTTTTT LCK lymphocyte-specific protein tyrosine kinase TRCN0000010175 CCGGGACACCCTGAGCTGCAAGATTCTCGAGAATCTTGCAGCTCAGGGTGTCTTTTT LCK lymphocyte-specific protein tyrosine kinase TRCN0000001599 CCGGAGCCATTAACTACGGGACATTCTCGAGAATGTCCCGTAGTTAATGGCTTTTTT LCK lymphocyte-specific protein tyrosine kinase TRCN0000001600 CCGGCATCAACAAACTCCTGGACATCTCGAGATGTCCAGGAGTTTGTTGATGTTTTT LCK lymphocyte-specific protein tyrosine kinase TRCN0000001601 CCGGAGCGCCAGAAGCCATTAACTACTCGAGTAGTTAATGGCTTCTGGCGCTTTTTT LIMK1 LIM domain kinase 1 TRCN0000000825 CCGGCAGTTGAGCATCTAGGAAGTACTCGAGTACTTCCTAGATGCTCAACTGTTTTT LIMK1 LIM domain kinase 1 TRCN0000000826 CCGGGACGAGATTGACCTGCTGATTCTCGAGAATCAGCAGGTCAATCTCGTCTTTTT LIMK1 LIM domain kinase 1 TRCN0000010554 CCGGCTACAAGGACAAGAGGCTCAACTCGAGTTGAGCCTCTTGTCCTTGTAGTTTTT LIMK1 LIM domain kinase 1 TRCN0000010555 CCGGCTACCTCCACTCCATGAACATCTCGAGATGTTCATGGAGTGGAGGTAGTTTTT LIMK1 LIM domain kinase 1 TRCN0000199315 CCGGCCCTGAGCTCTCCGGCTTATACTCGAGTATAAGCCGGAGAGCTCAGGGTTTTTTG LIMK2 LIM domain kinase 2 TRCN0000010241 CCGGCTGTATGAGCTGCAAGGTGATCTCGAGATCACCTTGCAGCTCATACAGTTTTT LIMK2 LIM domain kinase 2 TRCN0000010237 CCGGCAGAAGGTCAGGTTTGCCAAACTCGAGTTTGGCAAACCTGACCTTCTGTTTTT LIMK2 LIM domain kinase 2 TRCN0000010240 CCGGCCCTGAGATGCTGAACGGAAACTCGAGTTTCCGTTCAGCATCTCAGGGTTTTT LIMK2 LIM domain kinase 2 TRCN0000010242 CCGGCCAGACGAGCCAGACACTTCACTCGAGTGAAGTGTCTGGCTCGTCTGGTTTTT LIMK2 LIM domain kinase 2 TRCN0000195118 CCGGCAGAGTTTACTTGCTATATAGCTCGAGCTATATAGCAAGTAAACTCTGTTTTTTG LMTK2 lemur tyrosine kinase 2 TRCN0000010632 CCGGCTGACATGAGATTGGGAGGAACTCGAGTTCCTCCCAATCTCATGTCAGTTTTT LMTK2 lemur tyrosine kinase 2 TRCN0000010633 CCGGCCGGTCATTGTCATCTCAGATCTCGAGATCTGAGATGACAATGACCGGTTTTT LMTK2 lemur tyrosine kinase 2 TRCN0000010634 CCGGGCCAACCCAAAGGAACAAGATCTCGAGATCTTGTTCCTTTGGGTTGGCTTTTT LMTK2 lemur tyrosine kinase 2 TRCN0000010635 CCGGCCTTACTACATTCTTCAGCATCTCGAGATGCTGAAGAATGTAGTAAGGTTTTT LMTK2 lemur tyrosine kinase 2 TRCN0000194720 CCGGCCCACGTGTTTAGATGTTATTCTCGAGAATAACATCTAAACACGTGGGTTTTTTG

173 Supplement

LMTK3 lemur tyrosine kinase 3 TRCN0000021484 CCGGCGGAACTGAACTGAACTCTTTCTCGAGAAAGAGTTCAGTTCAGTTCCGTTTTT LMTK3 lemur tyrosine kinase 3 TRCN0000021485 CCGGGCCACGACTATTCTTGGACTTCTCGAGAAGTCCAAGAATAGTCGTGGCTTTTT LMTK3 lemur tyrosine kinase 3 TRCN0000021486 CCGGGCGGACTACTGGTATGACATTCTCGAGAATGTCATACCAGTAGTCCGCTTTTT LMTK3 lemur tyrosine kinase 3 TRCN0000021487 CCGGGCTGCCGTTTCTGCTGATTATCTCGAGATAATCAGCAGAAACGGCAGCTTTTT LMTK3 lemur tyrosine kinase 3 TRCN0000021488 CCGGCGGCTTCAAGGAATTTGAGAACTCGAGTTCTCAAATTCCTTGAAGCCGTTTTT LRRK1 leucine-rich repeat kinase 1 TRCN0000007038 CCGGCCCAGGTCTCAGATGGAATTACTCGAGTAATTCCATCTGAGACCTGGGTTTTT LRRK1 leucine-rich repeat kinase 1 TRCN0000007039 CCGGCGCCAGAGATTCTTCCTTTATCTCGAGATAAAGGAAGAATCTCTGGCGTTTTT LRRK1 leucine-rich repeat kinase 1 TRCN0000007040 CCGGCCAACACCATTCAGAGGGTATCTCGAGATACCCTCTGAATGGTGTTGGTTTTT LRRK1 leucine-rich repeat kinase 1 TRCN0000007041 CCGGCGGTGGAGATGTTATCGTCATCTCGAGATGACGATAACATCTCCACCGTTTTT LRRK1 leucine-rich repeat kinase 1 TRCN0000007042 CCGGCCTGGATTTAATTGAAGCCAACTCGAGTTGGCTTCAATTAAATCCAGGTTTTT LRRK2 leucine-rich repeat kinase 2 TRCN0000021459 CCGGCGTGTGTATGAAGGAATGTTACTCGAGTAACATTCCTTCATACACACGTTTTT LRRK2 leucine-rich repeat kinase 2 TRCN0000021460 CCGGCCCAGGATGTTGGAAATGATTCTCGAGAATCATTTCCAACATCCTGGGTTTTT LRRK2 leucine-rich repeat kinase 2 TRCN0000021461 CCGGGCCAGAGGAAATGTCATTTATCTCGAGATAAATGACATTTCCTCTGGCTTTTT LRRK2 leucine-rich repeat kinase 2 TRCN0000021462 CCGGCCACAAATTCAACGGAAAGAACTCGAGTTCTTTCCGTTGAATTTGTGGTTTTT LRRK2 leucine-rich repeat kinase 2 TRCN0000021463 CCGGCCCAAATTGGTGGAACTCTTACTCGAGTAAGAGTTCCACCAATTTGGGTTTTT LRRK2 leucine-rich repeat kinase 2 TRCN0000196822 CCGGGATAGGACAACTAGTACATTTCTCGAGAAATGTACTAGTTGTCCTATCTTTTTTG v-yes-1 Yamaguchi sarcoma viral related oncogene LYN TRCN0000010101 CCGGGGAAGAAGCCAACCTCATGAACTCGAGTTCATGAGGTTGGCTTCTTCCTTTTT homolog v-yes-1 Yamaguchi sarcoma viral related oncogene LYN TRCN0000010104 CCGGCGAAATTGTCACCTATGGGAACTCGAGTTCCCATAGGTGACAATTTCGTTTTT homolog v-yes-1 Yamaguchi sarcoma viral related oncogene LYN TRCN0000010105 CCGGGCAGAAGAGAGACCAACGTTTCTCGAGAAACGTTGGTCTCTCTTCTGCTTTTT homolog v-yes-1 Yamaguchi sarcoma viral related oncogene LYN TRCN0000010106 CCGGGCCAAACTCAACACCTTAGAACTCGAGTTCTAAGGTGTTGAGTTTGGCTTTTT homolog v-yes-1 Yamaguchi sarcoma viral related oncogene LYN TRCN0000010107 CCGGGCTATTACATCTCTCCACGAACTCGAGTTCGTGGAGAGATGTAATAGCTTTTT homolog MAK male germ cell-associated kinase TRCN0000001785 CCGGGCTGTGGTTCTTATTTGACTACTCGAGTAGTCAAATAAGAACCACAGCTTTTT MAK male germ cell-associated kinase TRCN0000001786 CCGGGATCCACTTAGCACCTCTCAACTCGAGTTGAGAGGTGCTAAGTGGATCTTTTT MAK male germ cell-associated kinase TRCN0000001787 CCGGCTCTATATGTTAAGGCCACTTCTCGAGAAGTGGCCTTAACATATAGAGTTTTT MAK male germ cell-associated kinase TRCN0000001788 CCGGCGTCAAATCATCTGGAATCAACTCGAGTTGATTCCAGATGATTTGACGTTTTT MAK male germ cell-associated kinase TRCN0000001789 CCGGCAATGCCAGTAATGAAGCTATCTCGAGATAGCTTCATTACTGGCATTGTTTTT MAP2K1 mitogen-activated protein kinase kinase 1 TRCN0000002329 CCGGGCTTCTATGGTGCGTTCTACACTCGAGTGTAGAACGCACCATAGAAGCTTTTT MAP2K1 mitogen-activated protein kinase kinase 1 TRCN0000002330 CCGGCTGATGCTGAGGAAGTGGATTCTCGAGAATCCACTTCCTCAGCATCAGTTTTT MAP2K1 mitogen-activated protein kinase kinase 1 TRCN0000002331 CCGGGAGGGAGAAGCACAAGATCATCTCGAGATGATCTTGTGCTTCTCCCTCTTTTT MAP2K1 mitogen-activated protein kinase kinase 1 TRCN0000002332 CCGGGATTACATAGTCAACGAGCCTCTCGAGAGGCTCGTTGACTATGTAATCTTTTT MAP2K1 mitogenactivated protein kinase kinase 1 TRCN0000199799 CCGGGTCCTACATGTCGCCAGAAAGCTCGAGCTTTCTGGCGACATGTAGGACTTTTTTG MAP2K2 mitogen-activated protein kinase kinase 2 TRCN0000007006 CCGGGACTATATTGTGAACGAGCCACTCGAGTGGCTCGTTCACAATATAGTCTTTTT MAP2K2 mitogen-activated protein kinase kinase 2 TRCN0000007007 CCGGTGGACTATATTGTGAACGAGCCTCGAGGCTCGTTCACAATATAGTCCATTTTT MAP2K2 mitogen-activated protein kinase kinase 2 TRCN0000011062 CCGGCAACATCCTCGTGAACTCTAGCTCGAGCTAGAGTTCACGAGGATGTTGTTTTT MAP2K2 mitogen-activated protein kinase kinase 2 TRCN0000195037 CCGGCTTCCAGGAGTTTGTCAATAACTCGAGTTATTGACAAACTCCTGGAAGTTTTTTG MAP2K2 mitogen-activated protein kinase kinase 2 TRCN0000195427 CCGGCGAACTCAAAGACGATGACTTCTCGAGAAGTCATCGTCTTTGAGTTCGTTTTTTG MAP2K3 mitogen-activated protein kinase kinase 3 TRCN0000009974 CCGGCATCCTGCGGTTCCCTTACGACTCGAGTCGTAAGGGAACCGCAGGATGTTTTT MAP2K3 mitogen-activated protein kinase kinase 3 TRCN0000009975 CCGGCGGACCTTCATCACCATTGGACTCGAGTCCAATGGTGATGAAGGTCCGTTTTT MAP2K3 mitogen-activated protein kinase kinase 3 TRCN0000009985 CCGGATTGCTGTGTCTATCGTGCGGCTCGAGCCGCACGATAGACACAGCAATTTTTT MAP2K3 mitogen-activated protein kinase kinase 3 TRCN0000009986 CCGGGCCCTCCAATGTCCTTATCAACTCGAGTTGATAAGGACATTGGAGGGCTTTTT MAP2K3 mitogenactivated protein kinase kinase 3 TRCN0000199303 CCGGCACAGCAAGCTGTCGGTGATCCTCGAGGATCACCGACAGCTTGCTGTGTTTTTTG MAP2K4 mitogen-activated protein kinase kinase 4 TRCN0000001390 CCGGCTTCTTATGGATTTGGATGTACTCGAGTACATCCAAATCCATAAGAAGTTTTT MAP2K4 mitogen-activated protein kinase kinase 4 TRCN0000001391 CCGGGATGTATGAAGAACGTGCCGTCTCGAGACGGCACGTTCTTCATACATCTTTTT MAP2K4 mitogen-activated protein kinase kinase 4 TRCN0000001392 CCGGACGAGGAGCTTATGGTTCTGTCTCGAGACAGAACCATAAGCTCCTCGTTTTTT MAP2K4 mitogen-activated protein kinase kinase 4 TRCN0000001393 CCGGGATATGATGTCCGCTCTGATGCTCGAGCATCAGAGCGGACATCATATCTTTTT MAP2K4 mitogen-activated protein kinase kinase 4 TRCN0000010496 CCGGTACATTGTGAGCTCTGGTTATCTCGAGATAACCAGAGCTCACAATGTATTTTTG MAP2K5 mitogen-activated protein kinase kinase 5 TRCN0000001466 CCGGAGGACCAGTAACCAAGGAGAACTCGAGTTCTCCTTGGTTACTGGTCCTTTTTT MAP2K5 mitogen-activated protein kinase kinase 5 TRCN0000001467 CCGGGCCCTCCAATATGCTAGTAAACTCGAGTTTACTAGCATATTGGAGGGCTTTTT MAP2K5 mitogen-activated protein kinase kinase 5 TRCN0000001468 CCGGCCGTTCATCGTGCAGTTCAATCTCGAGATTGAACTGCACGATGAACGGTTTTT MAP2K5 mitogen-activated protein kinase kinase 5 TRCN0000001470 CCGGCTGATGTCTGGAGCTTAGGAACTCGAGTTCCTAAGCTCCAGACATCAGTTTTT MAP2K5 mitogen-activated protein kinase kinase 5 TRCN0000197077 CCGGGCTGGTAATTCGCATCAAGATCTCGAGATCTTGATGCGAATTACCAGCTTTTTTG MAP2K6 mitogen-activated protein kinase kinase 6 TRCN0000009987 CCGGGGCCTACATACCCAGAGCTAACTCGAGTTAGCTCTGGGTATGTAGGCCTTTTT MAP2K6 mitogen-activated protein kinase kinase 6 TRCN0000009991 CCGGCAATGCTCTCGGTCAAGTGAACTCGAGTTCACTTGACCGAGAGCATTGTTTTT MAP2K6 mitogen-activated protein kinase kinase 6 TRCN0000009988 CCGGCCTATAATGGAACTGGGACGACTCGAGTCGTCCCAGTTCCATTATAGGTTTTT MAP2K6 mitogen-activated protein kinase kinase 6 TRCN0000009989 CCGGCCGAGCCACAGTAAATAGCCACTCGAGTGGCTATTTACTGTGGCTCGGTTTTT MAP2K6 mitogen-activated protein kinase kinase 6 TRCN0000009990 CCGGCGGCTACTGATGGATTTGGATCTCGAGATCCAAATCCATCAGTAGCCGTTTTT MAP2K7 mitogen-activated protein kinase kinase 7 TRCN0000001079 CCGGCACAGGAAGAGACCAAAGTATCTCGAGATACTTTGGTCTCTTCCTGTGTTTTT MAP2K7 mitogen-activated protein kinase kinase 7 TRCN0000010586 CCGGCCCTACATCGTGCAGTGCTTTCTCGAGAAAGCACTGCACGATGTAGGGTTTTT MAP2K7 mitogen-activated protein kinase kinase 7 TRCN0000010587 CCGGGAGCATTGAGATTGACCAGAACTCGAGTTCTGGTCAATCTCAATGCTCTTTTT MAP2K7 mitogen-activated protein kinase kinase 7 TRCN0000001080 CCGGCTACAAGAACTGCAAGACGGACTCGAGTCCGTCTTGCAGTTCTTGTAGTTTTT

174 Supplement

MAP2K7 mitogen-activated protein kinase kinase 7 TRCN0000010588 CCGGGATTGTGAAGGCGCTGTACTACTCGAGTAGTACAGCGCCTTCACAATCTTTTT MAP3K1 mitogen-activated protein kinase kinase kinase 1 TRCN0000006160 CCGGGCCTTTCGTATCTCCATGAAACTCGAGTTTCATGGAGATACGAAAGGCTTTTT MAP3K1 mitogen-activated protein kinase kinase kinase 1 TRCN0000006161 CCGGCCTCTCCTTTATCTCATCATTCTCGAGAATGATGAGATAAAGGAGAGGTTTTT MAP3K1 mitogen-activated protein kinase kinase kinase 1 TRCN0000006162 CCGGCGGTCGTGAGATGGAGAATAACTCGAGTTATTCTCCATCTCACGACCGTTTTT MAP3K1 mitogen-activated protein kinase kinase kinase 1 TRCN0000195000 CCGGCTGGAAATTGTATCGTGTAATCTCGAGATTACACGATACAATTTCCAGTTTTTTG MAP3K1 mitogen-activated protein kinase kinase kinase 1 TRCN0000196286 CCGGGCTCATTTGCTGAGTAAATATCTCGAGATATTTACTCAGCAAATGAGCTTTTTTG MAP3K10 mitogen-activated protein kinase kinase kinase 10 TRCN0000010674 CCGGGCAGGATGTTCACTCTATTTACTCGAGTAAATAGAGTGAACATCCTGCTTTTT MAP3K10 mitogen-activated protein kinase kinase kinase 10 TRCN0000001988 CCGGATGAACTACCTACACAATGATCTCGAGATCATTGTGTAGGTAGTTCATTTTTT MAP3K10 mitogen-activated protein kinase kinase kinase 10 TRCN0000001989 CCGGGAAGCAAACAGTGGTCATCAACTCGAGTTGATGACCACTGTTTGCTTCTTTTT MAP3K10 mitogen-activated protein kinase kinase kinase 10 TRCN0000001990 CCGGCCTCAAGTCCATCAACATCCTCTCGAGAGGATGTTGATGGACTTGAGGTTTTT MAP3K10 mitogen-activated protein kinase kinase kinase 10 TRCN0000001991 CCGGGAAGACTGGAAGCTGGAGATTCTCGAGAATCTCCAGCTTCCAGTCTTCTTTTT MAP3K11 mitogen-activated protein kinase kinase kinase 11 TRCN0000021564 CCGGCTTAGGAGGAGTCACAGCATACTCGAGTATGCTGTGACTCCTCCTAAGTTTTT MAP3K11 mitogen-activated protein kinase kinase kinase 11 TRCN0000021566 CCGGTCTTCCCGTCCAACTATGTGTCTCGAGACACATAGTTGGACGGGAAGATTTTT MAP3K11 mitogen-activated protein kinase kinase kinase 11 TRCN0000021567 CCGGAGCACAAGACCCTGAAGATCACTCGAGTGATCTTCAGGGTCTTGTGCTTTTTT MAP3K11 mitogen-activated protein kinase kinase kinase 11 TRCN0000021568 CCGGATTGAGAGTGACGACATGGAGCTCGAGCTCCATGTCGTCACTCTCAATTTTTT MAP3K11 mitogenactivated protein kinase kinase kinase 11 TRCN0000199543 CCGGCCTAGGGCTTAGAGCATGGACCTCGAGGTCCATGCTCTAAGCCCTAGGTTTTTTG MAP3K12 mitogen-activated protein kinase kinase kinase 12 TRCN0000000999 CCGGGCGCCACATAATCAACAGAAACTCGAGTTTCTGTTGATTATGTGGCGCTTTTT MAP3K12 mitogen-activated protein kinase kinase kinase 12 TRCN0000001000 CCGGCCTCAAAGAAACCGACATCAACTCGAGTTGATGTCGGTTTCTTTGAGGTTTTT MAP3K12 mitogen-activated protein kinase kinase kinase 12 TRCN0000001001 CCGGCAGGGAGCACTATGAAAGGAACTCGAGTTCCTTTCATAGTGCTCCCTGTTTTT MAP3K12 mitogen-activated protein kinase kinase kinase 12 TRCN0000001003 CCGGAGAAACCGACATCAAGCACTTCTCGAGAAGTGCTTGATGTCGGTTTCTTTTTT MAP3K12 mitogen-activated protein kinase kinase kinase 12 TRCN0000197106 CCGGGCACTGAATTGGACAACTCCACTCGAGTGGAGTTGTCCAATTCAGTGCTTTTTTG MAP3K13 mitogen-activated protein kinase kinase kinase 13 TRCN0000007102 CCGGCCTGAAGATCTCGTGACTATACTCGAGTATAGTCACGAGATCTTCAGGTTTTT MAP3K13 mitogen-activated protein kinase kinase kinase 13 TRCN0000007106 CCGGCCAGAACAGTATGGGTCCTTACTCGAGTAAGGACCCATACTGTTCTGGTTTTT MAP3K13 mitogen-activated protein kinase kinase kinase 13 TRCN0000194715 CCGGCCTGATGAGTTAGCTGATAAACTCGAGTTTATCAGCTAACTCATCAGGTTTTTTG MAP3K13 mitogen-activated protein kinase kinase kinase 13 TRCN0000197262 CCGGGCTAAGGGAACACGATGAATCCTCGAGGATTCATCGTGTTCCCTTAGCTTTTTTG MAP3K13 mitogen-activated protein kinase kinase kinase 13 TRCN0000007103 CCGGGCACCCTAACATCATCGCATTCTCGAGAATGCGATGATGTTAGGGTGCTTTTT MAP3K14 mitogen-activated protein kinase kinase kinase 14 TRCN0000000731 CCGGCCCAGAATTGTCCCTTTGTATCTCGAGATACAAAGGGACAATTCTGGGTTTTT MAP3K14 mitogen-activated protein kinase kinase kinase 14 TRCN0000000732 CCGGCCTCGATCAGAACTCCACAAACTCGAGTTTGTGGAGTTCTGATCGAGGTTTTT MAP3K14 mitogen-activated protein kinase kinase kinase 14 TRCN0000000733 CCGGGCTGTGTGTCTTCAACCTGATCTCGAGATCAGGTTGAAGACACACAGCTTTTT MAP3K14 mitogen-activated protein kinase kinase kinase 14 TRCN0000010542 CCGGCTCAGGACTCACGTAGCATTACTCGAGTAATGCTACGTGAGTCCTGAGTTTTT MAP3K14 mitogen-activated protein kinase kinase kinase 14 TRCN0000196415 CCGGGCTATTTCAATGGTGTGAAAGCTCGAGCTTTCACACCATTGAAATAGCTTTTTTG MAP3K15 mitogen-activated protein kinase kinase kinase 15 TRCN0000021404 CCGGCCGCTGTGTTTACATATTTAACTCGAGTTAAATATGTAAACACAGCGGTTTTT MAP3K15 mitogen-activated protein kinase kinase kinase 15 TRCN0000021406 CCGGGCACCGCAATATCGTTCAGTACTCGAGTACTGAACGATATTGCGGTGCTTTTT MAP3K15 mitogen-activated protein kinase kinase kinase 15 TRCN0000021407 CCGGCGCATGGATAATACTGAGGTTCTCGAGAACCTCAGTATTATCCATGCGTTTTT MAP3K15 mitogen-activated protein kinase kinase kinase 15 TRCN0000021408 CCGGCCTGCGATCATTAGTTCAGAACTCGAGTTCTGAACTAATGATCGCAGGTTTTT MAP3K15 mitogen-activated protein kinase kinase kinase 15 TRCN0000194862 CCGGCCTATCAAAGTTTGATGAAAGCTCGAGCTTTCATCAAACTTTGATAGGTTTTTTG MAP3K2 mitogen-activated protein kinase kinase kinase 2 TRCN0000002043 CCGGGCAACGTCAAACTAGGAGATTCTCGAGAATCTCCTAGTTTGACGTTGCTTTTT MAP3K2 mitogen-activated protein kinase kinase kinase 2 TRCN0000002044 CCGGCCAGATGAATTACACCAGGTTCTCGAGAACCTGGTGTAATTCATCTGGTTTTT MAP3K2 mitogen-activated protein kinase kinase kinase 2 TRCN0000002047 CCGGCAGAATACTAAAGCACCTCAACTCGAGTTGAGGTGCTTTAGTATTCTGTTTTT MAP3K2 mitogenactivated protein kinase kinase kinase 2 TRCN0000195221 CCGGCCCAAGTGTGTGGATCTATTACTCGAGTAATAGATCCACACACTTGGGTTTTTTG MAP3K2 mitogenactivated protein kinase kinase kinase 2 TRCN0000195723 CCGGCAATCCTACTTTGACCGTAATCTCGAGATTACGGTCAAAGTAGGATTGTTTTTTG MAP3K3 mitogen-activated protein kinase kinase kinase 3 TRCN0000002305 CCGGCGGCCTGTGAAATATGAAGATCTCGAGATCTTCATATTTCACAGGCCGTTTTT MAP3K3 mitogen-activated protein kinase kinase kinase 3 TRCN0000002307 CCGGCCAGGGTATGAAGAGTGTTATCTCGAGATAACACTCTTCATACCCTGGTTTTT MAP3K3 mitogen-activated protein kinase kinase kinase 3 TRCN0000002308 CCGGAGGAATACTCAGATCGGGAAACTCGAGTTTCCCGATCTGAGTATTCCTTTTTT MAP3K3 mitogen-activated protein kinase kinase kinase 3 TRCN0000010692 CCGGACCTCTTGATCTACATTACATCTCGAGATGTAATGTAGATCAAGAGGTTTTTT MAP3K3 mitogen-activated protein kinase kinase kinase 3 TRCN0000002306 CCGGGTGCGAGATCCAGTTGCTAAACTCGAGTTTAGCAACTGGATCTCGCACTTTTT MAP3K4 mitogen-activated protein kinase kinase kinase 4 TRCN0000000849 CCGGCCGTGACATTAAAGGTGCCAACTCGAGTTGGCACCTTTAATGTCACGGTTTTT MAP3K4 mitogen-activated protein kinase kinase kinase 4 TRCN0000000850 CCGGGCTTCGCCTTTGTTAGAGATACTCGAGTATCTCTAACAAAGGCGAAGCTTTTT MAP3K4 mitogen-activated protein kinase kinase kinase 4 TRCN0000000852 CCGGCAACCAAACATCAGAGGAATACTCGAGTATTCCTCTGATGTTTGGTTGTTTTT MAP3K4 mitogen-activated protein kinase kinase kinase 4 TRCN0000194922 CCGGCCATCTCTCTTGAGTATTAAGCTCGAGCTTAATACTCAAGAGAGATGGTTTTTTG MAP3K4 mitogen-activated protein kinase kinase kinase 4 TRCN0000196769 CCGGGCATGTTAAGTGCCATTACTACTCGAGTAGTAATGGCACTTAACATGCTTTTTTG MAP3K5 mitogen-activated protein kinase kinase kinase 5 TRCN0000000993 CCGGGCTTACCTCTTGTGGATCGTTCTCGAGAACGATCCACAAGAGGTAAGCTTTTT MAP3K5 mitogen-activated protein kinase kinase kinase 5 TRCN0000000994 CCGGGAAGACACTATAAGCCGGTTTCTCGAGAAACCGGCTTATAGTGTCTTCTTTTT MAP3K5 mitogenactivated protein kinase kinase kinase 5 TRCN0000195146 CCGGCCTTCTTATTTGTCTATCAACCTCGAGGTTGATAGACAAATAAGAAGGTTTTTTG MAP3K5 mitogenactivated protein kinase kinase kinase 5 TRCN0000219665 CCGGCAGTACTTCCGGGAATCTATACTCGAGTATAGATTCCCGGAAGTACTGTTTTTG MAP3K5 mitogen-activated protein kinase kinase kinase 5 TRCN0000000991 CCGGTGTTTAGGCTTCTGTGTGTTTCTCGAGAAACACACAGAAGCCTAAACATTTTT MAP3K6 mitogen-activated protein kinase kinase kinase 6 TRCN0000002342 CCGGCAACCATTCAAGACAGCCTGTCTCGAGACAGGCTGTCTTGAATGGTTGTTTTT MAP3K6 mitogen-activated protein kinase kinase kinase 6 TRCN0000002343 CCGGGTTGGAGTTTGATTATGAGTACTCGAGTACTCATAATCAAACTCCAACTTTTT MAP3K6 mitogen-activated protein kinase kinase kinase 6 TRCN0000002344 CCGGCATGTTCTTCAGCTCGGGTTTCTCGAGAAACCCGAGCTGAAGAACATGTTTTT MAP3K6 mitogen-activated protein kinase kinase kinase 6 TRCN0000002345 CCGGCGTGGAGAAGATGCAGTATTACTCGAGTAATACTGCATCTTCTCCACGTTTTT MAP3K6 mitogen-activated protein kinase kinase kinase 6 TRCN0000002346 CCGGAGCGTATTAAACAGAACACTTCTCGAGAAGTGTTCTGTTTAATACGCTTTTTT MAP3K7 mitogen-activated protein kinase kinase kinase 7 TRCN0000001554 CCGGGCAGTGATTCTTGGATTGTTTCTCGAGAAACAATCCAAGAATCACTGCTTTTT

175 Supplement

MAP3K7 mitogen-activated protein kinase kinase kinase 7 TRCN0000001555 CCGGCCCGTGTGAACCATCCTAATACTCGAGTATTAGGATGGTTCACACGGGTTTTT MAP3K7 mitogen-activated protein kinase kinase kinase 7 TRCN0000001556 CCGGCAGTGTGTCTTGTGATGGAATCTCGAGATTCCATCACAAGACACACTGTTTTT MAP3K7 mitogen-activated protein kinase kinase kinase 7 TRCN0000001557 CCGGGACACACATGACCAATAACAACTCGAGTTGTTATTGGTCATGTGTGTCTTTTT MAP3K7 mitogen-activated protein kinase kinase kinase 7 TRCN0000001558 CCGGTCCTGCCACAAATGATACTATCTCGAGATAGTATCATTTGTGGCAGGATTTTT MAP3K8 mitogen-activated protein kinase kinase kinase 8 TRCN0000010010 CCGGGAATGGCGTGTAAACTGATCCCTCGAGGGATCAGTTTACACGCCATTCTTTTT MAP3K8 mitogen-activated protein kinase kinase kinase 8 TRCN0000010013 CCGGCAAGAGCCGCAGACCTACTAACTCGAGTTAGTAGGTCTGCGGCTCTTGTTTTT MAP3K8 mitogen-activated protein kinase kinase kinase 8 TRCN0000010014 CCGGGCGTTCTAAGTCTCTGCTGCTCTCGAGAGCAGCAGAGACTTAGAACGCTTTTT MAP3K8 mitogen-activated protein kinase kinase kinase 8 TRCN0000196899 CCGGGAAGCTGACTTACAGGAATATCTCGAGATATTCCTGTAAGTCAGCTTCTTTTTTG MAP3K8 mitogen-activated protein kinase kinase kinase 8 TRCN0000010011 CCGGGGCCTAAGTGTTCAAATGACCCTCGAGGGTCATTTGAACACTTAGGCCTTTTT MAP3K9 mitogen-activated protein kinase kinase kinase 9 TRCN0000021496 CCGGGCGCTTCAAACGAGATCCTAACTCGAGTTAGGATCTCGTTTGAAGCGCTTTTT MAP3K9 mitogen-activated protein kinase kinase kinase 9 TRCN0000021497 CCGGCCCATCAGAATCTCCACATTTCTCGAGAAATGTGGAGATTCTGATGGGTTTTT MAP3K9 mitogen-activated protein kinase kinase kinase 9 TRCN0000195694 CCGGCCAGAGGGATGAACTACTTACCTCGAGGTAAGTAGTTCATCCCTCTGGTTTTTTG MAP3K9 mitogen-activated protein kinase kinase kinase 9 TRCN0000196575 CCGGGCGATGAAATTGTCGTGTATGCTCGAGCATACACGACAATTTCATCGCTTTTTTG MAP3K9 mitogen-activated protein kinase kinase kinase 9 TRCN0000021494 CCGGCCCTACTTCTTGCACTGATAACTCGAGTTATCAGTGCAAGAAGTAGGGTTTTT mitogen-activated protein kinase kinase kinase kinase MAP4K1 TRCN0000001632 CCGGACATGACTTTAGCCTCTGCAACTCGAGTTGCAGAGGCTAAAGTCATGTTTTTT 1 mitogen-activated protein kinase kinase kinase kinase MAP4K1 TRCN0000001633 CCGGGCCTTCCACAACTTCATCAAACTCGAGTTTGATGAAGTTGTGGAAGGCTTTTT 1 mitogen-activated protein kinase kinase kinase kinase MAP4K1 TRCN0000001635 CCGGGAAGAAGATACACAGGGACATCTCGAGATGTCCCTGTGTATCTTCTTCTTTTT 1 mitogen-activated protein kinase kinase kinase kinase MAP4K1 TRCN0000001636 CCGGTGGCAAGGAAGAACATGGTTTCTCGAGAAACCATGTTCTTCCTTGCCATTTTT 1 mitogen-activated protein kinase kinase kinase kinase MAP4K1 TRCN0000195724 CCGGCAGAAGGAAATCCTCATATTGCTCGAGCAATATGAGGATTTCCTTCTGTTTTTTG 1 mitogen-activated protein kinase kinase kinase kinase MAP4K2 TRCN0000195052 CCGGCAGTTTCACCAGGTGAAATTTCTCGAGAAATTTCACCTGGTGAAACTGTTTTTTG 2 mitogen-activated protein kinase kinase kinase kinase MAP4K2 TRCN0000196641 CCGGGATGTCAAACTGGCTGACTTTCTCGAGAAAGTCAGCCAGTTTGACATCTTTTTTG 2 mitogen-activated protein kinase kinase kinase kinase MAP4K2 TRCN0000002233 CCGGCAGGAGATTTACCATGCCACTCTCGAGAGTGGCATGGTAAATCTCCTGTTTTT 2 mitogen-activated protein kinase kinase kinase kinase MAP4K2 TRCN0000002234 CCGGCCCTGACCAAGAATCCTAAGACTCGAGTCTTAGGATTCTTGGTCAGGGTTTTT 2 mitogen-activated protein kinase kinase kinase kinase MAP4K2 TRCN0000002235 CCGGCGGTATTTAAGAGAGAACTATCTCGAGATAGTTCTCTCTTAAATACCGTTTTT 2 mitogen-activated protein kinase kinase kinase kinase MAP4K3 TRCN0000000664 CCGGCTGAAGACATACACTAAGAATCTCGAGATTCTTAGTGTATGTCTTCAGTTTTT 3 mitogen-activated protein kinase kinase kinase kinase MAP4K3 TRCN0000000665 CCGGGTGCCGAAGAAGGGATTTATACTCGAGTATAAATCCCTTCTTCGGCACTTTTT 3 mitogen-activated protein kinase kinase kinase kinase MAP4K3 TRCN0000000666 CCGGGTCCACTTAGAATGTTTGAAACTCGAGTTTCAAACATTCTAAGTGGACTTTTT 3 mitogen-activated protein kinase kinase kinase kinase MAP4K3 TRCN0000010534 CCGGGCCACCAAAGCCTAAGTCTATCTCGAGATAGACTTAGGCTTTGGTGGCTTTTT 3 mitogen-activated protein kinase kinase kinase kinase MAP4K3 TRCN0000195007 CCGGCACCCAAATATTGTTGCTTATCTCGAGATAAGCAACAATATTTGGGTGTTTTTTG 3 mitogen-activated protein kinase kinase kinase kinase MAP4K4 TRCN0000001829 CCGGGAGAAAGATGAAACTGAGTATCTCGAGATACTCAGTTTCATCTTTCTCTTTTT 4 mitogen-activated protein kinase kinase kinase kinase MAP4K4 TRCN0000001832 CCGGTCCTTCCTGTTCCTCTTATATCTCGAGATATAAGAGGAACAGGAAGGATTTTT 4 mitogen-activated protein kinase kinase kinase kinase MAP4K4 TRCN0000001830 CCGGGTCTACTATTTGTCCTGGTTACTCGAGTAACCAGGACAAATAGTAGACTTTTT 4 mitogen-activated protein kinase kinase kinase kinase MAP4K4 TRCN0000001831 CCGGCGAGAGGTGGAAGATAGATTTCTCGAGAAATCTATCTTCCACCTCTCGTTTTT 4 mitogenactivated protein kinase kinase kinase kinase MAP4K4 TRCN0000195121 CCGGCACAGAAACATTGCAACATATCTCGAGATATGTTGCAATGTTTCTGTGTTTTTTG 4 mitogen-activated protein kinase kinase kinase kinase MAP4K5 TRCN0000002187 CCGGGCCACCTATGTTTGATCTCCACTCGAGTGGAGATCAAACATAGGTGGCTTTTT 5 mitogen-activated protein kinase kinase kinase kinase MAP4K5 TRCN0000002188 CCGGCAACAAAGATTCCTGATACAACTCGAGTTGTATCAGGAATCTTTGTTGTTTTT 5 mitogen-activated protein kinase kinase kinase kinase MAP4K5 TRCN0000002189 CCGGGCTCTACTCTCACAATCTTATCTCGAGATAAGATTGTGAGAGTAGAGCTTTTT 5 mitogen-activated protein kinase kinase kinase kinase MAP4K5 TRCN0000002190 CCGGCAAAGTGAACAATCCAGATAACTCGAGTTATCTGGATTGTTCACTTTGTTTTT 5 mitogen-activated protein kinase kinase kinase kinase MAP4K5 TRCN0000002191 CCGGCTCTACATCTTGGCTGGACATCTCGAGATGTCCAGCCAAGATGTAGAGTTTTT 5 MAPK1 mitogen-activated protein kinase 1 TRCN0000010039 CCGGTGGAATTGGATGACTTGCCTACTCGAGTAGGCAAGTCATCCAATTCCATTTTT MAPK1 mitogen-activated protein kinase 1 TRCN0000010040 CCGGCAAAGTTCGAGTAGCTATCAACTCGAGTTGATAGCTACTCGAACTTTGTTTTT MAPK1 mitogen-activated protein kinase 1 TRCN0000010041 CCGGGACATTATTCGAGCACCAACCCTCGAGGGTTGGTGCTCGAATAATGTCTTTTT MAPK1 mitogen-activated protein kinase 1 TRCN0000010050 CCGGTATCCATTCAGCTAACGTTCTCTCGAGAGAACGTTAGCTGAATGGATATTTTT MAPK1 mitogen-activated protein kinase 1 TRCN0000195517 CCGGCCCATATCTGGAGCAGTATTACTCGAGTAATACTGCTCCAGATATGGGTTTTTTG MAPK10 mitogen-activated protein kinase 10 TRCN0000001021 CCGGCGACGCCTTACAGCATCCCTACTCGAGTAGGGATGCTGTAAGGCGTCGTTTTT MAPK10 mitogen-activated protein kinase 10 TRCN0000001941 CCGGCAATAAACTCAAAGCCAGCCACTCGAGTGGCTGGCTTTGAGTTTATTGTTTTT MAPK10 mitogen-activated protein kinase 10 TRCN0000196303 CCGGGAATTAGACCATGAGCGAATGCTCGAGCATTCGCTCATGGTCTAATTCTTTTTTG MAPK10 mitogen-activated protein kinase 10 TRCN0000001017 CCGGCCAATGATGCTTACTACAGAACTCGAGTTCTGTAGTAAGCATCATTGGTTTTT MAPK10 mitogen-activated protein kinase 10 TRCN0000001018 CCGGGTAAGAAACTATGTGGAGAATCTCGAGATTCTCCACATAGTTTCTTACTTTTT MAPK11 mitogen-activated protein kinase 11 TRCN0000195259 CCGGCATGCTCAACTGGATGCATTACTCGAGTAATGCATCCAGTTGAGCATGTTTTTTG MAPK11 mitogen-activated protein kinase 11 TRCN0000195286 CCGGCACGTTCAATTCCTGGTTTACCTCGAGGTAAACCAGGAATTGAACGTGTTTTTTG MAPK11 mitogen-activated protein kinase 11 TRCN0000196579 CCGGGAGAATCTACACGCATGTATGCTCGAGCATACATGCGTGTAGATTCTCTTTTTTG MAPK11 mitogen-activated protein kinase 11 TRCN0000199347 CCGGCCTGTCCTCTTCTGGCTACTGCTCGAGCAGTAGCCAGAAGAGGACAGGTTTTTTG

176 Supplement

MAPK11 mitogen-activated protein kinase 11 TRCN0000199575 CCGGGCCACGTCCATCGAGGACTTCCTCGAGGAAGTCCTCGATGGACGTGGCTTTTTTG MAPK12 mitogen-activated protein kinase 12 TRCN0000006145 CCGGCTGGATGACTTCACGGACTTTCTCGAGAAAGTCCGTGAAGTCATCCAGTTTTT MAPK12 mitogen-activated protein kinase 12 TRCN0000006147 CCGGCTGGACGTATTCACTCCTGATCTCGAGATCAGGAGTGAATACGTCCAGTTTTT MAPK12 mitogen-activated protein kinase 12 TRCN0000006148 CCGGCCAGGTCCAGAAGTATGATGACTCGAGTCATCATACTTCTGGACCTGGTTTTT MAPK12 mitogen-activated protein kinase 12 TRCN0000006146 CCGGCATCTTGAATTGGATGCGCTACTCGAGTAGCGCATCCAATTCAAGATGTTTTT MAPK12 mitogen-activated protein kinase 12 TRCN0000006149 CCGGGCCCTTCCAGTCCGAGCTGTTCTCGAGAACAGCTCGGACTGGAAGGGCTTTTT MAPK13 mitogen-activated protein kinase 13 TRCN0000000827 CCGGCCGTTTGATGATTCCTTAGAACTCGAGTTCTAAGGAATCATCAAACGGTTTTT MAPK13 mitogen-activated protein kinase 13 TRCN0000009973 CCGGCTGAACGACAAAGCGGCCAAACTCGAGTTTGGCCGCTTTGTCGTTCAGTTTTT MAPK13 mitogen-activated protein kinase 13 TRCN0000009979 CCGGGCGCAACTTCTATGACTTCTACTCGAGTAGAAGTCATAGAAGTTGCGCTTTTT MAPK13 mitogen-activated protein kinase 13 TRCN0000009980 CCGGCTGTGAATGAGGACTGTGAACCTCGAGGTTCACAGTCCTCATTCACAGTTTTT MAPK13 mitogen-activated protein kinase 13 TRCN0000009981 CCGGTCTGTGGGCTGTATCATGGCACTCGAGTGCCATGATACAGCCCACAGATTTTT MAPK14 mitogen-activated protein kinase 14 TRCN0000000509 CCGGGCCGTATAGGATGTCAGACAACTCGAGTTGTCTGACATCCTATACGGCTTTTT MAPK14 mitogen-activated protein kinase 14 TRCN0000000510 CCGGCCATGTTCAGTTCCTTATCTACTCGAGTAGATAAGGAACTGAACATGGTTTTT MAPK14 mitogen-activated protein kinase 14 TRCN0000000511 CCGGCCATGAGGCAAGAAACTATATCTCGAGATATAGTTTCTTGCCTCATGGTTTTT MAPK14 mitogen-activated protein kinase 14 TRCN0000010051 CCGGGTTACGTGTGGCAGTGAAGAACTCGAGTTCTTCACTGCCACACGTAACTTTTT MAPK14 mitogen-activated protein kinase 14 TRCN0000010052 CCGGGTTCAGTTCCTTATCTACCAACTCGAGTTGGTAGATAAGGAACTGAACTTTTT MAPK15 mitogen-activated protein kinase 15 TRCN0000038661 CCGGGCTGCTCTCTTCGCACCGATACTCGAGTATCGGTGCGAAGAGAGCAGCTTTTTG MAPK15 mitogen-activated protein kinase 15 TRCN0000199135 CCGGCACTGACCTGAACGCAGTCATCTCGAGATGACTGCGTTCAGGTCAGTGTTTTTTG MAPK15 mitogen-activated protein kinase 15 TRCN0000199687 CCGGGCCGCGTCTATCAGATGATCCCTCGAGGGATCATCTGATAGACGCGGCTTTTTTG MAPK15 mitogen-activated protein kinase 15 TRCN0000002212 CCGGATAAGACAGATGCCCAGAGAACTCGAGTTCTCTGGGCATCTGTCTTATTTTTT MAPK15 mitogen-activated protein kinase 15 TRCN0000002213 CCGGCCACTGACTTCCTCCAATAAACTCGAGTTTATTGGAGGAAGTCAGTGGTTTTT MAPK3 mitogen-activated protein kinase 3 TRCN0000006150 CCGGCCTGAATTGTATCATCAACATCTCGAGATGTTGATGATACAATTCAGGTTTTT MAPK3 mitogen-activated protein kinase 3 TRCN0000006151 CCGGCGACCTTAAGATTTGTGATTTCTCGAGAAATCACAAATCTTAAGGTCGTTTTT MAPK3 mitogen-activated protein kinase 3 TRCN0000006152 CCGGCTATACCAAGTCCATCGACATCTCGAGATGTCGATGGACTTGGTATAGTTTTT MAPK3 mitogen-activated protein kinase 3 TRCN0000010998 CCGGGCAGCTGAGCAATGACCATATCTCGAGATATGGTCATTGCTCAGCTGCTTTTT MAPK3 mitogenactivated protein kinase 3 TRCN0000195323 CCGGCAACATGAAGGCCCGAAACTACTCGAGTAGTTTCGGGCCTTCATGTTGTTTTTTG MAPK4 mitogen-activated protein kinase 4 TRCN0000001374 CCGGCTCACACCACACGCCTTAAATCTCGAGATTTAAGGCGTGTGGTGTGAGTTTTT MAPK4 mitogen-activated protein kinase 4 TRCN0000001375 CCGGACTACACCAAAGCCATCGACACTCGAGTGTCGATGGCTTTGGTGTAGTTTTTT MAPK4 mitogen-activated protein kinase 4 TRCN0000001376 CCGGGAAGGTCGCTGTGAAGAAGATCTCGAGATCTTCTTCACAGCGACCTTCTTTTT MAPK4 mitogen-activated protein kinase 4 TRCN0000001377 CCGGAGTGAACAGTGAAGCCATCGACTCGAGTCGATGGCTTCACTGTTCACTTTTTT MAPK4 mitogen-activated protein kinase 4 TRCN0000001378 CCGGGATCAGCATTACTCCCACAAGCTCGAGCTTGTGGGAGTAATGCTGATCTTTTT MAPK4 mitogen-activated protein kinase 4 TRCN0000199263 CCGGCATCGTGCTGATGGCCGCTAACTCGAGTTAGCGGCCATCAGCACGATGTTTTTTG MAPK4 mitogen-activated protein kinase 4 TRCN0000199437 CCGGGATCGCGCAGTGGGTCAAGAGCTCGAGCTCTTGACCCACTGCGCGATCTTTTTTG MAPK4 mitogen-activated protein kinase 4 TRCN0000199817 CCGGGCGACCTCAATGGTGCGTGCACTCGAGTGCACGCACCATTGAGGTCGCTTTTTTG MAPK4 mitogen-activated protein kinase 4 TRCN0000200005 CCGGCTGGAGACCATCCCTGTAATCCTCGAGGATTACAGGGATGGTCTCCAGTTTTTTG MAPK6 mitogen-activated protein kinase 6 TRCN0000001568 CCGGGCTGTCCACGTACTTAATTTACTCGAGTAAATTAAGTACGTGGACAGCTTTTT MAPK6 mitogen-activated protein kinase 6 TRCN0000001569 CCGGGACATGACTGAGCCACACAAACTCGAGTTTGTGTGGCTCAGTCATGTCTTTTT MAPK6 mitogen-activated protein kinase 6 TRCN0000001570 CCGGTGATCTGGGTTCTAGGTATATCTCGAGATATACCTAGAACCCAGATCATTTTT MAPK6 mitogen-activated protein kinase 6 TRCN0000001571 CCGGGCTCTCTTACGGAACTGAACACTCGAGTGTTCAGTTCCGTAAGAGAGCTTTTT MAPK6 mitogen-activated protein kinase 6 TRCN0000194711 CCGGCACTAGTTACTTGGACAAGTTCTCGAGAACTTGTCCAAGTAACTAGTGTTTTTTG MAPK7 mitogen-activated protein kinase 7 TRCN0000001354 CCGGCCCTAATGCTTTCGATGTGGTCTCGAGACCACATCGAAAGCATTAGGGTTTTT MAPK7 mitogen-activated protein kinase 7 TRCN0000001355 CCGGAGACAATACTAAGGCTGCCCTCTCGAGAGGGCAGCCTTAGTATTGTCTTTTTT MAPK7 mitogen-activated protein kinase 7 TRCN0000001356 CCGGCTTCGATGTGACCTTTGACGTCTCGAGACGTCAAAGGTCACATCGAAGTTTTT MAPK7 mitogen-activated protein kinase 7 TRCN0000010262 CCGGGCTGCCCTGCTCAAGTCTTTGCTCGAGCAAAGACTTGAGCAGGGCAGCTTTTT MAPK7 mitogen-activated protein kinase 7 TRCN0000010271 CCGGCCAGTCCAACCTACCAGTCCTCTCGAGAGGACTGGTAGGTTGGACTGGTTTTT MAPK8 mitogen-activated protein kinase 8 TRCN0000001055 CCGGGAGTCGGTTAGTCATTGATAGCTCGAGCTATCAATGACTAACCGACTCTTTTT MAPK8 mitogen-activated protein kinase 8 TRCN0000001056 CCGGGCCCAGTAATATAGTAGTAAACTCGAGTTTACTACTATATTACTGGGCTTTTT MAPK8 mitogen-activated protein kinase 8 TRCN0000001057 CCGGGTCTGGTATGATCCTTCTGAACTCGAGTTCAGAAGGATCATACCAGACTTTTT MAPK8 mitogen-activated protein kinase 8 TRCN0000010580 CCGGCCACAGAAATCCCTAGAAGAACTCGAGTTCTTCTAGGGATTTCTGTGGTTTTT MAPK8 mitogen-activated protein kinase 8 TRCN0000010581 CCGGGACTCAGAACACAACAAACTTCTCGAGAAGTTTGTTGTGTTCTGAGTCTTTTT MAPK9 mitogen-activated protein kinase 9 TRCN0000000945 CCGGCTGTGAGGAATTATGTCGAAACTCGAGTTTCGACATAATTCCTCACAGTTTTT MAPK9 mitogen-activated protein kinase 9 TRCN0000001012 CCGGGAGCAGTTAGAGTAGGTGAATCTCGAGATTCACCTACTCTAACTGCTCTTTTT MAPK9 mitogen-activated protein kinase 9 TRCN0000001013 CCGGGATGTGTATTTGGTTATGGAACTCGAGTTCCATAACCAAATACACATCTTTTT MAPK9 mitogen-activated protein kinase 9 TRCN0000001014 CCGGCTGTGAGGAATTATGTCGAAACTCGAGTTTCGACATAATTCCTCACAGTTTTT MAPK9 mitogen-activated protein kinase 9 TRCN0000001015 CCGGAGGGATTGTTTGTGCTGCATTCTCGAGAATGCAGCACAAACAATCCCTTTTTT mitogen-activated protein kinase-activated protein MAPKAPK2 TRCN0000002282 CCGGCTCTTTGACCACTCCTTGTTACTCGAGTAACAAGGAGTGGTCAAAGAGTTTTT kinase 2 mitogen-activated protein kinase-activated protein MAPKAPK2 TRCN0000002283 CCGGGACTACGAGCAGATCAAGATACTCGAGTATCTTGATCTGCTCGTAGTCTTTTT kinase 2 mitogen-activated protein kinase-activated protein MAPKAPK2 TRCN0000002284 CCGGGCAATCAACAAAGGTCCCTCACTCGAGTGAGGGACCTTTGTTGATTGCTTTTT kinase 2 mitogen-activated protein kinase-activated protein MAPKAPK2 TRCN0000002285 CCGGCCAGCACTCGATTGTTGTAAACTCGAGTTTACAACAATCGAGTGCTGGTTTTT kinase 2 mitogen-activated protein kinase-activated protein MAPKAPK2 TRCN0000002286 CCGGAGAAAGAGAAGCATCCGAAATCTCGAGATTTCGGATGCTTCTCTTTCTTTTTT kinase 2

177 Supplement

mitogen-activated protein kinase-activated protein MAPKAPK3 TRCN0000006153 CCGGGCCTGCATAACAGACTGAAATCTCGAGATTTCAGTCTGTTATGCAGGCTTTTT kinase 3 mitogen-activated protein kinase-activated protein MAPKAPK3 TRCN0000006154 CCGGCCCTGCTATACTCCCTATTATCTCGAGATAATAGGGAGTATAGCAGGGTTTTT kinase 3 mitogen-activated protein kinase-activated protein MAPKAPK3 TRCN0000006156 CCGGCCTCATCATCATGGAATGCATCTCGAGATGCATTCCATGATGATGAGGTTTTT kinase 3 mitogen-activated protein kinase-activated protein MAPKAPK3 TRCN0000195452 CCGGCATTAACCTGAGGTCTCTTTCCTCGAGGAAAGAGACCTCAGGTTAATGTTTTTTG kinase 3 mitogen-activated protein kinase-activated protein MAPKAPK3 TRCN0000196478 CCGGGAACTTAAGGTGGGAGATATTCTCGAGAATATCTCCCACCTTAAGTTCTTTTTTG kinase 3 mitogen-activated protein kinase-activated protein MAPKAPK5 TRCN0000000681 CCGGGCGGCACTGTCACTTGTTAAACTCGAGTTTAACAAGTGACAGTGCCGCTTTTT kinase 5 mitogen-activated protein kinase-activated protein MAPKAPK5 TRCN0000000682 CCGGGAAATTGTGAAGCAGGTGATACTCGAGTATCACCTGCTTCACAATTTCTTTTT kinase 5 mitogen-activated protein kinase-activated protein MAPKAPK5 TRCN0000194823 CCGGCCCAAACATAGTTCAGATTATCTCGAGATAATCTGAACTATGTTTGGGTTTTTTG kinase 5 mitogen-activated protein kinase-activated protein MAPKAPK5 TRCN0000195129 CCGGCAGTATCAATTGGACTCAGAACTCGAGTTCTGAGTCCAATTGATACTGTTTTTTG kinase 5 mitogen-activated protein kinase-activated protein MAPKAPK5 TRCN0000195326 CCGGCCAAAGGACAGTGTCTATATCCTCGAGGATATAGACACTGTCCTTTGGTTTTTTG kinase 5 MARK1 MAP/microtubule affinity-regulating kinase 1 TRCN0000006328 CCGGCCCATGTAGAATTTGCCCTTACTCGAGTAAGGGCAAATTCTACATGGGTTTTT MARK1 MAP/microtubule affinity-regulating kinase 1 TRCN0000006329 CCGGGCACGAGATGAAATAAATGATCTCGAGATCATTTATTTCATCTCGTGCTTTTT MARK1 MAP/microtubule affinity-regulating kinase 1 TRCN0000006330 CCGGGCAGCACAACAGTTGGATCAACTCGAGTTGATCCAACTGTTGTGCTGCTTTTT MARK1 MAP/microtubule affinity-regulating kinase 1 TRCN0000006331 CCGGGCGGTTCACATGGAGTATGAACTCGAGTTCATACTCCATGTGAACCGCTTTTT MARK1 MAP/microtubule affinity-regulating kinase 1 TRCN0000006332 CCGGCCTGCTGTATCATATACCAAACTCGAGTTTGGTATATGATACAGCAGGTTTTT MARK2 MAP/microtubule affinity-regulating kinase 2 TRCN0000001581 CCGGTGCACAGAGTATTTCGCCTAACTCGAGTTAGGCGAAATACTCTGTGCATTTTT MARK2 MAP/microtubule affinity-regulating kinase 2 TRCN0000001583 CCGGGTGGCGGAGAGGTATTTGATTCTCGAGAATCAAATACCTCTCCGCCACTTTTT MARK2 MAP/microtubule affinity-regulating kinase 2 TRCN0000001584 CCGGAGATGATGAACTAAAGCCTTACTCGAGTAAGGCTTTAGTTCATCATCTTTTTT MARK2 MAP/microtubule affinity-regulating kinase 2 TRCN0000001582 CCGGCACCAGAAGTTTATTGTCCATCTCGAGATGGACAATAAACTTCTGGTGTTTTT MARK2 MAP/microtubule affinity-regulating kinase 2 TRCN0000001585 CCGGTGGGTTATACACGGGAAGAGACTCGAGTCTCTTCCCGTGTATAACCCATTTTT MARK3 MAP/microtubule affinity-regulating kinase 3 TRCN0000001567 CCGGTGAATGAACGAGACACTGAAACTCGAGTTTCAGTGTCTCGTTCATTCATTTTT MARK3 MAP/microtubule affinity-regulating kinase 3 TRCN0000010641 CCGGCCAGTTCTAGCAGCAATCTTTCTCGAGAAAGATTGCTGCTAGAACTGGTTTTT MARK3 MAP/microtubule affinity-regulating kinase 3 TRCN0000001564 CCGGTGTGTGTGAAGTGGTGTATATCTCGAGATATACACCACTTCACACACATTTTT MARK3 MAP/microtubule affinity-regulating kinase 3 TRCN0000001565 CCGGCATCCCAATATAGTGAAGTTACTCGAGTAACTTCACTATATTGGGATGTTTTT MARK3 MAP/microtubule affinity-regulating kinase 3 TRCN0000001566 CCGGCCAATTAAACGCGGCACTCTACTCGAGTAGAGTGCCGCGTTTAATTGGTTTTT MARK4 MAP/microtubule affinity-regulating kinase 4 TRCN0000007156 CCGGCCCTTTATCATCACCTCAGTTCTCGAGAACTGAGGTGATGATAAAGGGTTTTT MARK4 MAP/microtubule affinity-regulating kinase 4 TRCN0000007158 CCGGGCCATCTACCTTGGGATCAAACTCGAGTTTGATCCCAAGGTAGATGGCTTTTT MARK4 MAP/microtubule affinity-regulating kinase 4 TRCN0000007159 CCGGCCCAACATCGTGAAGCTCTTTCTCGAGAAAGAGCTTCACGATGTTGGGTTTTT MARK4 MAP/microtubule affinity-regulating kinase 4 TRCN0000197038 CCGGGCAGCCTGTTGCCCAATAAATCTCGAGATTTATTGGGCAACAGGCTGCTTTTTTG MARK4 MAP/microtubule affinity-regulating kinase 4 TRCN0000199158 CCGGCGAGCCAAGTTCCGACAGATTCTCGAGAATCTGTCGGAACTTGGCTCGTTTTTTG MAST1 microtubule associated serine/threonine kinase 1 TRCN0000199538 CCGGGCCTTTGTGGAGCGCGATATCCTCGAGGATATCGCGCTCCACAAAGGCTTTTTTG MAST1 microtubule associated serine/threonine kinase 1 TRCN0000021544 CCGGCGTGATGATGAATCACGTCTACTCGAGTAGACGTGATTCATCATCACGTTTTT MAST1 microtubule associated serine/threonine kinase 1 TRCN0000021545 CCGGCCACGGTCTACTTCTATGAATCTCGAGATTCATAGAAGTAGACCGTGGTTTTT MAST1 microtubule associated serine/threonine kinase 1 TRCN0000021546 CCGGCGCAGCAGCTACAAGGCTAAACTCGAGTTTAGCCTTGTAGCTGCTGCGTTTTT MAST1 microtubule associated serine/threonine kinase 1 TRCN0000021548 CCGGGCACAGTTTCTTTCGAGACCTCTCGAGAGGTCTCGAAAGAAACTGTGCTTTTT MAST2 microtubule associated serine/threonine kinase 2 TRCN0000001734 CCGGAGACCTGTGTAATATATGCTCCTCGAGGAGCATATATTACACAGGTCTTTTTT MAST2 microtubule associated serine/threonine kinase 2 TRCN0000001735 CCGGCCAGTATCCTTTGACAGTGAACTCGAGTTCACTGTCAAAGGATACTGGTTTTT MAST2 microtubule associated serine/threonine kinase 2 TRCN0000001736 CCGGGCACAAATGGAAGAGCGACTACTCGAGTAGTCGCTCTTCCATTTGTGCTTTTT MAST2 microtubule associated serine/threonine kinase 2 TRCN0000197248 CCGGGAGGACTTCGAGACCATTAAGCTCGAGCTTAATGGTCTCGAAGTCCTCTTTTTTG MAST2 microtubule associated serine/threonine kinase 2 TRCN0000219731 CCGGTGTGGACATGGTGCGTCTATACTCGAGTATAGACGCACCATGTCCACATTTTTG MAST3 microtubule associated serine/threonine kinase 3 TRCN0000021439 CCGGCCCAGCCTAATTTATTACTTTCTCGAGAAAGTAATAAATTAGGCTGGGTTTTT MAST3 microtubule associated serine/threonine kinase 3 TRCN0000200003 CCGGCGAGCCTTTCTGCCGACACAGCTCGAGCTGTGTCGGCAGAAAGGCTCGTTTTTTG MAST3 microtubule associated serine/threonine kinase 3 TRCN0000021441 CCGGGCTGGAGTACCTGCATAACTACTCGAGTAGTTATGCAGGTACTCCAGCTTTTT MAST3 microtubule associated serine/threonine kinase 3 TRCN0000021442 CCGGGAGCGTGACATTCTCACCTTTCTCGAGAAAGGTGAGAATGTCACGCTCTTTTT MAST3 microtubule associated serine/threonine kinase 3 TRCN0000021443 CCGGTGCCCAAGTTTGCCTTCTCATCTCGAGATGAGAAGGCAAACTTGGGCATTTTT microtubule associated serine/threonine kinase MAST4 TRCN0000037874 CCGGGAGGAGCTTGACCACATATTACTCGAGTAATATGTGGTCAAGCTCCTCTTTTTG family member 4 microtubule associated serine/threonine kinase MAST4 TRCN0000037875 CCGGGAAGAGGAAGTTTGATAGATTCTCGAGAATCTATCAAACTTCCTCTTCTTTTTG family member 4 microtubule associated serine/threonine kinase MAST4 TRCN0000037876 CCGGTCAGAAACTCTGTCGGAGGAACTCGAGTTCCTCCGACAGAGTTTCTGATTTTTG family member 4 microtubule associated serine/threonine kinase MAST4 TRCN0000037877 CCGGGTGAGGATGGAAGACAGCTAACTCGAGTTAGCTGTCTTCCATCCTCACTTTTTG family member 4 microtubule associated serine/threonine kinase MAST4 TRCN0000037878 CCGGGAAGTTTGATAGATTCCCAGACTCGAGTCTGGGAATCTATCAAACTTCTTTTTG family member 4 MASTL microtubule associated serine/threonine kinase-like TRCN0000002278 CCGGCCCATTCATTGTCCATTTGTACTCGAGTACAAATGGACAATGAATGGGTTTTT MASTL microtubule associated serine/threonine kinase-like TRCN0000002277 CCGGGTCAGCCCTTAGATTCAGATACTCGAGTATCTGAATCTAAGGGCTGACTTTTT MASTL microtubule associated serine/threonine kinase-like TRCN0000002279 CCGGGCTCTTGTGTAAACCTTGCTACTCGAGTAGCAAGGTTTACACAAGAGCTTTTT MASTL microtubule associated serine/threonine kinase-like TRCN0000002280 CCGGAGCCTCGTGTTATAGAATGAACTCGAGTTCATTCTATAACACGAGGCTTTTTT MASTL microtubule associated serine/threonine kinase-like TRCN0000002281 CCGGCCACAACAAGTATTCCAGAATCTCGAGATTCTGGAATACTTGTTGTGGTTTTT MATK megakaryocyte-associated tyrosine kinase TRCN0000002223 CCGGCTTCTGCAACCTCATGGACATCTCGAGATGTCCATGAGGTTGCAGAAGTTTTT MATK megakaryocyte-associated tyrosine kinase TRCN0000002219 CCGGGCATTTGACATTGGGAGCACACTCGAGTGTGCTCCCAATGTCAAATGCTTTTT

178 Supplement

MATK megakaryocyte-associated tyrosine kinase TRCN0000002220 CCGGGACGAAGATGCAACACGAGAACTCGAGTTCTCGTGTTGCATCTTCGTCTTTTT MATK megakaryocyte-associated tyrosine kinase TRCN0000002221 CCGGCAAGTCGGATGTCTGGAGTTTCTCGAGAAACTCCAGACATCCGACTTGTTTTT MATK megakaryocyte-associated tyrosine kinase TRCN0000002222 CCGGGACGGATTCTAAGGACTCTAACTCGAGTTAGAGTCCTTAGAATCCGTCTTTTT MELK maternal embryonic leucine zipper kinase TRCN0000001642 CCGGCTCTTAACTATGTCTCTTTGTCTCGAGACAAAGAGACATAGTTAAGAGTTTTT MELK maternal embryonic leucine zipper kinase TRCN0000001643 CCGGGCCTGAAAGAAACTCCAATTACTCGAGTAATTGGAGTTTCTTTCAGGCTTTTT MELK maternal embryonic leucine zipper kinase TRCN0000001644 CCGGCTGAGTTAATACAAGGCAAATCTCGAGATTTGCCTTGTATTAACTCAGTTTTT MELK maternal embryonic leucine zipper kinase TRCN0000001645 CCGGCAGAAACAACAGGCAAACAATCTCGAGATTGTTTGCCTGTTGTTTCTGTTTTT MELK maternal embryonic leucine zipper kinase TRCN0000001646 CCGGGAACCAGCATAAGAGAGAAATCTCGAGATTTCTCTCTTATGCTGGTTCTTTTT MERTK c-mer proto-oncogene tyrosine kinase TRCN0000000862 CCGGGCTTCTGGTCTTGATGTATTTCTCGAGAAATACATCAAGACCAGAAGCTTTTT MERTK c-mer proto-oncogene tyrosine kinase TRCN0000000865 CCGGCCTGCATACTTACTTACTTTACTCGAGTAAAGTAAGTAAGTATGCAGGTTTTT MERTK c-mer proto-oncogene tyrosine kinase TRCN0000000863 CCGGGCTCAATCAATGTACCTAATACTCGAGTATTAGGTACATTGATTGAGCTTTTT MERTK c-mer proto-oncogene tyrosine kinase TRCN0000000864 CCGGCGAGCCATTGAACTTACCTTACTCGAGTAAGGTAAGTTCAATGGCTCGTTTTT MERTK c-mer proto-oncogene tyrosine kinase TRCN0000000866 CCGGGAAGATTTACAGTGGCGATTACTCGAGTAATCGCCACTGTAAATCTTCTTTTT met proto-oncogene (hepatocyte growth factor MET TRCN0000009851 CCGGCATGTGAACGCTACTTATGTGCTCGAGCACATAAGTAGCGTTCACATGTTTTTG receptor) met proto-oncogene (hepatocyte growth factor MET TRCN0000010379 CCGGCATCAGAACCAGAGGCTTGGTCTCGAGACCAAGCCTCTGGTTCTGATGTTTTTG receptor) met proto-oncogene (hepatocyte growth factor MET TRCN0000040044 CCGGGCACGATGAATACATTGAAATCTCGAGATTTCAATGTATTCATCGTGCTTTTTG receptor) met proto-oncogene (hepatocyte growth factor MET TRCN0000040047 CCGGGCCAGCCTGAATGATGACATTCTCGAGAATGTCATCATTCAGGCTGGCTTTTTG receptor) met proto-oncogene (hepatocyte growth factor MET TRCN0000121087 CCGGGCACTATTATAGGACTTGTATCTCGAGATACAAGTCCTATAATAGTGCTTTTTG receptor) MGC42105 serine/threonine-protein kinase NIM1 TRCN0000007069 CCGGCGAGCACTACATCGGCATTTACTCGAGTAAATGCCGATGTAGTGCTCGTTTTT MGC42105 serine/threonine-protein kinase NIM1 TRCN0000007070 CCGGGAGGCTACTATCCCGAGAAATCTCGAGATTTCTCGGGATAGTAGCCTCTTTTT MGC42105 serine/threonine-protein kinase NIM1 TRCN0000007071 CCGGGATAAGACACACATCCAAATTCTCGAGAATTTGGATGTGTGTCTTATCTTTTT MGC42105 serine/threonine-protein kinase NIM1 TRCN0000011068 CCGGCGGATAGGCTTCTACCGAATTCTCGAGAATTCGGTAGAAGCCTATCCGTTTTT MGC42105 serine/threonine-protein kinase NIM1 TRCN0000011069 CCGGCCCTACACCTTTGGAACCTTTCTCGAGAAAGGTTCCAAAGGTGTAGGGTTTTT MINK1 misshapen-like kinase 1 (zebrafish) TRCN0000006238 CCGGGCAGACTTTGTGTTGCTGAAACTCGAGTTTCAGCAACACAAAGTCTGCTTTTT MINK1 misshapen-like kinase 1 (zebrafish) TRCN0000006239 CCGGCCGGAAGTACAAGAAGCGATTCTCGAGAATCGCTTCTTGTACTTCCGGTTTTT MINK1 misshapen-like kinase 1 (zebrafish) TRCN0000006240 CCGGGCTACTGAAGTTTCCCTTCATCTCGAGATGAAGGGAAACTTCAGTAGCTTTTT MINK1 misshapen-like kinase 1 (zebrafish) TRCN0000011004 CCGGCCCAGGAATTGAGTGGGCCTACTCGAGTAGGCCCACTCAATTCCTGGGTTTTT MINK1 misshapen-like kinase 1 (zebrafish) TRCN0000011005 CCGGGCGGATTAAGTTCCTGGTCATCTCGAGATGACCAGGAACTTAATCCGCTTTTT MKNK2 MAP kinase interacting serine/threonine kinase 2 TRCN0000006098 CCGGCCTAGAGCTGATTGAGTTCTTCTCGAGAAGAACTCAATCAGCTCTAGGTTTTT MKNK2 MAP kinase interacting serine/threonine kinase 2 TRCN0000199237 CCGGCCTGCATCAACCTGATCACCACTCGAGTGGTGATCAGGTTGATGCAGGTTTTTTG MKNK2 MAP kinase interacting serine/threonine kinase 2 TRCN0000199614 CCGGGCAGGTTTGAAGACGTCTACCCTCGAGGGTAGACGTCTTCAAACCTGCTTTTTTG MKNK2 MAP kinase interacting serine/threonine kinase 2 TRCN0000199708 CCGGGCTGGCCTTCTCCCTAGACCACTCGAGTGGTCTAGGGAGAAGGCCAGCTTTTTTG MKNK2 MAP kinase interacting serine/threonine kinase 2 TRCN0000199855 CCGGGAGGCTAGCATCTACGACAAGCTCGAGCTTGTCGTAGATGCTAGCCTCTTTTTTG MLKL mixed lineage kinase domain-like TRCN0000003224 CCGGTCCCGTTTCAAGGCTGTAATTCTCGAGAATTACAGCCTTGAAACGGGATTTTT MLKL mixed lineage kinase domain-like TRCN0000003226 CCGGCCCAACATCCTGCGTATATTTCTCGAGAAATATACGCAGGATGTTGGGTTTTT MLKL mixed lineage kinase domain-like TRCN0000003227 CCGGCCTTCGGCATTGGGTTATCTACTCGAGTAGATAACCCAATGCCGAAGGTTTTT MLKL mixed lineage kinase domain-like TRCN0000194846 CCGGCCTCTGACAGTAACTTTGATACTCGAGTATCAAAGTTACTGTCAGAGGTTTTTTG MLKL mixed lineage kinase domain-like TRCN0000196317 CCGGGAAGCTTCACTGAGACGATTACTCGAGTAATCGTCTCAGTGAAGCTTCTTTTTTG v-mos Moloney murine sarcoma viral oncogene MOS TRCN0000001705 CCGGAGGACAGTTAAGTTTGGGAAACTCGAGTTTCCCAAACTTAACTGTCCTTTTTT homolog v-mos Moloney murine sarcoma viral oncogene MOS TRCN0000001706 CCGGGTGACGCCTAAAGCCGACATTCTCGAGAATGTCGGCTTTAGGCGTCACTTTTT homolog v-mos Moloney murine sarcoma viral oncogene MOS TRCN0000001707 CCGGGCACCAAGAACCGACTAGCATCTCGAGATGCTAGTCGGTTCTTGGTGCTTTTT homolog v-mos Moloney murine sarcoma viral oncogene MOS TRCN0000010648 CCGGGAGGACAGTTAAGTTTGGGAACTCGAGTTCCCAAACTTAACTGTCCTCTTTTT homolog v-mos Moloney murine sarcoma viral oncogene MOS TRCN0000010649 CCGGCGGTGTTCCTGTGGCCATAAACTCGAGTTTATGGCCACAGGAACACCGTTTTT homolog macrophage stimulating 1 receptor (c-met-related MST1R TRCN0000003107 CCGGCCTCCTATTTCTACGTGGCATCTCGAGATGCCACGTAGAAATAGGAGGTTTTT tyrosine kinase) macrophage stimulating 1 receptor (c-met-related MST1R TRCN0000003109 CCGGGAGATGAATGTGCGTCCAGAACTCGAGTTCTGGACGCACATTCATCTCTTTTT tyrosine kinase) macrophage stimulating 1 receptor (c-met-related MST1R TRCN0000003110 CCGGGCTGGCTCTCATTGGTATCATCTCGAGATGATACCAATGAGAGCCAGCTTTTT tyrosine kinase) macrophage stimulating 1 receptor (c-met-related MST1R TRCN0000121148 CCGGGCGTAGATGGTGAATGTCATACTCGAGTATGACATTCACCATCTACGCTTTTTG tyrosine kinase) macrophage stimulating 1 receptor (c-met-related MST1R TRCN0000121150 CCGGCGTGTAACTGTGGTTGAGCAACTCGAGTTGCTCAACCACAGTTACACGTTTTTG tyrosine kinase) MST4 serine/threonine protein kinase MST4 TRCN0000003191 CCGGCCTCTTGGTGTATAGTATTTACTCGAGTAAATACTATACACCAAGAGGTTTTT MST4 serine/threonine protein kinase MST4 TRCN0000003192 CCGGCATCATTTCGTCCTACAGCAACTCGAGTTGCTGTAGGACGAAATGATGTTTTT MST4 serine/threonine protein kinase MST4 TRCN0000003193 CCGGCCAGATTGCTACCATGCTAAACTCGAGTTTAGCATGGTAGCAATCTGGTTTTT MST4 serine/threonine protein kinase MST4 TRCN0000003194 CCGGGATCCAAAGAAAGTACAGAATCTCGAGATTCTGTACTTTCTTTGGATCTTTTT MST4 serine/threonine protein kinase MST4 TRCN0000003195 CCGGCTTAAACAGCAGGACGAGAATCTCGAGATTCTCGTCCTGCTGTTTAAGTTTTT mechanistic target of rapamycin (serine/threonine MTOR TRCN0000038674 CCGGCCGCTAGTAGGGAGGTTTATTCTCGAGAATAAACCTCCCTACTAGCGGTTTTTG kinase) mechanistic target of rapamycin (serine/threonine MTOR TRCN0000038675 CCGGCCTGGCAACAATAGGAGAATTCTCGAGAATTCTCCTATTGTTGCCAGGTTTTTG kinase) mechanistic target of rapamycin (serine/threonine MTOR TRCN0000038676 CCGGCCTCCTATTGTTAAGTTGTTTCTCGAGAAACAACTTAACAATAGGAGGTTTTTG kinase)

179 Supplement

mechanistic target of rapamycin (serine/threonine MTOR TRCN0000038677 CCGGGCCAGAATCTATTCATTCTTTCTCGAGAAAGAATGAATAGATTCTGGCTTTTTG kinase) mechanistic target of rapamycin (serine/threonine MTOR TRCN0000038678 CCGGGCATGGAAGAATACACCTGTACTCGAGTACAGGTGTATTCTTCCATGCTTTTTG kinase) MUSK muscle, skeletal, receptor tyrosine kinase TRCN0000002164 CCGGGTAAGTTTGTTCACCGAGATTCTCGAGAATCTCGGTGAACAAACTTACTTTTT MUSK muscle, skeletal, receptor tyrosine kinase TRCN0000002165 CCGGCCAGGACTCTACACATGCATACTCGAGTATGCATGTGTAGAGTCCTGGTTTTT MUSK muscle, skeletal, receptor tyrosine kinase TRCN0000002166 CCGGGCAGACTACTACAAAGCTAATCTCGAGATTAGCTTTGTAGTAGTCTGCTTTTT MUSK muscle, skeletal, receptor tyrosine kinase TRCN0000002167 CCGGGTCATTTACTACGTGCGAGATCTCGAGATCTCGCACGTAGTAAATGACTTTTT MUSK muscle, skeletal, receptor tyrosine kinase TRCN0000010683 CCGGGCCTGGAATGAACTGAAAGTACTCGAGTACTTTCAGTTCATTCCAGGCTTTTT MYLK myosin light chain kinase TRCN0000000935 CCGGGACGGGAACTGCTCTTTAATTCTCGAGAATTAAAGAGCAGTTCCCGTCTTTTT MYLK myosin light chain kinase TRCN0000000937 CCGGCTGAAGGACTGCGCTGTTATTCTCGAGAATAACAGCGCAGTCCTTCAGTTTTT MYLK myosin light chain kinase TRCN0000010567 CCGGGCTAATGAAAGATACCAAGAACTCGAGTTCTTGGTATCTTTCATTAGCTTTTT MYLK myosin light chain kinase TRCN0000195567 CCGGCCACAGTATTGCCACAGTTTACTCGAGTAAACTGTGGCAATACTGTGGTTTTTTG MYLK myosin light chain kinase TRCN0000196279 CCGGGTGACCAATGTAATCTCAAAGCTCGAGCTTTGAGATTACATTGGTCACTTTTTTG MYLK2 myosin light chain kinase 2 TRCN0000010566 CCGGCATCAAGAAACAGACTCCCAACTCGAGTTGGGAGTCTGTTTCTTGATGTTTTT MYLK2 myosin light chain kinase 2 TRCN0000219654 CCGGGAAAGGCTGCAACGCTGATTCCTCGAGGAATCAGCGTTGCAGCCTTTCTTTTTG MYLK2 myosin light chain kinase 2 TRCN0000000932 CCGGGCTTGTGCCTTGTAAATAAATCTCGAGATTTATTTACAAGGCACAAGCTTTTT MYLK2 myosin light chain kinase 2 TRCN0000000933 CCGGCGGGCATTTGGTGAAGATCATCTCGAGATGATCTTCACCAAATGCCCGTTTTT MYLK2 myosin light chain kinase 2 TRCN0000000934 CCGGCTATCTGGCAACTGGTACTTTCTCGAGAAAGTACCAGTTGCCAGATAGTTTTT MYLK3 myosin light chain kinase 3 TRCN0000001842 CCGGTCAATCAGACAGGACATCAAACTCGAGTTTGATGTCCTGTCTGATTGATTTTT MYLK3 myosin light chain kinase 3 TRCN0000001843 CCGGTGAGGAGAATAAAGAGCGAGTCTCGAGACTCGCTCTTTATTCTCCTCATTTTT MYLK3 myosin light chain kinase 3 TRCN0000001844 CCGGTGCAGAAATACATAGCTCAAACTCGAGTTTGAGCTATGTATTTCTGCATTTTT MYLK3 myosin light chain kinase 3 TRCN0000001845 CCGGCTTCAACTCTGCTGCTCCAATCTCGAGATTGGAGCAGCAGAGTTGAAGTTTTT MYLK3 myosin light chain kinase 3 TRCN0000001846 CCGGACTCGTCTCAAATCCCAACTACTCGAGTAGTTGGGATTTGAGACGAGTTTTTT MYLK4 myosin light chain kinase family, member 4 TRCN0000037445 CCGGCCAGGACTTTGTGACCAAATACTCGAGTATTTGGTCACAAAGTCCTGGTTTTTG MYLK4 myosin light chain kinase family, member 4 TRCN0000037446 CCGGCAGCTTCTATACTGTGAGCAACTCGAGTTGCTCACAGTATAGAAGCTGTTTTTG MYLK4 myosin light chain kinase family, member 4 TRCN0000037447 CCGGCTTCGAGTCTAAGAACGACATCTCGAGATGTCGTTCTTAGACTCGAAGTTTTTG MYLK4 myosin light chain kinase family, member 4 TRCN0000037448 CCGGGTGTGTGAATCGGGATGCTAACTCGAGTTAGCATCCCGATTCACACACTTTTTG MYLK4 myosin light chain kinase family, member 4 TRCN0000197260 CCGGGCATGCCACATTGGTAATTTGCTCGAGCAAATTACCAATGTGGCATGCTTTTTTG MYO3A myosin IIIA TRCN0000002197 CCGGCCTGATGGATTTGTTGTCTAACTCGAGTTAGACAACAAATCCATCAGGTTTTT MYO3A myosin IIIA TRCN0000002198 CCGGCCCATTACAAACTGCCTGAAACTCGAGTTTCAGGCAGTTTGTAATGGGTTTTT MYO3A myosin IIIA TRCN0000002199 CCGGTAGCGGTTGAATCTTAGAGAACTCGAGTTCTCTAAGATTCAACCGCTATTTTT MYO3A myosin IIIA TRCN0000002200 CCGGGCACTTTCTGACCACCCTAATCTCGAGATTAGGGTGGTCAGAAAGTGCTTTTT MYO3A myosin IIIA TRCN0000002201 CCGGGCGGTATTCATTCAGAGCAAACTCGAGTTTGCTCTGAATGAATACCGCTTTTT NEK1 NIMA (never in mitosis gene a)-related kinase 1 TRCN0000021583 CCGGCCTTGCTGATTGGACTTTCAACTCGAGTTGAAAGTCCAATCAGCAAGGTTTTT NEK1 NIMA (never in mitosis gene a)related kinase 1 TRCN0000219755 CCGGGGATCTGTTTAAGCGAATAAACTCGAGTTTATTCGCTTAAACAGATCCTTTTTG NEK1 NIMA (never in mitosis gene a)-related kinase 1 TRCN0000021579 CCGGCCTCAACTATATGAAAGCATTCTCGAGAATGCTTTCATATAGTTGAGGTTTTT NEK1 NIMA (never in mitosis gene a)-related kinase 1 TRCN0000021580 CCGGCGAGAAATACTTCGTAGATTACTCGAGTAATCTACGAAGTATTTCTCGTTTTT NEK1 NIMA (never in mitosis gene a)-related kinase 1 TRCN0000021581 CCGGCCGCTAAATATGGAATACCTTCTCGAGAAGGTATTCCATATTTAGCGGTTTTT NEK10 NIMA (never in mitosis gene a)- related kinase 10 TRCN0000002287 CCGGCACAGCAGATTACCATTTATTCTCGAGAATAAATGGTAATCTGCTGTGTTTTT NEK10 NIMA (never in mitosis gene a)- related kinase 10 TRCN0000002288 CCGGCCTCTTGACCTGCTTCTGAAACTCGAGTTTCAGAAGCAGGTCAAGAGGTTTTT NEK10 NIMA (never in mitosis gene a)- related kinase 10 TRCN0000002289 CCGGCATTGCCAGAACACATTATATCTCGAGATATAATGTGTTCTGGCAATGTTTTT NEK10 NIMA (never in mitosis gene a)- related kinase 10 TRCN0000002290 CCGGGCTCGTCCAGATATTGTAGAACTCGAGTTCTACAATATCTGGACGAGCTTTTT NEK10 NIMA (never in mitosis gene a)- related kinase 10 TRCN0000002291 CCGGGCAGAGTAACCCTTGTAATTTCTCGAGAAATTACAAGGGTTACTCTGCTTTTT NEK11 NIMA (never in mitosis gene a)- related kinase 11 TRCN0000001961 CCGGCCAAACGAGGAGAGGAATTAACTCGAGTTAATTCCTCTCCTCGTTTGGTTTTT NEK11 NIMA (never in mitosis gene a)- related kinase 11 TRCN0000001962 CCGGCCAGAGAAAGAAATCAGGAATCTCGAGATTCCTGATTTCTTTCTCTGGTTTTT NEK11 NIMA (never in mitosis gene a)- related kinase 11 TRCN0000001963 CCGGGCGTTAGAAAGACCAGAGAAACTCGAGTTTCTCTGGTCTTTCTAACGCTTTTT NEK11 NIMA (never in mitosis gene a)- related kinase 11 TRCN0000001964 CCGGCCATGACTAATAAGGAAGATACTCGAGTATCTTCCTTATTAGTCATGGTTTTT NEK11 NIMA (never in mitosis gene a)- related kinase 11 TRCN0000001965 CCGGCCTTACCTTGATGAGCAGCTACTCGAGTAGCTGCTCATCAAGGTAAGGTTTTT NEK2 NIMA (never in mitosis gene a)-related kinase 2 TRCN0000000948 CCGGGCCATGCCTTTCTGTATAGTACTCGAGTACTATACAGAAAGGCATGGCTTTTT NEK2 NIMA (never in mitosis gene a)-related kinase 2 TRCN0000000950 CCGGCGTTACTCTGATGAATTGAATCTCGAGATTCAATTCATCAGAGTAACGTTTTT NEK2 NIMA (never in mitosis gene a)-related kinase 2 TRCN0000000951 CCGGGCAGACGAGCAAAGAAGAAATCTCGAGATTTCTTCTTTGCTCGTCTGCTTTTT NEK2 NIMA (never in mitosis gene a)-related kinase 2 TRCN0000000952 CCGGCCTGTATTGAGTGAGCTGAAACTCGAGTTTCAGCTCACTCAATACAGGTTTTT NEK2 NIMA (never in mitosis gene a)-related kinase 2 TRCN0000000949 CCGGCGTTCGTTACTATGATCGGATCTCGAGATCCGATCATAGTAACGAACGTTTTT NEK3 NIMA (never in mitosis gene a)-related kinase 3 TRCN0000001471 CCGGGCAGTCCCATAGAACAGAAATCTCGAGATTTCTGTTCTATGGGACTGCTTTTT NEK3 NIMA (never in mitosis gene a)-related kinase 3 TRCN0000001472 CCGGCCTTATTATGTGCCTCCAGAACTCGAGTTCTGGAGGCACATAATAAGGTTTTT NEK3 NIMA (never in mitosis gene a)-related kinase 3 TRCN0000001473 CCGGCGAAGCATAACACACCAAGAACTCGAGTTCTTGGTGTGTTATGCTTCGTTTTT NEK3 NIMA (never in mitosis gene a)-related kinase 3 TRCN0000001475 CCGGCCTAGTCAAGCAGATGTTTAACTCGAGTTAAACATCTGCTTGACTAGGTTTTT NEK3 NIMA (never in mitosis gene a)-related kinase 3 TRCN0000001474 CCGGCCAGTTCACCAAATCTTCATACTCGAGTATGAAGATTTGGTGAACTGGTTTTT NEK4 NIMA (never in mitosis gene a)-related kinase 4 TRCN0000001696 CCGGCGGCAAGCAGTATGTCATCAACTCGAGTTGATGACATACTGCTTGCCGTTTTT NEK4 NIMA (never in mitosis gene a)-related kinase 4 TRCN0000001697 CCGGGATTACTGTTTACTGAGCCTTCTCGAGAAGGCTCAGTAAACAGTAATCTTTTT NEK4 NIMA (never in mitosis gene a)-related kinase 4 TRCN0000001698 CCGGCCACAATCAGTAGCGTAAATACTCGAGTATTTACGCTACTGATTGTGGTTTTT NEK4 NIMA (never in mitosis gene a)-related kinase 4 TRCN0000001699 CCGGCCAGCTCTTGTCTCAGTTGAACTCGAGTTCAACTGAGACAAGAGCTGGTTTTT

180 Supplement

NEK4 NIMA (never in mitosis gene a)-related kinase 4 TRCN0000194871 CCGGCCTTAAGGAGTAGTTGATAAACTCGAGTTTATCAACTACTCCTTAAGGTTTTTTG NEK5 NIMA (never in mitosis gene a)-related kinase 5 TRCN0000021409 CCGGGCTGCCTTCAAGCATCTGTTTCTCGAGAAACAGATGCTTGAAGGCAGCTTTTT NEK5 NIMA (never in mitosis gene a)-related kinase 5 TRCN0000021410 CCGGGCCTTCTTCAATTCATTTCAACTCGAGTTGAAATGAATTGAAGAAGGCTTTTT NEK5 NIMA (never in mitosis gene a)-related kinase 5 TRCN0000021411 CCGGGCCCACCAAGATCAAGGATATCTCGAGATATCCTTGATCTTGGTGGGCTTTTT NEK5 NIMA (never in mitosis gene a)-related kinase 5 TRCN0000021412 CCGGCCAACAGTACCACAATGACATCTCGAGATGTCATTGTGGTACTGTTGGTTTTT NEK5 NIMA (never in mitosis gene a)-related kinase 5 TRCN0000021413 CCGGGTAATGGAGAAGAGCCTAGATCTCGAGATCTAGGCTCTTCTCCATTACTTTTT NEK6 NIMA (never in mitosis gene a)-related kinase 6 TRCN0000001724 CCGGGAACCACCCAAATATCATCAACTCGAGTTGATGATATTTGGGTGGTTCTTTTT NEK6 NIMA (never in mitosis gene a)-related kinase 6 TRCN0000001725 CCGGCGAAGACAACGAGCTGAACATCTCGAGATGTTCAGCTCGTTGTCTTCGTTTTT NEK6 NIMA (never in mitosis gene a)-related kinase 6 TRCN0000001726 CCGGGCAACTTCCTAGCGTGACTTTCTCGAGAAAGTCACGCTAGGAAGTTGCTTTTT NEK6 NIMA (never in mitosis gene a)-related kinase 6 TRCN0000001723 CCGGCCCGGAGAGGACAGTATGGAACTCGAGTTCCATACTGTCCTCTCCGGGTTTTT NEK6 NIMA (never in mitosis gene a)-related kinase 6 TRCN0000001727 CCGGGCAACTGAACCACCCAAATATCTCGAGATATTTGGGTGGTTCAGTTGCTTTTT NEK7 NIMA (never in mitosis gene a)-related kinase 7 TRCN0000001966 CCGGGCGGACAATTTAGTGAAGTTTCTCGAGAAACTTCACTAAATTGTCCGCTTTTT NEK7 NIMA (never in mitosis gene a)-related kinase 7 TRCN0000001967 CCGGCTTTAGTTGGTACGCCTTATTCTCGAGAATAAGGCGTACCAACTAAAGTTTTT NEK7 NIMA (never in mitosis gene a)-related kinase 7 TRCN0000001968 CCGGTCAGATCACTATTCAGAAGAACTCGAGTTCTTCTGAATAGTGATCTGATTTTT NEK7 NIMA (never in mitosis gene a)-related kinase 7 TRCN0000001969 CCGGGAAGAGTGTAACCAAAGTAATCTCGAGATTACTTTGGTTACACTCTTCTTTTT NEK7 NIMA (never in mitosis gene a)-related kinase 7 TRCN0000010671 CCGGTGGCTGCATTACAAAGTCCTTCTCGAGAAGGACTTTGTAATGCAGCCATTTTT NEK8 NIMA (never in mitosis gene a)- related kinase 8 TRCN0000007087 CCGGCCTTGGATATGGAAACCTCAACTCGAGTTGAGGTTTCCATATCCAAGGTTTTT NEK8 NIMA (never in mitosis gene a)- related kinase 8 TRCN0000007088 CCGGCCTGGAAGACAAAGCCCTTATCTCGAGATAAGGGCTTTGTCTTCCAGGTTTTT NEK8 NIMA (never in mitosis gene a)- related kinase 8 TRCN0000007089 CCGGCTCGGGTGATTGCTACACTTTCTCGAGAAAGTGTAGCAATCACCCGAGTTTTT NEK8 NIMA (never in mitosis gene a)- related kinase 8 TRCN0000007090 CCGGGCTGGTGATCATCAAGCAGATCTCGAGATCTGCTTGATGATCACCAGCTTTTT NEK8 NIMA (never in mitosis gene a)- related kinase 8 TRCN0000007091 CCGGGCCCACCATTGTGGAGGCTTTCTCGAGAAAGCCTCCACAATGGTGGGCTTTTT NEK9 NIMA (never in mitosis gene a)- related kinase 9 TRCN0000000928 CCGGGCCTTGATTATTGTTGCAGTTCTCGAGAACTGCAACAATAATCAAGGCTTTTT NEK9 NIMA (never in mitosis gene a)- related kinase 9 TRCN0000000929 CCGGCCGAGGAATGGAAGGTTTAATCTCGAGATTAAACCTTCCATTCCTCGGTTTTT NEK9 NIMA (never in mitosis gene a)- related kinase 9 TRCN0000000930 CCGGCCAAAGGAACTCAGACAGCAACTCGAGTTGCTGTCTGAGTTCCTTTGGTTTTT NEK9 NIMA (never in mitosis gene a)- related kinase 9 TRCN0000010564 CCGGGTACATTTGGAGAGTGGCATTCTCGAGAATGCCACTCTCCAAATGTACTTTTT NEK9 NIMA (never in mitosis gene a)- related kinase 9 TRCN0000000931 CCGGGTGAAGATCGTGCAAGGAATTCTCGAGAATTCCTTGCACGATCTTCACTTTTT NLK nemo-like kinase TRCN0000002067 CCGGCTTTGCAGGATGTTGGTCTTTCTCGAGAAAGACCAACATCCTGCAAAGTTTTT NLK nemo-like kinase TRCN0000002069 CCGGGCTCAGATCATGTCAAAGTTTCTCGAGAAACTTTGACATGATCTGAGCTTTTT NLK nemo-like kinase TRCN0000002070 CCGGGAAGGCGCTAAGGCACATATACTCGAGTATATGTGCCTTAGCGCCTTCTTTTT NLK nemo-like kinase TRCN0000002071 CCGGGTGGGTAGAGAGAATGAGTTTCTCGAGAAACTCATTCTCTCTACCCACTTTTT NLK nemo like kinase TRCN0000194681 CCGGCGGATAGACCTATTGGATATGCTCGAGCATATCCAATAGGTCTATCCGTTTTTTG natriuretic peptide receptor A/guanylate cyclase A NPR1 TRCN0000007325 CCGGGCCAAAGGATGGAAGTAATTTCTCGAGAAATTACTTCCATCCTTTGGCTTTTT (atrionatriuretic peptide receptor A) natriuretic peptide receptor A/guanylate cyclase A NPR1 TRCN0000007326 CCGGGCCTCAAGAATGGAGTCTAATCTCGAGATTAGACTCCATTCTTGAGGCTTTTT (atrionatriuretic peptide receptor A) natriuretic peptide receptor A/guanylate cyclase A NPR1 TRCN0000007328 CCGGGCTGTCATAGACAACTTTGATCTCGAGATCAAAGTTGTCTATGACAGCTTTTT (atrionatriuretic peptide receptor A) natriuretic peptide receptor A/guanylate cyclase A NPR1 TRCN0000007329 CCGGGCTTTCAAGGTGTGACAGGATCTCGAGATCCTGTCACACCTTGAAAGCTTTTT (atrionatriuretic peptide receptor A) natriuretic peptide receptor A/guanylate cyclase A NPR1 TRCN0000007327 CCGGCCCAGATAATCCCGAGTACTTCTCGAGAAGTACTCGGGATTATCTGGGTTTTT (atrionatriuretic peptide receptor A) natriuretic peptide receptor B/guanylate cyclase B NPR2 TRCN0000001315 CCGGCACTTCTTAATGACCTGTATACTCGAGTATACAGGTCATTAAGAAGTGTTTTT (atrionatriuretic peptide receptor B) natriuretic peptide receptor B/guanylate cyclase B NPR2 TRCN0000000427 CCGGCGAATGGAGTCTAATGGTCAACTCGAGTTGACCATTAGACTCCATTCGTTTTT (atrionatriuretic peptide receptor B) natriuretic peptide receptor B/guanylate cyclase B NPR2 TRCN0000000428 CCGGCGTGGGAGTTTACAGGATATTCTCGAGAATATCCTGTAAACTCCCACGTTTTT (atrionatriuretic peptide receptor B) natriuretic peptide receptor B/guanylate cyclase B NPR2 TRCN0000000429 CCGGGCTCTGCTCTACCAAATCCTACTCGAGTAGGATTTGGTAGAGCAGAGCTTTTT (atrionatriuretic peptide receptor B) natriuretic peptide receptor B/guanylate cyclase B NPR2 TRCN0000000430 CCGGCACTTCTTAATGACCTGTATACTCGAGTATACAGGTCATTAAGAAGTGTTTTT (atrionatriuretic peptide receptor B) NRBP1 nuclear receptor binding protein 1 TRCN0000001437 CCGGCCCTCTGCACTTTGTTTACTTCTCGAGAAGTAAACAAAGTGCAGAGGGTTTTT NRBP1 nuclear receptor binding protein 1 TRCN0000001438 CCGGCCAACACATGATCCCAGAGAACTCGAGTTCTCTGGGATCATGTGTTGGTTTTT NRBP1 nuclear receptor binding protein 1 TRCN0000001439 CCGGTGTCGAGAAGAGCAGAAGAATCTCGAGATTCTTCTGCTCTTCTCGACATTTTT NRBP1 nuclear receptor binding protein 1 TRCN0000001440 CCGGAGGCGAGAAGAGGTGAATCAACTCGAGTTGATTCACCTCTTCTCGCCTTTTTT NRBP1 nuclear receptor binding protein 1 TRCN0000001441 CCGGCATCTGGGAGTCTGAAGCAATCTCGAGATTGCTTCAGACTCCCAGATGTTTTT NRBP2 nuclear receptor binding protein 2 TRCN0000021400 CCGGCCTTCATGGAGCTGGACAAATCTCGAGATTTGTCCAGCTCCATGAAGGTTTTT NRBP2 nuclear receptor binding protein 2 TRCN0000021403 CCGGATGTCAGGAATGGAATCTACCCTCGAGGGTAGATTCCATTCCTGACATTTTTT NRBP2 hypothetical protein LOC340371 TRCN0000195525 CCGGCCCTAAGGACTCATGAGATTACTCGAGTAATCTCATGAGTCCTTAGGGTTTTTTG NRBP2 hypothetical protein LOC340371 TRCN0000196994 CCGGGCGCATTCATGCCTTTCTAAACTCGAGTTTAGAAAGGCATGAATGCGCTTTTTTG NRBP2 hypothetical protein LOC340371 TRCN0000197184 CCGGGTACTCGGAAGTCTCCTTCATCTCGAGATGAAGGAGACTTCCGAGTACTTTTTTG NRK Nik related kinase TRCN0000037489 CCGGCCTGAGTCATTACGAGTAAATCTCGAGATTTACTCGTAATGACTCAGGTTTTTG NRK Nik related kinase TRCN0000037490 CCGGGCAGCCAATATAGGCAGTGAACTCGAGTTCACTGCCTATATTGGCTGCTTTTTG NRK Nik related kinase TRCN0000037491 CCGGCGGTCACTGATGTAGTGAGAACTCGAGTTCTCACTACATCAGTGACCGTTTTTG NRK Nik related kinase TRCN0000037492 CCGGCGCCAAACTCAAATAACTCAACTCGAGTTGAGTTATTTGAGTTTGGCGTTTTTG NRK Nik related kinase TRCN0000037493 CCGGCCTGAGGTGATTGACTGTGATCTCGAGATCACAGTCAATCACCTCAGGTTTTTG NTRK1 neurotrophic tyrosine kinase, receptor, type 1 TRCN0000001992 CCGGTATCTACAGCACCGACTATTACTCGAGTAATAGTCGGTGCTGTAGATATTTTT NTRK1 neurotrophic tyrosine kinase, receptor, type 1 TRCN0000001993 CCGGTGCCTTCATGGACAACCCTTTCTCGAGAAAGGGTTGTCCATGAAGGCATTTTT

181 Supplement

NTRK1 neurotrophic tyrosine kinase, receptor, type 1 TRCN0000001994 CCGGTGGCATGAGCAGGGATATCTACTCGAGTAGATATCCCTGCTCATGCCATTTTT NTRK1 neurotrophic tyrosine kinase, receptor, type 1 TRCN0000001995 CCGGCATCGAGAACCCACAATACTTCTCGAGAAGTATTGTGGGTTCTCGATGTTTTT NTRK1 neurotrophic tyrosine kinase, receptor, type 1 TRCN0000001996 CCGGTACATCGAGAACCAGCAGCATCTCGAGATGCTGCTGGTTCTCGATGTATTTTT NTRK2 neurotrophic tyrosine kinase, receptor, type 2 TRCN0000002242 CCGGCCACTCCATCACATCTCCAATCTCGAGATTGGAGATGTGATGGAGTGGTTTTT NTRK2 neurotrophic tyrosine kinase, receptor, type 2 TRCN0000002243 CCGGCCAACTATCACATTTCTCGAACTCGAGTTCGAGAAATGTGATAGTTGGTTTTT NTRK2 neurotrophic tyrosine kinase, receptor, type 2 TRCN0000002244 CCGGGAGGAAGAACATCAAGGGCATCTCGAGATGCCCTTGATGTTCTTCCTCTTTTT NTRK2 neurotrophic tyrosine kinase, receptor, type 2 TRCN0000002245 CCGGGCACATCAAGCGACATAACATCTCGAGATGTTATGTCGCTTGATGTGCTTTTT NTRK2 neurotrophic tyrosine kinase, receptor, type 2 TRCN0000002246 CCGGCCTTGTTGTATTCCTGCCTTTCTCGAGAAAGGCAGGAATACAACAAGGTTTTT NTRK3 neurotrophic tyrosine kinase, receptor, type 3 TRCN0000002309 CCGGCACTACAACAATGGCAACTATCTCGAGATAGTTGCCATTGTTGTAGTGTTTTT NTRK3 neurotrophic tyrosine kinase, receptor, type 3 TRCN0000002313 CCGGCACGGACATCTCAAGGAATATCTCGAGATATTCCTTGAGATGTCCGTGTTTTT NTRK3 neurotrophic tyrosine kinase, receptor, type 3 TRCN0000194821 CCGGCCAATCTACCTGGACATTCTTCTCGAGAAGAATGTCCAGGTAGATTGGTTTTTTG NTRK3 neurotrophic tyrosine kinase, receptor, type 3 TRCN0000002310 CCGGCAAAGAGGTGTACGATGTCATCTCGAGATGACATCGTACACCTCTTTGTTTTT NTRK3 neurotrophic tyrosine kinase, receptor, type 3 TRCN0000002311 CCGGGCACATTAAGAGGAGAGACATCTCGAGATGTCTCTCCTCTTAATGTGCTTTTT NUAK1 NUAK family, SNF1-like kinase, 1 TRCN0000000901 CCGGGCTCGATGACAACTGCAATATCTCGAGATATTGCAGTTGTCATCGAGCTTTTT NUAK1 NUAK family, SNF1-like kinase, 1 TRCN0000000902 CCGGGATCCTGAAGAAGCGAAGCAACTCGAGTTGCTTCGCTTCTTCAGGATCTTTTT NUAK1 NUAK family, SNF1-like kinase, 1 TRCN0000000899 CCGGGCACCGTCTTAGTTTACACATCTCGAGATGTGTAAACTAAGACGGTGCTTTTT NUAK1 NUAK family, SNF1-like kinase, 1 TRCN0000000900 CCGGGCAGAGAGAATCAGGTTACTACTCGAGTAGTAACCTGATTCTCTCTGCTTTTT NUAK1 NUAK family, SNF1-like kinase, 1 TRCN0000000903 CCGGACCATCCTCATATCATCAGTACTCGAGTACTGATGATATGAGGATGGTTTTTT NUAK2 NUAK family, SNF1-like kinase, 2 TRCN0000003207 CCGGCTCTCCAACCTCTACCATCAACTCGAGTTGATGGTAGAGGTTGGAGAGTTTTT NUAK2 NUAK family, SNF1-like kinase, 2 TRCN0000003208 CCGGCCCTCACATCATTGCCATCCACTCGAGTGGATGGCAATGATGTGAGGGTTTTT NUAK2 NUAK family, SNF1-like kinase, 2 TRCN0000010767 CCGGCCGGTGGCTGTTGATGGTGAACTCGAGTTCACCATCAACAGCCACCGGTTTTT NUAK2 NUAK family, SNF1-like kinase, 2 TRCN0000003205 CCGGGACCATAAGATCCTAGTGAAACTCGAGTTTCACTAGGATCTTATGGTCTTTTT NUAK2 NUAK family, SNF1-like kinase, 2 TRCN0000003206 CCGGGCTGAACGAAGAGGATACTAACTCGAGTTAGTATCCTCTTCGTTCAGCTTTTT obscurin, cytoskeletal calmodulin and titin-interacting OBSCN TRCN0000195565 CCGGCCTGTCATCAGCTGGTACAAACTCGAGTTTGTACCAGCTGATGACAGGTTTTTTG RhoGEF obscurin, cytoskeletal calmodulin and titin-interacting OBSCN TRCN0000199121 CCGGCTCAGGACTGTGGACGAAGGACTCGAGTCCTTCGTCCACAGTCCTGAGTTTTTTG RhoGEF obscurin, cytoskeletal calmodulin and titin-interacting OBSCN TRCN0000021599 CCGGCCTTCTTACCTCACTCAACTTCTCGAGAAGTTGAGTGAGGTAAGAAGGTTTTT RhoGEF obscurin, cytoskeletal calmodulin and titin-interacting OBSCN TRCN0000021600 CCGGCCCAGATTATACTGGTTCAAACTCGAGTTTGAACCAGTATAATCTGGGTTTTT RhoGEF obscurin, cytoskeletal calmodulin and titin-interacting OBSCN TRCN0000021601 CCGGCCTGCCAGATTCATAGAAGATCTCGAGATCTTCTATGAATCTGGCAGGTTTTT RhoGEF OXSR1 oxidative-stress responsive 1 TRCN0000001586 CCGGGCGTATCTCTGTTGCTTCTATCTCGAGATAGAAGCAACAGAGATACGCTTTTT OXSR1 oxidative-stress responsive 1 TRCN0000001587 CCGGGCAGAACTATTAAGGCACAAACTCGAGTTTGTGCCTTAATAGTTCTGCTTTTT OXSR1 oxidative-stress responsive 1 TRCN0000001588 CCGGGCCATCATCCTAATATTGTATCTCGAGATACAATATTAGGATGATGGCTTTTT OXSR1 oxidative-stress responsive 1 TRCN0000001589 CCGGCCTGATGATGGTAAACTGATACTCGAGTATCAGTTTACCATCATCAGGTTTTT OXSR1 oxidative-stress responsive 1 TRCN0000010643 CCGGGTGGAGGTTCTGTTCTGGATACTCGAGTATCCAGAACAGAACCTCCACTTTTT PAK1 p21 protein (Cdc42/Rac)-activated kinase 1 TRCN0000002224 CCGGCCAAGAAAGAGCTGATTATTACTCGAGTAATAATCAGCTCTTTCTTGGTTTTT PAK1 p21 protein (Cdc42/Rac)-activated kinase 1 TRCN0000002226 CCGGGCGATCCTAAGAAGAAATATACTCGAGTATATTTCTTCTTAGGATCGCTTTTT PAK1 p21 protein (Cdc42/Rac)-activated kinase 1 TRCN0000002227 CCGGCTTCTCCCATTTCCTGATCTACTCGAGTAGATCAGGAAATGGGAGAAGTTTTT PAK1 p21 protein (Cdc42/Rac)-activated kinase 1 TRCN0000195500 CCGGCCCTAAACCATGGTTCTAAACCTCGAGGTTTAGAACCATGGTTTAGGGTTTTTTG PAK1 p21 protein (Cdc42/Rac)-activated kinase 1 TRCN0000195636 CCGGCATGGGAGAACAACCACATTTCTCGAGAAATGTGGTTGTTCTCCCATGTTTTTTG PAK2 p21 protein (Cdc42/Rac)-activated kinase 2 TRCN0000002115 CCGGCTCTAGGAACCAAAGTGATTTCTCGAGAAATCACTTTGGTTCCTAGAGTTTTT PAK2 p21 protein (Cdc42/Rac)-activated kinase 2 TRCN0000002116 CCGGCAGACCTCCAATATCACCAAACTCGAGTTTGGTGATATTGGAGGTCTGTTTTT PAK2 p21 protein (Cdc42/Rac)-activated kinase 2 TRCN0000002118 CCGGTGGGAATGGAAGGATCTGTTACTCGAGTAACAGATCCTTCCATTCCCATTTTT PAK2 p21 (CDKN1A)-activated kinase 2 TRCN0000194671 CCGGCGGGATTTCTTAAATCGATGTCTCGAGACATCGATTTAAGAAATCCCGTTTTTTG PAK2 p21 (CDKN1A)-activated kinase 2 TRCN0000199395 CCGGCCATCCATGTTGGCTTTGATGCTCGAGCATCAAAGCCAACATGGATGGTTTTTTG PAK3 p21 protein (Cdc42/Rac)-activated kinase 3 TRCN0000003242 CCGGGAACAGAAGAAGAACCCACAACTCGAGTTGTGGGTTCTTCTTCTGTTCTTTTT PAK3 p21 protein (Cdc42/Rac)-activated kinase 3 TRCN0000003243 CCGGCAACCCAAGAAGGAATTAATTCTCGAGAATTAATTCCTTCTTGGGTTGTTTTT PAK3 p21 protein (Cdc42/Rac)-activated kinase 3 TRCN0000003244 CCGGGTGGGTGATGAACTATGGGTACTCGAGTACCCATAGTTCATCACCCACTTTTT PAK3 p21 protein (Cdc42/Rac)-activated kinase 3 TRCN0000003245 CCGGCCAAACTTCCAACATAACAAACTCGAGTTTGTTATGTTGGAAGTTTGGTTTTT PAK3 p21 protein (Cdc42/Rac)-activated kinase 3 TRCN0000003246 CCGGCTAAGAAGCATTGTGAGTGTTCTCGAGAACACTCACAATGCTTCTTAGTTTTT PAK4 p21 protein (Cdc42/Rac)-activated kinase 4 TRCN0000010197 CCGGGAGCCACAGCGAGTATCCCATCTCGAGATGGGATACTCGCTGTGGCTCTTTTT PAK4 p21 protein (Cdc42/Rac)-activated kinase 4 TRCN0000010198 CCGGCGAGAATGTGGTGGAGATGTACTCGAGTACATCTCCACCACATTCTCGTTTTT PAK4 p21 protein (Cdc42/Rac)-activated kinase 4 TRCN0000010199 CCGGGACTCGATCCTGCTGACCCATCTCGAGATGGGTCAGCAGGATCGAGTCTTTTT PAK4 p21 protein (Cdc42/Rac)-activated kinase 4 TRCN0000010200 CCGGCGACCAGCACGAGCAGAAGTTCTCGAGAACTTCTGCTCGTGCTGGTCGTTTTT PAK4 p21 protein (Cdc42/Rac)-activated kinase 4 TRCN0000010201 CCGGCTGCTGGACGAGTTTGAGAACCTCGAGGTTCTCAAACTCGTCCAGCAGTTTTT PAK6 p21 protein (Cdc42/Rac)-activated kinase 6 TRCN0000001747 CCGGCATCCAGAAGTTGTCAGTCATCTCGAGATGACTGACAACTTCTGGATGTTTTT PAK6 p21 protein (Cdc42/Rac)-activated kinase 6 TRCN0000001748 CCGGAGATCAGCAAAGACGTCCCTACTCGAGTAGGGACGTCTTTGCTGATCTTTTTT PAK6 p21 protein (Cdc42/Rac)-activated kinase 6 TRCN0000001749 CCGGGCACAGGGATATTTCTAAGAACTCGAGTTCTTAGAAATATCCCTGTGCTTTTT PAK6 p21 protein (Cdc42/Rac)-activated kinase 6 TRCN0000001750 CCGGCGTCTCCCAAGTCAGGCTGAACTCGAGTTCAGCCTGACTTGGGAGACGTTTTT PAK6 p21 protein (Cdc42/Rac)-activated kinase 6 TRCN0000001751 CCGGAGTGATCTCCAGGTCTTTGTACTCGAGTACAAAGACCTGGAGATCACTTTTTT PAK7 p21 protein (Cdc42/Rac)-activated kinase 7 TRCN0000007107 CCGGGCCTCCATAAATATGATCTATCTCGAGATAGATCATATTTATGGAGGCTTTTT PAK7 p21 protein (Cdc42/Rac)-activated kinase 7 TRCN0000007108 CCGGCGGGATTACCACCATGACAATCTCGAGATTGTCATGGTGGTAATCCCGTTTTT

182 Supplement

PAK7 p21 protein (Cdc42/Rac)-activated kinase 7 TRCN0000007109 CCGGGCTCCTATGAAGACAATCGTTCTCGAGAACGATTGTCTTCATAGGAGCTTTTT PAK7 p21 protein (Cdc42/Rac)-activated kinase 7 TRCN0000007110 CCGGGCCAAAGTCTTCGTACCTGAACTCGAGTTCAGGTACGAAGACTTTGGCTTTTT PAK7 p21 protein (Cdc42/Rac)-activated kinase 7 TRCN0000007111 CCGGCCGGATAAAGTTGTCTGATTTCTCGAGAAATCAGACAACTTTATCCGGTTTTT PASK PAS domain containing serine/threonine kinase TRCN0000007055 CCGGCCTTGCGTACAACAGCTCATTCTCGAGAATGAGCTGTTGTACGCAAGGTTTTT PASK PAS domain containing serine/threonine kinase TRCN0000199084 CCGGCGTCATGTGACAGTCTCTTTGCTCGAGCAAAGAGACTGTCACATGACGTTTTTTG PASK PAS domain containing serine/threonine kinase TRCN0000199253 CCGGCCTAGACCTCTTCGCTTTCATCTCGAGATGAAAGCGAAGAGGTCTAGGTTTTTTG PASK PAS domain containing serine/threonine kinase TRCN0000199716 CCGGGCCCTTGCTATGGGAGTGAATCTCGAGATTCACTCCCATAGCAAGGGCTTTTTTG PASK PAS domain containing serine/threonine kinase TRCN0000007052 CCGGCAGAAGACAGTGATGCTGTATCTCGAGATACAGCATCACTGTCTTCTGTTTTT PBK PDZ binding kinase TRCN0000001805 CCGGCTCTTCTCTGTATGCACTAATCTCGAGATTAGTGCATACAGAGAAGAGTTTTT PBK PDZ binding kinase TRCN0000001806 CCGGCACCAAGCAAATTATCAGAAACTCGAGTTTCTGATAATTTGCTTGGTGTTTTT PBK PDZ binding kinase TRCN0000001807 CCGGGAATATGGCAAGAGGGTTAAACTCGAGTTTAACCCTCTTGCCATATTCTTTTT PBK PDZ binding kinase TRCN0000196313 CCGGGATTCCACACATTAATCTTTCCTCGAGGAAAGATTAATGTGTGGAATCTTTTTTG PBK PDZ binding kinase TRCN0000196720 CCGGGCCTTCATCATCCAAACATTGCTCGAGCAATGTTTGGATGATGAAGGCTTTTTTG platelet-derived growth factor receptor, alpha PDGFRA TRCN0000001425 CCGGCGGTGAAAGACAGTGGAGATTCTCGAGAATCTCCACTGTCTTTCACCGTTTTT polypeptide platelet-derived growth factor receptor, alpha PDGFRA TRCN0000194855 CCGGCCCTCTGAAATAATGGGATTACTCGAGTAATCCCATTATTTCAGAGGGTTTTTTG polypeptide platelet-derived growth factor receptor, alpha PDGFRA TRCN0000195132 CCGGCTACTACTGTTATCAGTAATGCTCGAGCATTACTGATAACAGTAGTAGTTTTTTG polypeptide platelet-derived growth factor receptor, alpha PDGFRA TRCN0000196272 CCGGGCTTAATTGCTGATACCATATCTCGAGATATGGTATCAGCAATTAAGCTTTTTTG polypeptide platelet-derived growth factor receptor, alpha PDGFRA TRCN0000196928 CCGGGCTAGCAATTGCGACCTTAATCTCGAGATTAAGGTCGCAATTGCTAGCTTTTTTG polypeptide platelet-derived growth factor receptor, beta PDGFRB TRCN0000001997 CCGGGCTCACCATCATCTCCCTTATCTCGAGATAAGGGAGATGATGGTGAGCTTTTT polypeptide platelet-derived growth factor receptor, beta PDGFRB TRCN0000001998 CCGGCCAAAGGAGGACCCATCTATACTCGAGTATAGATGGGTCCTCCTTTGGTTTTT polypeptide platelet-derived growth factor receptor, beta PDGFRB TRCN0000001999 CCGGCCCTCAGTCTTAATCCATCCACTCGAGTGGATGGATTAAGACTGAGGGTTTTT polypeptide platelet-derived growth factor receptor, beta PDGFRB TRCN0000002000 CCGGGTGGATTCTGATGCCTACTATCTCGAGATAGTAGGCATCAGAATCCACTTTTT polypeptide platelet-derived growth factor receptor, beta PDGFRB TRCN0000002001 CCGGGACTCGAATTACATCTCCAAACTCGAGTTTGGAGATGTAATTCGAGTCTTTTT polypeptide PDIK1L PDLIM1 interacting kinase 1 like TRCN0000002294 CCGGTGGGCGAATGAAACAACTGATCTCGAGATCAGTTGTTTCATTCGCCCATTTTT PDIK1L PDLIM1 interacting kinase 1 like TRCN0000197287 CCGGGAAGAACCTGTCAGTGTAAACCTCGAGGTTTACACTGACAGGTTCTTCTTTTTTG PDIK1L PDLIM1 interacting kinase 1 like TRCN0000002292 CCGGCACGGCTCTAATTCTTCCCTTCTCGAGAAGGGAAGAATTAGAGCCGTGTTTTT PDIK1L PDLIM1 interacting kinase 1 like TRCN0000002293 CCGGCTAAGCAGTATCAAGAGCCAACTCGAGTTGGCTCTTGATACTGCTTAGTTTTT PDIK1L PDLIM1 interacting kinase 1 like TRCN0000002295 CCGGCGCCTATTATTTGTGGTTTGTCTCGAGACAAACCACAAATAATAGGCGTTTTT PDK1 pyruvate dehydrogenase kinase, isozyme 1 TRCN0000006260 CCGGCGGATCAGAAACCGACACAATCTCGAGATTGTGTCGGTTTCTGATCCGTTTTT PDK1 pyruvate dehydrogenase kinase, isozyme 1 TRCN0000006261 CCGGGCTCTGTCAACAGACTCAATACTCGAGTATTGAGTCTGTTGACAGAGCTTTTT PDK1 pyruvate dehydrogenase kinase, isozyme 1 TRCN0000006263 CCGGCCAGGGTGTGATTGAATACAACTCGAGTTGTATTCAATCACACCCTGGTTTTT PDK1 pyruvate dehydrogenase kinase, isozyme 1 TRCN0000194672 CCGGCATCCGTTCAATTGGTACAAACTCGAGTTTGTACCAATTGAACGGATGTTTTTTG PDK1 pyruvate dehydrogenase kinase, isozyme 1 TRCN0000196635 CCGGGATCAGTGAATGCTTGTGAAACTCGAGTTTCACAAGCATTCACTGATCTTTTTTG PDK2 pyruvate dehydrogenase kinase, isozyme 2 TRCN0000002314 CCGGCACCTCTACCACATGCTCTTTCTCGAGAAAGAGCATGTGGTAGAGGTGTTTTT PDK2 pyruvate dehydrogenase kinase, isozyme 2 TRCN0000002315 CCGGACAGCCGATTCACATGGTCTACTCGAGTAGACCATGTGAATCGGCTGTTTTTT PDK2 pyruvate dehydrogenase kinase, isozyme 2 TRCN0000002316 CCGGGTACATAGAGCACTTCAGCAACTCGAGTTGCTGAAGTGCTCTATGTACTTTTT PDK2 pyruvate dehydrogenase kinase, isozyme 2 TRCN0000002317 CCGGAGGAGATCAATGCAGCCAACTCTCGAGAGTTGGCTGCATTGATCTCCTTTTTT PDK2 pyruvate dehydrogenase kinase, isozyme 2 TRCN0000002318 CCGGACCTTGTTAGACCGAGAGCTTCTCGAGAAGCTCTCGGTCTAACAAGGTTTTTT PDK3 pyruvate dehydrogenase kinase, isozyme 3 TRCN0000000260 CCGGAGAGTTGGTATATGCAGAGTTCTCGAGAACTCTGCATATACCAACTCTTTTTT PDK3 pyruvate dehydrogenase kinase, isozyme 3 TRCN0000000262 CCGGGCTGGCTAACACAATGAGAGACTCGAGTCTCTCATTGTGTTAGCCAGCTTTTT PDK3 pyruvate dehydrogenase kinase, isozyme 3 TRCN0000194808 CCGGCTAATCCTGTTCATCCTAAACCTCGAGGTTTAGGATGAACAGGATTAGTTTTTTG PDK3 pyruvate dehydrogenase kinase, isozyme 3 TRCN0000000259 CCGGGTTTGCAGTTTGTCCTCATAACTCGAGTTATGAGGACAAACTGCAAACTTTTT PDK3 pyruvate dehydrogenase kinase, isozyme 3 TRCN0000194875 CCGGCCTAAACACATAGGAAGTATCCTCGAGGATACTTCCTATGTGTTTAGGTTTTTTG PDK4 pyruvate dehydrogenase kinase, isozyme 4 TRCN0000006264 CCGGCCCGTGTCAATTAACATTTAACTCGAGTTAAATGTTAATTGACACGGGTTTTT PDK4 pyruvate dehydrogenase kinase, isozyme 4 TRCN0000006265 CCGGCCGCCTCTTTAGTTATACATACTCGAGTATGTATAACTAAAGAGGCGGTTTTT PDK4 pyruvate dehydrogenase kinase, isozyme 4 TRCN0000194917 CCGGCTTTGTCTTCTGAGTCTATAGCTCGAGCTATAGACTCAGAAGACAAAGTTTTTTG PDK4 pyruvate dehydrogenase kinase, isozyme 4 TRCN0000197231 CCGGGTGCAAGACTACAGGAGTTAACTCGAGTTAACTCCTGTAGTCTTGCACTTTTTTG PDK4 pyruvate dehydrogenase kinase, isozyme 4 TRCN0000219734 CCGGGGATGCTCTGTGATCAGTATTCTCGAGAATACTGATCACAGAGCATCCTTTTTG PDPK1 3-phosphoinositide dependent protein kinase-1 TRCN0000001476 CCGGGCAGCAACATAGAGCAGTACACTCGAGTGTACTGCTCTATGTTGCTGCTTTTT PDPK1 3-phosphoinositide dependent protein kinase-1 TRCN0000001477 CCGGTCACAGAAGGACCACATTTATCTCGAGATAAATGTGGTCCTTCTGTGATTTTT PDPK1 3-phosphoinositide dependent protein kinase-1 TRCN0000001478 CCGGAGTGGATAAGCGGAAGGGTTTCTCGAGAAACCCTTCCGCTTATCCACTTTTTT PDPK1 3-phosphoinositide dependent protein kinase-1 TRCN0000001479 CCGGCGGAAGGGTTTATTTGCAAGACTCGAGTCTTGCAAATAAACCCTTCCGTTTTT PDPK1 3-phosphoinositide dependent protein kinase-1 TRCN0000001480 CCGGTCGACCAGAGGCCAAGAATTTCTCGAGAAATTCTTGGCCTCTGGTCGATTTTT PEAK1 NKF3 kinase family member TRCN0000037439 CCGGCCCATGAAGTAACAGAGGATTCTCGAGAATCCTCTGTTACTTCATGGGTTTTTG PEAK1 NKF3 kinase family member TRCN0000037441 CCGGCGGTTTACTATACTGCTTCATCTCGAGATGAAGCAGTATAGTAAACCGTTTTTG PEAK1 NKF3 kinase family member TRCN0000037442 CCGGCCTCTAGTAATAATCAGGATACTCGAGTATCCTGATTATTACTAGAGGTTTTTG PEAK1 NKF3 kinase family member TRCN0000037443 CCGGCCACAAGTGTAATAAGCCATACTCGAGTATGGCTTATTACACTTGTGGTTTTTG PEAK1 NKF3 kinase family member TRCN0000037440 CCGGCCCACTATGATAGTGGCAGATCTCGAGATCTGCCACTATCATAGTGGGTTTTTG

183 Supplement

PHKG1 phosphorylase kinase, gamma 1 (muscle) TRCN0000006201 CCGGGCCACCATCTCCATTTCTCTTCTCGAGAAGAGAAATGGAGATGGTGGCTTTTT PHKG1 phosphorylase kinase, gamma 1 (muscle) TRCN0000006203 CCGGGCTGATGCTGAGGATGATCATCTCGAGATGATCATCCTCAGCATCAGCTTTTT PHKG1 phosphorylase kinase, gamma 1 (muscle) TRCN0000006204 CCGGCTATGAGAATTATGAGCCCAACTCGAGTTGGGCTCATAATTCTCATAGTTTTT PHKG1 phosphorylase kinase, gamma 1 (muscle) TRCN0000006202 CCGGGCACAGGACTTCTATGAGAATCTCGAGATTCTCATAGAAGTCCTGTGCTTTTT PHKG1 phosphorylase kinase, gamma 1 (muscle) TRCN0000006205 CCGGGCCTACGCTTTCCGAATCTATCTCGAGATAGATTCGGAAAGCGTAGGCTTTTT PHKG2 phosphorylase kinase, gamma 2 (testis) TRCN0000000398 CCGGCTAATGATCCTGCTACCCTCTCTCGAGAGAGGGTAGCAGGATCATTAGTTTTT PHKG2 phosphorylase kinase, gamma 2 (testis) TRCN0000000400 CCGGCGTTGTGTTCATCGAGCTACTCTCGAGAGTAGCTCGATGAACACAACGTTTTT PHKG2 phosphorylase kinase, gamma 2 (testis) TRCN0000000401 CCGGCGCCAGAGATCCTTAAATGCTCTCGAGAGCATTTAAGGATCTCTGGCGTTTTT PHKG2 phosphorylase kinase, gamma 2 (testis) TRCN0000010056 CCGGCGGCCACTGACCAAGAATGCACTCGAGTGCATTCTTGGTCAGTGGCCGTTTTT PHKG2 phosphorylase kinase, gamma 2 (testis) TRCN0000010068 CCGGCTAGCGCCAGAGATCCTTAAACTCGAGTTTAAGGATCTCTGGCGCTAGTTTTT PIK3R4 phosphoinositide-3-kinase, regulatory subunit 4 TRCN0000000885 CCGGGTCTCCATATTACTGTTTCATCTCGAGATGAAACAGTAATATGGAGACTTTTT PIK3R4 phosphoinositide-3-kinase, regulatory subunit 4 TRCN0000000886 CCGGCCCTGAACAAGTGCTAAATAACTCGAGTTATTTAGCACTTGTTCAGGGTTTTT PIK3R4 phosphoinositide-3-kinase, regulatory subunit 4 TRCN0000000888 CCGGGCACCACCACTTTCTGAATTACTCGAGTAATTCAGAAAGTGGTGGTGCTTTTT PIK3R4 phosphoinositide-3-kinase, regulatory subunit 4 TRCN0000010562 CCGGCGGAGGAGAACTTGCTATATTCTCGAGAATATAGCAAGTTCTCCTCCGTTTTT PIK3R4 phosphoinositide-3-kinase, regulatory subunit 4, p150 TRCN0000195336 CCGGCAAGAATCAGCCAGCCAACAACTCGAGTTGTTGGCTGGCTGATTCTTGTTTTTTG PIM1 pim-1 oncogene TRCN0000010116 CCGGACGTGGAGAAGGACCGGATTTCTCGAGAAATCCGGTCCTTCTCCACGTTTTTT PIM1 pim-1 oncogene TRCN0000010118 CCGGACATCCTTATCGACCTCAATCCTCGAGGATTGAGGTCGATAAGGATGTTTTTT PIM1 pim-1 oncogene TRCN0000010119 CCGGTCTACACGGACTTCGATGGGACTCGAGTCCCATCGAAGTCCGTGTAGATTTTT PIM1 pim-1 oncogene TRCN0000196869 CCGGGATACTCTCTTCTTCTCATAGCTCGAGCTATGAGAAGAAGAGAGTATCTTTTTTG PIM1 pim-1 oncogene TRCN0000199011 CCGGCATCCGCGTCTCCGACAACTTCTCGAGAAGTTGTCGGAGACGCGGATGTTTTTTG PIM2 pim-2 oncogene TRCN0000001627 CCGGCCAGTCATTAAAGTCCAGTATCTCGAGATACTGGACTTTAATGACTGGTTTTT PIM2 pim-2 oncogene TRCN0000001628 CCGGGCCCAGGATCTCTTTGACTATCTCGAGATAGTCAAAGAGATCCTGGGCTTTTT PIM2 pim-2 oncogene TRCN0000001629 CCGGGATGAACCCTACACTGACTTTCTCGAGAAAGTCAGTGTAGGGTTCATCTTTTT PIM2 pim-2 oncogene TRCN0000001630 CCGGCCAGGATCTCTTTGACTATATCTCGAGATATAGTCAAAGAGATCCTGGTTTTT PIM2 pim-2 oncogene TRCN0000001631 CCGGGCTTGACTGGTTTGAGACACACTCGAGTGTGTCTCAAACCAGTCAAGCTTTTT PIM3 pim-3 oncogene TRCN0000037414 CCGGCGCCTGTCAGAAGATGAACATCTCGAGATGTTCATCTTCTGACAGGCGTTTTTG PIM3 pim-3 oncogene TRCN0000037415 CCGGGCAGGACCTCTTCGACTTTATCTCGAGATAAAGTCGAAGAGGTCCTGCTTTTTG PIM3 pim-3 oncogene TRCN0000037416 CCGGCGTGCTTCTCTACGATATGGTCTCGAGACCATATCGTAGAGAAGCACGTTTTTG PIM3 pim-3 oncogene TRCN0000037417 CCGGCAAGGCGGACAAGGAGAGCTTCTCGAGAAGCTCTCCTTGTCCGCCTTGTTTTTG PIM3 pim-3 oncogene TRCN0000037418 CCGGCGGCCGTCGCTGGATCAGATTCTCGAGAATCTGATCCAGCGACGGCCGTTTTTG PINK1 PTEN induced putative kinase 1 TRCN0000007100 CCGGGTTCCTCGTTATGAAGAACTACTCGAGTAGTTCTTCATAACGAGGAACTTTTT PINK1 PTEN induced putative kinase 1 TRCN0000007101 CCGGCGGCTGGAGGAGTATCTGATACTCGAGTATCAGATACTCCTCCAGCCGTTTTT PINK1 PTEN induced putative kinase 1 TRCN0000199193 CCGGCGGACGCTGTTCCTCGTTATGCTCGAGCATAACGAGGAACAGCGTCCGTTTTTTG PINK1 PTEN induced putative kinase 1 TRCN0000199255 CCGGCCTAACCGTCTCCGCTTCTTCCTCGAGGAAGAAGCGGAGACGGTTAGGTTTTTTG PINK1 PTEN induced putative kinase 1 TRCN0000199446 CCGGGAAGCCACCATGCCTACATTGCTCGAGCAATGTAGGCATGGTGGCTTCTTTTTTG protein kinase domain containing, cytoplasmic PKDCC TRCN0000037529 CCGGGCGGAACCTCTATAATGCCTACTCGAGTAGGCATTATAGAGGTTCCGCTTTTTG homolog (mouse) protein kinase domain containing, cytoplasmic PKDCC TRCN0000037530 CCGGCAGTACCGAGTACCAGTGTATCTCGAGATACACTGGTACTCGGTACTGTTTTTG homolog (mouse) protein kinase domain containing, cytoplasmic PKDCC TRCN0000037532 CCGGCTGCCTCCTTTCAGTGTTCAACTCGAGTTGAACACTGAAAGGAGGCAGTTTTTG homolog (mouse) protein kinase domain containing, cytoplasmic PKDCC TRCN0000037533 CCGGCCTCTATAATGCCTACAGGTTCTCGAGAACCTGTAGGCATTATAGAGGTTTTTG homolog (mouse) PKDCC hypothetical protein BC007901 TRCN0000197269 CCGGGATCCCAACAAGACCACATATCTCGAGATATGTGGTCTTGTTGGGATCTTTTTTG protein kinase, membrane associated PKMYT1 TRCN0000006235 CCGGCCAGACTCTGCCTCTGCACTTCTCGAGAAGTGCAGAGGCAGAGTCTGGTTTTT tyrosine/threonine 1 protein kinase, membrane associated PKMYT1 TRCN0000006237 CCGGGCTGCGTTCTGTCCTTGTCATCTCGAGATGACAAGGACAGAACGCAGCTTTTT tyrosine/threonine 1 protein kinase, membrane associated PKMYT1 TRCN0000199190 CCGGCTGAGTTCACTGCCGGTCTGTCTCGAGACAGACCGGCAGTGAACTCAGTTTTTTG tyrosine/threonine 1 protein kinase, membrane associated PKMYT1 TRCN0000199578 CCGGGCAGCGGATGTGTTCAGTCTGCTCGAGCAGACTGAACACATCCGCTGCTTTTTTG tyrosine/threonine 1 protein kinase, membrane associated PKMYT1 TRCN0000199754 CCGGGTCTTCAAGGTGCGCTCCAAGCTCGAGCTTGGAGCGCACCTTGAAGACTTTTTTG tyrosine/threonine 1 PKN1 protein kinase N1 TRCN0000001481 CCGGGATGTGTGAGAAGCGGATATTCTCGAGAATATCCGCTTCTCACACATCTTTTT PKN1 protein kinase N1 TRCN0000001482 CCGGCATGATCCAGACCTACAGCAACTCGAGTTGCTGTAGGTCTGGATCATGTTTTT PKN1 protein kinase N1 TRCN0000001483 CCGGTCAAAGCAGAAGCCGAGAACACTCGAGTGTTCTCGGCTTCTGCTTTGATTTTT PKN1 protein kinase N1 TRCN0000001484 CCGGCTGATGTGTGAGAAGCGGATACTCGAGTATCCGCTTCTCACACATCAGTTTTT PKN1 protein kinase N1 TRCN0000001485 CCGGAGAACATGATCCAGACCTACACTCGAGTGTAGGTCTGGATCATGTTCTTTTTT PKN2 protein kinase N2 TRCN0000006251 CCGGGCAGGAATTAAATGCACATATCTCGAGATATGTGCATTTAATTCCTGCTTTTT PKN2 protein kinase N2 TRCN0000006253 CCGGGCACATTCATACTGATGTCTTCTCGAGAAGACATCAGTATGAATGTGCTTTTT PKN2 protein kinase N2 TRCN0000194752 CCGGCAATCATGTAACAGGCTTATACTCGAGTATAAGCCTGTTACATGATTGTTTTTTG PKN2 protein kinase N2 TRCN0000196735 CCGGGCAGGGTCTATTTACACAATTCTCGAGAATTGTGTAAATAGACCCTGCTTTTTTG PKN2 protein kinase N2 TRCN0000219649 CCGGGTCCACGTCAAAGTATGATATCTCGAGATATCATACTTTGACGTGGACTTTTTG PKN3 protein kinase N3 TRCN0000001321 CCGGGACAGGGAAATACTACGCCATCTCGAGATGGCGTAGTATTTCCCTGTCTTTTT PKN3 protein kinase N3 TRCN0000001322 CCGGCATGTGGAGCTGAAGGTGAAACTCGAGTTTCACCTTCAGCTCCACATGTTTTT PKN3 protein kinase N3 TRCN0000001323 CCGGACACGAGAAGAAGATCATTTACTCGAGTAAATGATCTTCTTCTCGTGTTTTTT PKN3 protein kinase N3 TRCN0000001324 CCGGACCTTCTGCGATCCTGTCATTCTCGAGAATGACAGGATCGCAGAAGGTTTTTT

184 Supplement

PKN3 protein kinase N3 TRCN0000196963 CCGGGCAAGGGCTTGAGTTCATTCACTCGAGTGAATGAACTCAAGCCCTTGCTTTTTTG PLK1 polo-like kinase 1 (Drosophila) TRCN0000006246 CCGGCCAACCATTAACGAGCTGCTTCTCGAGAAGCAGCTCGTTAATGGTTGGTTTTT PLK1 polo-like kinase 1 (Drosophila) TRCN0000006247 CCGGCGATACTACCTACGGCAAATTCTCGAGAATTTGCCGTAGGTAGTATCGTTTTT PLK1 polo-like kinase 1 (Drosophila) TRCN0000006248 CCGGCGCCTCATCCTCTACAATGATCTCGAGATCATTGTAGAGGATGAGGCGTTTTT PLK1 polo-like kinase 1 (Drosophila) TRCN0000121072 CCGGCCTCCTCACTCCCACCTGCATCTCGAGATGCAGGTGGGAGTGAGGAGGTTTTTG PLK1 polo-like kinase 1 (Drosophila) TRCN0000121073 CCGGCGAGCTGCTTAATGACGAGTTCTCGAGAACTCGTCATTAAGCAGCTCGTTTTTG PLK2 polo-like kinase 2 (Drosophila) TRCN0000000868 CCGGGTAGAAGGTCAATGGCTCATACTCGAGTATGAGCCATTGACCTTCTACTTTTT PLK2 polo-like kinase 2 (Drosophila) TRCN0000000869 CCGGGTGACGGTGCTGAAATACTTTCTCGAGAAAGTATTTCAGCACCGTCACTTTTT PLK2 polo-like kinase 2 (Drosophila) TRCN0000000870 CCGGGAACACAGAAGGAGAACGATACTCGAGTATCGTTCTCCTTCTGTGTTCTTTTT PLK2 polo-like kinase 2 (Drosophila) TRCN0000010560 CCGGTGGCTGCGTAACTGTGAACTACTCGAGTAGTTCACAGTTACGCAGCCATTTTT PLK2 polo-like kinase 2 (Drosophila) TRCN0000195469 CCGGCTCACAGCAGAGTAGCTAAACCTCGAGGTTTAGCTACTCTGCTGTGAGTTTTTTG PLK3 polo-like kinase 3 (Drosophila) TRCN0000000760 CCGGGACGCTGACAACATCTACATTCTCGAGAATGTAGATGTTGTCAGCGTCTTTTT PLK3 polo-like kinase 3 (Drosophila) TRCN0000199862 CCGGGCCCTTGCCTTTGTGGCCTTCCTCGAGGAAGGCCACAAAGGCAAGGGCTTTTTTG PLK3 polo-like kinase 3 (Drosophila) TRCN0000000759 CCGGGGCGTTATTTATGGACCACTTCTCGAGAAGTGGTCCATAAATAACGCCTTTTT PLK3 polo-like kinase 3 (Drosophila) TRCN0000000761 CCGGCAGCGCGAGAAGATCCTAAATCTCGAGATTTAGGATCTTCTCGCGCTGTTTTT PLK3 polo-like kinase 3 (Drosophila) TRCN0000000762 CCGGAGTGTGGAAGAGGTAGAGGTACTCGAGTACCTCTACCTCTTCCACACTTTTTT PLK4 polo-like kinase 4 (Drosophila) TRCN0000002371 CCGGCGTTGGTTGCTCACAGGTTAACTCGAGTTAACCTGTGAGCAACCAACGTTTTT PLK4 polo-like kinase 4 (Drosophila) TRCN0000002373 CCGGGAACGATGTCACTCAGCAGAACTCGAGTTCTGCTGAGTGACATCGTTCTTTTT PLK4 polo-like kinase 4 (Drosophila) TRCN0000002374 CCGGGCAATTATGTGTATCTGGTATCTCGAGATACCAGATACACATAATTGCTTTTT PLK4 polo-like kinase 4 (Drosophila) TRCN0000002375 CCGGCCCTCTATGGTTACAAATGAACTCGAGTTCATTTGTAACCATAGAGGGTTTTT PLK4 polo-like kinase 4 (Drosophila) TRCN0000121077 CCGGCTCCTTTCAGACATATAAGTTCTCGAGAACTTATATGTCTGAAAGGAGTTTTTG pregnancy up-regulated non-ubiquitously expressed PNCK TRCN0000021569 CCGGGCTATGAGTTTGACTCTCCTTCTCGAGAAGGAGAGTCAAACTCATAGCTTTTT CaM kinase pregnancy up-regulated non-ubiquitously expressed PNCK TRCN0000021570 CCGGCGAGAGCCCTTCCCACCTCTACTCGAGTAGAGGTGGGAAGGGCTCTCGTTTTT CaM kinase pregnancy up-regulated non-ubiquitously expressed PNCK TRCN0000021572 CCGGGATCGCAGTGCTCCGTAGGATCTCGAGATCCTACGGAGCACTGCGATCTTTTT CaM kinase pregnancy up-regulated non-ubiquitously expressed PNCK TRCN0000021573 CCGGCCTCGTGGCCCTCAAGTGCATCTCGAGATGCACTTGAGGGCCACGAGGTTTTT CaM kinase pregnancy up-regulated non-ubiquitously expressed PNCK TRCN0000021571 CCGGCATCAGCAGCGTCTACGAGATCTCGAGATCTCGTAGACGCTGCTGATGTTTTT CaM kinase protein kinase, AMP-activated, alpha 1 catalytic PRKAA1 TRCN0000000861 CCGGGTTGCCTACCATCTCATAATACTCGAGTATTATGAGATGGTAGGCAACTTTTT subunit protein kinase, AMP-activated, alpha 1 catalytic PRKAA1 TRCN0000000857 CCGGGCATAATAAGTCACAGCCAAACTCGAGTTTGGCTGTGACTTATTATGCTTTTT subunit protein kinase, AMP-activated, alpha 1 catalytic PRKAA1 TRCN0000000858 CCGGCCATCCTGAAAGAGTACCATTCTCGAGAATGGTACTCTTTCAGGATGGTTTTT subunit protein kinase, AMP-activated, alpha 1 catalytic PRKAA1 TRCN0000000859 CCGGCCTGGAAGTCACACAATAGAACTCGAGTTCTATTGTGTGACTTCCAGGTTTTT subunit protein kinase, AMP-activated, alpha 1 catalytic PRKAA1 TRCN0000000860 CCGGTGATTGATGATGAAGCCTTAACTCGAGTTAAGGCTTCATCATCAATCATTTTT subunit protein kinase, AMP-activated, alpha 2 catalytic PRKAA2 TRCN0000002168 CCGGGCTGTGAAAGAAGTGTGTGAACTCGAGTTCACACACTTCTTTCACAGCTTTTT subunit protein kinase, AMP-activated, alpha 2 catalytic PRKAA2 TRCN0000002170 CCGGGTGGCTTATCATCTTATCATTCTCGAGAATGATAAGATGATAAGCCACTTTTT subunit protein kinase, AMP-activated, alpha 2 catalytic PRKAA2 TRCN0000002171 CCGGCCCACTGAAACGAGCAACTATCTCGAGATAGTTGCTCGTTTCAGTGGGTTTTT subunit protein kinase, AMP-activated, alpha 2 catalytic PRKAA2 TRCN0000002169 CCGGCGCAGTTTAGATGTTGTTGGACTCGAGTCCAACAACATCTAAACTGCGTTTTT subunit protein kinase, AMP-activated, alpha 2 catalytic PRKAA2 TRCN0000002172 CCGGGCTGTGTTTATCGCCCAATTTCTCGAGAAATTGGGCGATAAACACAGCTTTTT subunit PRKACA protein kinase, cAMP-dependent, catalytic, alpha TRCN0000001370 CCGGCAGGAAGCCCAGATAATCAGACTCGAGTCTGATTATCTGGGCTTCCTGTTTTT PRKACA protein kinase, cAMP-dependent, catalytic, alpha TRCN0000001371 CCGGAGGTGGTGAAACTGAAACAGACTCGAGTCTGTTTCAGTTTCACCACCTTTTTT PRKACA protein kinase, cAMP-dependent, catalytic, alpha TRCN0000001372 CCGGGAAATCCGGGTCTCCATCAATCTCGAGATTGATGGAGACCCGGATTTCTTTTT PRKACA protein kinase, cAMP-dependent, catalytic, alpha TRCN0000001373 CCGGGATCGAACACACCCTGAATGACTCGAGTCATTCAGGGTGTGTTCGATCTTTTT PRKACA protein kinase, cAMP-dependent, catalytic, alpha TRCN0000010620 CCGGCTCAAACTTATACATGGTCATCTCGAGATGACCATGTATAAGTTTGAGTTTTT PRKACB protein kinase, cAMP-dependent, catalytic, beta TRCN0000002002 CCGGAGGAGTGCTAATCTATGAAATCTCGAGATTTCATAGATTAGCACTCCTTTTTT PRKACB protein kinase, cAMP-dependent, catalytic, beta TRCN0000002003 CCGGCCTCCATTCACTAGACCTCATCTCGAGATGAGGTCTAGTGAATGGAGGTTTTT PRKACB protein kinase, cAMP-dependent, catalytic, beta TRCN0000002004 CCGGGCCAACTGACTTAACAACATTCTCGAGAATGTTGTTAAGTCAGTTGGCTTTTT PRKACB protein kinase, cAMP-dependent, catalytic, beta TRCN0000002005 CCGGACTCAGAATAATGCCGGACTTCTCGAGAAGTCCGGCATTATTCTGAGTTTTTT PRKACB protein kinase, cAMP-dependent, catalytic, beta TRCN0000002006 CCGGCACGACAGATTGGATTGCTATCTCGAGATAGCAATCCAATCTGTCGTGTTTTT PRKACG protein kinase, cAMP-dependent, catalytic, gamma TRCN0000022354 CCGGAGTGGGCTGTTTGCTAGAATACTCGAGTATTCTAGCAAACAGCCCACTTTTTT PRKACG protein kinase, cAMP-dependent, catalytic, gamma TRCN0000022355 CCGGCATACTGAACGAGAAGCGCATCTCGAGATGCGCTTCTCGTTCAGTATGTTTTT PRKACG protein kinase, cAMP-dependent, catalytic, gamma TRCN0000022356 CCGGTATGAGAAGAAGGTGGAAGCTCTCGAGAGCTTCCACCTTCTTCTCATATTTTT PRKACG protein kinase, cAMP-dependent, catalytic, gamma TRCN0000022357 CCGGATACTGAACGAGAAGCGCATCCTCGAGGATGCGCTTCTCGTTCAGTATTTTTT PRKACG protein kinase, cAMP-dependent, catalytic, gamma TRCN0000022358 CCGGACATACTGAACGAGAAGCGCACTCGAGTGCGCTTCTCGTTCAGTATGTTTTTT PRKCA protein kinase C, alpha TRCN0000001690 CCGGCTTTGGAGTTTCGGAGCTGATCTCGAGATCAGCTCCGAAACTCCAAAGTTTTT PRKCA protein kinase C, alpha TRCN0000001691 CCGGCGAGCTATTTCAGTCTATCATCTCGAGATGATAGACTGAAATAGCTCGTTTTT PRKCA protein kinase C, alpha TRCN0000001692 CCGGCATGGAACTCAGGCAGAAATTCTCGAGAATTTCTGCCTGAGTTCCATGTTTTT PRKCA protein kinase C, alpha TRCN0000001693 CCGGCCCGTCTTAACACCACCTGATCTCGAGATCAGGTGGTGTTAAGACGGGTTTTT PRKCA protein kinase C, alpha TRCN0000001694 CCGGACGGCTTGTGTCTGATTCCATCTCGAGATGGAATCAGACACAAGCCGTTTTTT PRKCB protein kinase C, beta TRCN0000003117 CCGGGCTGAAAGAATCGGACAAAGACTCGAGTCTTTGTCCGATTCTTTCAGCTTTTT

185 Supplement

PRKCB protein kinase C, beta TRCN0000003118 CCGGCAAGTTTAAGATCCACACGTACTCGAGTACGTGTGGATCTTAAACTTGTTTTT PRKCB protein kinase C, beta TRCN0000195381 CCGGCCTGTCAGATCCCTACGTAAACTCGAGTTTACGTAGGGATCTGACAGGTTTTTTG PRKCB protein kinase C, beta TRCN0000196399 CCGGGAAACAAAGATGGTTGTATTCCTCGAGGAATACAACCATCTTTGTTTCTTTTTTG PRKCB protein kinase C, beta TRCN0000196841 CCGGGACGACCTGCTTTGATTTAACCTCGAGGTTAAATCAAAGCAGGTCGTCTTTTTTG PRKCD protein kinase C, delta TRCN0000010193 CCGGGGCCGCTTTGAACTCTACCGTCTCGAGACGGTAGAGTTCAAAGCGGCCTTTTT PRKCD protein kinase C, delta TRCN0000010202 CCGGGCAAGACAACAGTGGGACCTACTCGAGTAGGTCCCACTGTTGTCTTGCTTTTT PRKCD protein kinase C, delta TRCN0000195408 CCGGCAGAGCCTGTTGGGATATATCCTCGAGGATATATCCCAACAGGCTCTGTTTTTTG PRKCD protein kinase C, delta TRCN0000010194 CCGGCAAGGCTACAAATGCAGGCAACTCGAGTTGCCTGCATTTGTAGCCTTGTTTTT PRKCD protein kinase C, delta TRCN0000010203 CCGGGCAGGGATTAAAGTGTGAAGACTCGAGTCTTCACACTTTAATCCCTGCTTTTT PRKCE protein kinase C, epsilon TRCN0000000846 CCGGCCACAAGTTCGGTATCCACAACTCGAGTTGTGGATACCGAACTTGTGGTTTTT PRKCE protein kinase C, epsilon TRCN0000000845 CCGGCCCTTCAAACCACGCATTAAACTCGAGTTTAATGCGTGGTTTGAAGGGTTTTT PRKCE protein kinase C, epsilon TRCN0000000847 CCGGTGTCATAGGAAAGCAGGGATACTCGAGTATCCCTGCTTTCCTATGACATTTTT PRKCE protein kinase C, epsilon TRCN0000000848 CCGGGCCAGAAGGAAGAGTGTATGTCTCGAGACATACACTCTTCCTTCTGGCTTTTT PRKCE protein kinase C, epsilon TRCN0000195163 CCGGCATCCTAAGTTCCTAGCATAACTCGAGTTATGCTAGGAACTTAGGATGTTTTTTG PRKCG protein kinase C, gamma TRCN0000002324 CCGGTCTGTCGATTGGTGGTCCTTTCTCGAGAAAGGACCACCAATCGACAGATTTTT PRKCG protein kinase C, gamma TRCN0000002325 CCGGGTGGAATGAGACCTTTGTGTTCTCGAGAACACAAAGGTCTCATTCCACTTTTT PRKCG protein kinase C, gamma TRCN0000002326 CCGGCCGATATTCTCCCTGACCTTACTCGAGTAAGGTCAGGGAGAATATCGGTTTTT PRKCG protein kinase C, gamma TRCN0000002327 CCGGCAATGGTCTCTCTGATCCCTACTCGAGTAGGGATCAGAGAGACCATTGTTTTT PRKCG protein kinase C, gamma TRCN0000010693 CCGGGCTTTGTGGTTCATCGACGATCTCGAGATCGTCGATGAACCACAAAGCTTTTT PRKCH protein kinase C, eta TRCN0000006298 CCGGCCAGGATGAGTTTAGAAACTTCTCGAGAAGTTTCTAAACTCATCCTGGTTTTT PRKCH protein kinase C, eta TRCN0000194660 CCGGCATTCAGAAGTCTCGTCGTTTCTCGAGAAACGACGAGACTTCTGAATGTTTTTTG PRKCH protein kinase C, eta TRCN0000195662 CCGGCCAAGCAGAAGACCAACAAACCTCGAGGTTTGTTGGTCTTCTGCTTGGTTTTTTG PRKCH protein kinase C, eta TRCN0000196300 CCGGGTCTACTAATTTACCTGAATGCTCGAGCATTCAGGTAAATTAGTAGACTTTTTTG PRKCH protein kinase C, eta TRCN0000006294 CCGGGCTTCTTAATTCAAGAGACAACTCGAGTTGTCTCTTGAATTAAGAAGCTTTTT PRKCI protein kinase C, iota TRCN0000006037 CCGGGCCTGGATACAATTAACCATTCTCGAGAATGGTTAATTGTATCCAGGCTTTTT PRKCI protein kinase C, iota TRCN0000006039 CCGGCCTGAAGAACATGCCAGATTTCTCGAGAAATCTGGCATGTTCTTCAGGTTTTT PRKCI protein kinase C, iota TRCN0000006040 CCGGCCTTTAGACTTTATGAGCTAACTCGAGTTAGCTCATAAAGTCTAAAGGTTTTT PRKCI protein kinase C, iota TRCN0000006041 CCGGCCAGTCTAGGTCTTCAGGATTCTCGAGAATCCTGAAGACCTAGACTGGTTTTT PRKCI protein kinase C, iota TRCN0000195098 CCGGCAACTTTGATTCTCAGTTTACCTCGAGGTAAACTGAGAATCAAAGTTGTTTTTTG PRKCQ protein kinase C, theta TRCN0000001790 CCGGCGGGAGATCAACTGGGAGGAACTCGAGTTCCTCCCAGTTGATCTCCCGTTTTT PRKCQ protein kinase C, theta TRCN0000001791 CCGGCAAGGCCGAATGCTAATGAATCTCGAGATTCATTAGCATTCGGCCTTGTTTTT PRKCQ protein kinase C, theta TRCN0000001793 CCGGCAATAAAGACTGAGACCCGTTCTCGAGAACGGGTCTCAGTCTTTATTGTTTTT PRKCQ protein kinase C, theta TRCN0000195468 CCGGCGGGCAGATGTATATCCAGAACTCGAGTTCTGGATATACATCTGCCCGTTTTTTG PRKCQ protein kinase C, theta TRCN0000197216 CCGGGTGGTCTTGATGGACGATGATCTCGAGATCATCGTCCATCAAGACCACTTTTTTG PRKCZ protein kinase C, zeta TRCN0000001218 CCGGCGCGTGATTGACCCTTTAACTCTCGAGAGTTAAAGGGTCAATCACGCGTTTTT PRKCZ protein kinase C, zeta TRCN0000001220 CCGGCTGGTGCGGTTGAAGAAGAATCTCGAGATTCTTCTTCAACCGCACCAGTTTTT PRKCZ protein kinase C, zeta TRCN0000001221 CCGGGCCTCCAGTAGACGACAAGAACTCGAGTTCTTGTCGTCTACTGGAGGCTTTTT PRKCZ protein kinase C, zeta TRCN0000001222 CCGGCCCGGACATGAACACAGAGGACTCGAGTCCTCTGTGTTCATGTCCGGGTTTTT PRKCZ protein kinase C, zeta TRCN0000001219 CCGGGCCACAGATCACAGACGACTACTCGAGTAGTCGTCTGTGATCTGTGGCTTTTT PRKD1 protein kinase D1 TRCN0000002124 CCGGCCCACGCTCTCTTTGTTCATTCTCGAGAATGAACAAAGAGAGCGTGGGTTTTT PRKD1 protein kinase D1 TRCN0000194689 CCGGCAATTCACCTTGACAAGATTTCTCGAGAAATCTTGTCAAGGTGAATTGTTTTTTG PRKD1 protein kinase D1 TRCN0000195251 CCGGCAGGAAGAGATGTAGCTATTACTCGAGTAATAGCTACATCTCTTCCTGTTTTTTG PRKD1 protein kinase D1 TRCN0000196650 CCGGGAAACACGAAACTTGTTATTGCTCGAGCAATAACAAGTTTCGTGTTTCTTTTTTG PRKD1 protein kinase D1 TRCN0000002125 CCGGCTAAGGAACAAGGGCTACAATCTCGAGATTGTAGCCCTTGTTCCTTAGTTTTT PRKD2 protein kinase D2 TRCN0000001947 CCGGCAGTTTGGAGTGGTCTATGGACTCGAGTCCATAGACCACTCCAAACTGTTTTT PRKD2 protein kinase D2 TRCN0000001948 CCGGCTTCTACGGCCTTTACGACAACTCGAGTTGTCGTAAAGGCCGTAGAAGTTTTT PRKD2 protein kinase D2 TRCN0000001950 CCGGCACGACCAACAGATACTATAACTCGAGTTATAGTATCTGTTGGTCGTGTTTTT PRKD2 protein kinase D2 TRCN0000001949 CCGGCGTGGCAGTTAAGGTCATTGACTCGAGTCAATGACCTTAACTGCCACGTTTTT PRKD2 protein kinase D2 TRCN0000010670 CCGGGTTGGGTGGTTCATTACAGCACTCGAGTGCTGTAATGAACCACCCAACTTTTT PRKD3 protein kinase D3 TRCN0000001412 CCGGCGGGAAACTGAATAATAAGAACTCGAGTTCTTATTATTCAGTTTCCCGTTTTT PRKD3 protein kinase D3 TRCN0000001413 CCGGCGAGTCTTTGTAGTAATGGAACTCGAGTTCCATTACTACAAAGACTCGTTTTT PRKD3 protein kinase D3 TRCN0000001415 CCGGCCAGGAACCAAGTAAGAGAATCTCGAGATTCTCTTACTTGGTTCCTGGTTTTT PRKD3 protein kinase D3 TRCN0000001416 CCGGCAGGACTATCAGACTTGGCTTCTCGAGAAGCCAAGTCTGATAGTCCTGTTTTT PRKD3 protein kinase D3 TRCN0000195275 CCGGCACTTCATTATGGCTCCTAATCTCGAGATTAGGAGCCATAATGAAGTGTTTTTTG PRKDC protein kinase, DNA-activated, catalytic polypeptide TRCN0000006255 CCGGGCAGATAGAAAGCATTACATTCTCGAGAATGTAATGCTTTCTATCTGCTTTTT PRKDC protein kinase, DNA-activated, catalytic polypeptide TRCN0000006256 CCGGCCGGTAAAGATCCTAATTCTACTCGAGTAGAATTAGGATCTTTACCGGTTTTT PRKDC protein kinase, DNA-activated, catalytic polypeptide TRCN0000006257 CCGGCCAGTGAAAGTCTGAATCATTCTCGAGAATGATTCAGACTTTCACTGGTTTTT PRKDC protein kinase, DNA-activated, catalytic polypeptide TRCN0000006258 CCGGCCACCCTTTGTCTCTTGTATTCTCGAGAATACAAGAGACAAAGGGTGGTTTTT PRKDC protein kinase, DNA-activated, catalytic polypeptide TRCN0000006259 CCGGGCAGCCTTATTACAAAGACATCTCGAGATGTCTTTGTAATAAGGCTGCTTTTT PRKG1 protein kinase, cGMP-dependent, type I TRCN0000000996 CCGGGTCCATATACTTGTCTAACTACTCGAGTAGTTAGACAAGTATATGGACTTTTT PRKG1 protein kinase, cGMP-dependent, type I TRCN0000000998 CCGGCAGAACATTTAAGGACAGCAACTCGAGTTGCTGTCCTTAAATGTTCTGTTTTT PRKG1 protein kinase, cGMP-dependent, type I TRCN0000010030 CCGGTCCTAATGTATGAACTCCTGACTCGAGTCAGGAGTTCATACATTAGGATTTTT

186 Supplement

PRKG1 protein kinase, cGMP-dependent, type I TRCN0000194729 CCGGCCAGTCTTTCTTAGAACTTTACTCGAGTAAAGTTCTAAGAAAGACTGGTTTTTTG PRKG1 protein kinase, cGMP-dependent, type I TRCN0000000997 CCGGGCTGGATGATGTTTCTAATAACTCGAGTTATTAGAAACATCATCCAGCTTTTT PRKG2 protein kinase, cGMP-dependent, type II TRCN0000001509 CCGGCCCAAGCTAGAGATGAACAATCTCGAGATTGTTCATCTCTAGCTTGGGTTTTT PRKG2 protein kinase, cGMP-dependent, type II TRCN0000001510 CCGGGCAAACCTGAACCGTGATGATCTCGAGATCATCACGGTTCAGGTTTGCTTTTT PRKG2 protein kinase, cGMP-dependent, type II TRCN0000194661 CCGGCAAAGGAGATTACATCATTAGCTCGAGCTAATGATGTAATCTCCTTTGTTTTTTG PRKG2 protein kinase, cGMP-dependent, type II TRCN0000197044 CCGGGCTCATTACAGATGCCCTTAACTCGAGTTAAGGGCATCTGTAATGAGCTTTTTTG PRKG2 protein kinase, cGMP-dependent, type II TRCN0000001507 CCGGCCAATCATATCCTTCTCGTTTCTCGAGAAACGAGAAGGATATGATTGGTTTTT PRKX protein kinase, X-linked TRCN0000001781 CCGGCAAGGCGATTAGGAAACATGACTCGAGTCATGTTTCCTAATCGCCTTGTTTTT PRKX protein kinase, X-linked TRCN0000001782 CCGGCTAAAGCAGGAGCAACACGTACTCGAGTACGTGTTGCTCCTGCTTTAGTTTTT PRKX protein kinase, X-linked TRCN0000001783 CCGGGCGATTAGGAAACATGAAGAACTCGAGTTCTTCATGTTTCCTAATCGCTTTTT PRKX protein kinase, X-linked TRCN0000001784 CCGGCCTACTGTGATGTCTTGGTTTCTCGAGAAACCAAGACATCACAGTAGGTTTTT PRKX protein kinase, X-linked TRCN0000010652 CCGGCAAGATAGCTGGTGACGGCGACTCGAGTCGCCGTCACCAGCTATCTTGTTTTT PRKY protein kinase, Y-linked TRCN0000006343 CCGGCCTCGACAAGTCATGCTGTTTCTCGAGAAACAGCATGACTTGTCGAGGTTTTT PRKY protein kinase, Y-linked TRCN0000006344 CCGGCCCAGACATTTGGATTTCCATCTCGAGATGGAAATCCAAATGTCTGGGTTTTT PRKY protein kinase, Y-linked TRCN0000006345 CCGGCCGTTTGGCATTTATCAGAAACTCGAGTTTCTGATAAATGCCAAACGGTTTTT PRKY protein kinase, Y-linked TRCN0000006346 CCGGCGGCATCCTGATATTCGAGATCTCGAGATCTCGAATATCAGGATGCCGTTTTT PRKY protein kinase, Y-linked TRCN0000199051 CCGGCCCGAAGTCATTCAGAGCAAGCTCGAGCTTGCTCTGAATGACTTCGGGTTTTTTG PRPF4B PRP4 pre-mRNA processing factor 4 homolog B (yeast) TRCN0000000719 CCGGCCCTATCAACTGTCTTATGTACTCGAGTACATAAGACAGTTGATAGGGTTTTT PRPF4B PRP4 pre-mRNA processing factor 4 homolog B (yeast) TRCN0000000720 CCGGGCTGCTGATGTTAAAGAGTATCTCGAGATACTCTTTAACATCAGCAGCTTTTT PRPF4B PRP4 pre-mRNA processing factor 4 homolog B (yeast) TRCN0000000721 CCGGCTCAAGATCAAGCAAGGAAATCTCGAGATTTCCTTGCTTGATCTTGAGTTTTT PRPF4B PRP4 pre-mRNA processing factor 4 homolog B (yeast) TRCN0000000722 CCGGGAATGAAAGTTGAGCAGGAATCTCGAGATTCCTGCTCAACTTTCATTCTTTTT PRPF4B PRP4 pre-mRNA processing factor 4 homolog B (yeast) TRCN0000000723 CCGGAGCAAGTCAAAGGAGAGGAAACTCGAGTTTCCTCTCCTTTGACTTGCTTTTTT PSK prostate derived STE20-like kinase PSK TRCN0000001442 CCGGCTAGAGCATTGAGCACTTTATCTCGAGATAAAGTGCTCAATGCTCTAGTTTTT PSK prostate derived STE20-like kinase PSK TRCN0000001443 CCGGCCACCGCTCTTTAACATGAATCTCGAGATTCATGTTAAAGAGCGGTGGTTTTT PSK prostate derived STE20-like kinase PSK TRCN0000001444 CCGGGCTTGGCTGGTAATGGAGTATCTCGAGATACTCCATTACCAGCCAAGCTTTTT PSK prostate derived STE20-like kinase PSK TRCN0000001445 CCGGCACCTCTCACAGCTCCATTATCTCGAGATAATGGAGCTGTGAGAGGTGTTTTT PSK prostate derived STE20-like kinase PSK TRCN0000001446 CCGGACTCCCACAACATGATCCATACTCGAGTATGGATCATGTTGTGGGAGTTTTTT PSKH1 protein serine kinase H1 TRCN0000001712 CCGGGCACCGCTCCATATCCCAGAACTCGAGTTCTGGGATATGGAGCGGTGCTTTTT PSKH1 protein serine kinase H1 TRCN0000001708 CCGGTCCCTTCACAGCATTAACCTTCTCGAGAAGGTTAATGCTGTGAAGGGATTTTT PSKH1 protein serine kinase H1 TRCN0000001711 CCGGCCGCTCCACACGCTCCAATAACTCGAGTTATTGGAGCGTGTGGAGCGGTTTTT PSKH1 protein serine kinase H1 TRCN0000199111 CCGGCCGCCCTTGGTGCCTTCTTTGCTCGAGCAAAGAAGGCACCAAGGGCGGTTTTTTG PSKH1 protein serine kinase H1 TRCN0000199307 CCGGCCCGTTGATGTCCATTCCATTCTCGAGAATGGAATGGACATCAACGGGTTTTTTG PSKH2 protein serine kinase H2 TRCN0000003214 CCGGGAGCAGAAGACCACCAAGAAACTCGAGTTTCTTGGTGGTCTTCTGCTCTTTTT PSKH2 protein serine kinase H2 TRCN0000003215 CCGGCGGGTTAGCCATCGTTACATTCTCGAGAATGTAACGATGGCTAACCCGTTTTT PSKH2 protein serine kinase H2 TRCN0000003216 CCGGTGATGGGATTAGGTATTTGCACTCGAGTGCAAATACCTAATCCCATCATTTTT PSKH2 protein serine kinase H2 TRCN0000003217 CCGGGAGGATCAAGTTTACATGGTACTCGAGTACCATGTAAACTTGATCCTCTTTTT PSKH2 protein serine kinase H2 TRCN0000003218 CCGGACTGGACAATGAAGACACTCTCTCGAGAGAGTGTCTTCATTGTCCAGTTTTTT PTK2 PTK2 protein tyrosine kinase 2 TRCN0000001617 CCGGGAGAGCATGAAGCAAAGAATTCTCGAGAATTCTTTGCTTCATGCTCTCTTTTT PTK2 PTK2 protein tyrosine kinase 2 TRCN0000001620 CCGGCCGGTCGAATGATAAGGTGTACTCGAGTACACCTTATCATTCGACCGGTTTTT PTK2 PTK2 protein tyrosine kinase 2 TRCN0000001621 CCGGCGACAGCAACAGGAAATGGAACTCGAGTTCCATTTCCTGTTGCTGTCGTTTTT PTK2 PTK2 protein tyrosine kinase 2 TRCN0000121127 CCGGCGTGTGGATATGTGAAGCATTCTCGAGAATGCTTCACATATCCACACGTTTTTG PTK2 PTK2 protein tyrosine kinase 2 TRCN0000121128 CCGGCCAGGGATTATGAGATTCAAACTCGAGTTTGAATCTCATAATCCCTGGTTTTTG PTK2B PTK2B protein tyrosine kinase 2 beta TRCN0000000769 CCGGCGTGAAGATGTGGTCCTGAATCTCGAGATTCAGGACCACATCTTCACGTTTTT PTK2B PTK2B protein tyrosine kinase 2 beta TRCN0000195241 CCGGCATTCAAGGATGGAACATTACCTCGAGGTAATGTTCCATCCTTGAATGTTTTTTG PTK2B PTK2B protein tyrosine kinase 2 beta TRCN0000196917 CCGGGATGACCTGGTGTACCTCAATCTCGAGATTGAGGTACACCAGGTCATCTTTTTTG PTK2B PTK2B protein tyrosine kinase 2 beta TRCN0000199334 CCGGCGTATCCTCAAGGTCTGCTTCCTCGAGGAAGCAGACCTTGAGGATACGTTTTTTG PTK2B PTK2B protein tyrosine kinase 2 beta TRCN0000199771 CCGGGCCGTCATCTTCACGGACAGACTCGAGTCTGTCCGTGAAGATGACGGCTTTTTTG PTK6 PTK6 protein tyrosine kinase 6 TRCN0000021551 CCGGACCTCTCCCATGACCACAATACTCGAGTATTGTGGTCATGGGAGAGGTTTTTT PTK6 PTK6 protein tyrosine kinase 6 TRCN0000021552 CCGGTACCTCTCCCATGACCACAATCTCGAGATTGTGGTCATGGGAGAGGTATTTTT PTK6 PTK6 protein tyrosine kinase 6 TRCN0000194770 CCGGCATCCATGGTTAAGTCATAAACTCGAGTTTATGACTTAACCATGGATGTTTTTTG PTK6 PTK6 protein tyrosine kinase 6 TRCN0000196912 CCGGGTGCAGGAAAGGTTCACAAATCTCGAGATTTGTGAACCTTTCCTGCACTTTTTTG PTK6 PTK6 protein tyrosine kinase 6 TRCN0000199853 CCGGGCTCCGCGACTCTGATGAGAACTCGAGTTCTCATCAGAGTCGCGGAGCTTTTTTG PTK7 PTK7 protein tyrosine kinase 7 TRCN0000006431 CCGGCACAGGGTTAATGAGTCTCTTCTCGAGAAGAGACTCATTAACCCTGTGTTTTT PTK7 PTK7 protein tyrosine kinase 7 TRCN0000006433 CCGGCCACAGCACAAGTGATAAGATCTCGAGATCTTATCACTTGTGCTGTGGTTTTT PTK7 PTK7 protein tyrosine kinase 7 TRCN0000006434 CCGGCCTCATGTTCTACTGCAAGAACTCGAGTTCTTGCAGTAGAACATGAGGTTTTT PTK7 PTK7 protein tyrosine kinase 7 TRCN0000006435 CCGGCCTGAGGATTTCCAAGAGCAACTCGAGTTGCTCTTGGAAATCCTCAGGTTTTT PTK7 PTK7 protein tyrosine kinase 7 TRCN0000006432 CCGGCCTTGAGCATTGCTGATGAAACTCGAGTTTCATCAGCAATGCTCAAGGTTTTT PXK PX domain containing serine/threonine kinase TRCN0000001800 CCGGGCCTTCCTTCTACCGATCTTACTCGAGTAAGATCGGTAGAAGGAAGGCTTTTT PXK PX domain containing serine/threonine kinase TRCN0000001801 CCGGGTCTAATCAAACTTCTGCCTTCTCGAGAAGGCAGAAGTTTGATTAGACTTTTT PXK PX domain containing serine/threonine kinase TRCN0000001802 CCGGACAGCCACAAACAGTACTATTCTCGAGAATAGTACTGTTTGTGGCTGTTTTTT PXK PX domain containing serine/threonine kinase TRCN0000001803 CCGGCCACAGTTTAAGATCCCTACACTCGAGTGTAGGGATCTTAAACTGTGGTTTTT PXK PX domain containing serine/threonine kinase TRCN0000001804 CCGGTCCGCAAACTATACTGAGATTCTCGAGAATCTCAGTATAGTTTGCGGATTTTT

187 Supplement

RAF1 v-raf-1 murine leukemia viral oncogene homolog 1 TRCN0000001064 CCGGCATGAGTATTTAGAGGAAGTACTCGAGTACTTCCTCTAAATACTCATGTTTTT RAF1 v-raf-1 murine leukemia viral oncogene homolog 1 TRCN0000001065 CCGGGCTTCCTTATTCTCACATCAACTCGAGTTGATGTGAGAATAAGGAAGCTTTTT RAF1 v-raf-1 murine leukemia viral oncogene homolog 1 TRCN0000001068 CCGGGAGACATGAAATCCAACAATACTCGAGTATTGTTGGATTTCATGTCTCTTTTT RAF1 v-raf-1 murine leukemia viral oncogene homolog 1 TRCN0000195502 CCGGCTACTCCTATGGCATCGTATTCTCGAGAATACGATGCCATAGGAGTAGTTTTTTG RAF1 v-raf-1 murine leukemia viral oncogene homolog 1 TRCN0000195646 CCGGCCAACACTCTCTACCGAAGATCTCGAGATCTTCGGTAGAGAGTGTTGGTTTTTTG RAGE renal tumor antigen TRCN0000001713 CCGGCAAGAAGACAGATCCGCAGAACTCGAGTTCTGCGGATCTGTCTTCTTGTTTTT RAGE renal tumor antigen TRCN0000001714 CCGGCTGGTTCTCTTGCACTAATATCTCGAGATATTAGTGCAAGAGAACCAGTTTTT RAGE renal tumor antigen TRCN0000001715 CCGGACCTCTACTAACAACCAATTTCTCGAGAAATTGGTTGTTAGTAGAGGTTTTTT RAGE renal tumor antigen TRCN0000001716 CCGGCTGGGCTAATATACTTGTAAACTCGAGTTTACAAGTATATTAGCCCAGTTTTT RAGE renal tumor antigen TRCN0000001717 CCGGCGGCTGTGTGTTCTACGAGATCTCGAGATCTCGTAGAACACACAGCCGTTTTT RET ret proto-oncogene TRCN0000000404 CCGGCCGCTGGTGGACTGTAATAATCTCGAGATTATTACAGTCCACCAGCGGTTTTT RET ret proto-oncogene TRCN0000000405 CCGGGCTGCATGAGAACAACTGGATCTCGAGATCCAGTTGTTCTCATGCAGCTTTTT RET ret proto-oncogene TRCN0000009863 CCGGTGTTGTGGAGACCCAAGACATCTCGAGATGTCTTGGGTCTCCACAACATTTTTG RET ret proto-oncogene TRCN0000010238 CCGGGGGCGACCGTACATGACTATACTCGAGTATAGTCATGTACGGTCGCCCTTTTT RET ret proto-oncogene TRCN0000010239 CCGGGCAAGGAGATGGCAAAGGGATCTCGAGATCCCTTTGCCATCTCCTTGCTTTTT RIOK1 RIO kinase 1 (yeast) TRCN0000037399 CCGGGCAGATATGTATCGCATCAAACTCGAGTTTGATGCGATACATATCTGCTTTTTG RIOK1 RIO kinase 1 (yeast) TRCN0000037400 CCGGCCAGACTGTTACAGGATTGAACTCGAGTTCAATCCTGTAACAGTCTGGTTTTTG RIOK1 RIO kinase 1 (yeast) TRCN0000196278 CCGGGTCATGAGTTTCATCGGTAAACTCGAGTTTACCGATGAAACTCATGACTTTTTTG RIOK1 RIO kinase 1 (yeast) TRCN0000196981 CCGGGAGACTTGAAGACAGTCAAAGCTCGAGCTTTGACTGTCTTCAAGTCTCTTTTTTG RIOK1 RIO kinase 1 (yeast) TRCN0000037401 CCGGGCCAAGGGTTATGTCTGGAATCTCGAGATTCCAGACATAACCCTTGGCTTTTTG RIOK2 RIO kinase 2 (yeast) TRCN0000037505 CCGGCGGTTGACAAATGCAGGATATCTCGAGATATCCTGCATTTGTCAACCGTTTTTG RIOK2 RIO kinase 2 (yeast) TRCN0000037507 CCGGCGTCGATTGCAGAAAGGAGAACTCGAGTTCTCCTTTCTGCAATCGACGTTTTTG RIOK2 RIO kinase 2 (yeast) TRCN0000194682 CCGGCTAATTGCCTTGTCGTCATTACTCGAGTAATGACGACAAGGCAATTAGTTTTTTG RIOK2 RIO kinase 2 (yeast) TRCN0000196672 CCGGGCAGTTTGATTGCTTCTATAGCTCGAGCTATAGAAGCAATCAAACTGCTTTTTTG RIOK2 RIO kinase 2 (yeast) TRCN0000196684 CCGGGAGCTATGAATCAGTATAGAACTCGAGTTCTATACTGATTCATAGCTCTTTTTTG RIOK3 RIO kinase 3 (yeast) TRCN0000005418 CCGGGCTCAGCATTGAGAGAATAAACTCGAGTTTATTCTCTCAATGCTGAGCTTTTT RIOK3 RIO kinase 3 (yeast) TRCN0000005419 CCGGGCCTACTATCAAACTCTTCATCTCGAGATGAAGAGTTTGATAGTAGGCTTTTT RIOK3 RIO kinase 3 (yeast) TRCN0000005420 CCGGCCTGAGTTTCAGGTAGGAGATCTCGAGATCTCCTACCTGAAACTCAGGTTTTT RIOK3 RIO kinase 3 (yeast) TRCN0000005421 CCGGCCACCACTACTATATGATGAACTCGAGTTCATCATATAGTAGTGGTGGTTTTT RIOK3 RIO kinase 3 (yeast) TRCN0000194747 CCGGCAATGCTGTTTCAGGCTTAAACTCGAGTTTAAGCCTGAAACAGCATTGTTTTTTG receptor (TNFRSF)-interacting serine-threonine RIPK1 TRCN0000000705 CCGGAGGTCATGTTCTTTCAGCTTACTCGAGTAAGCTGAAAGAACATGACCTTTTTT kinase 1 receptor (TNFRSF)-interacting serine-threonine RIPK1 TRCN0000000706 CCGGCAGCACAAATACGAACTTCAACTCGAGTTGAAGTTCGTATTTGTGCTGTTTTT kinase 1 receptor (TNFRSF)-interacting serine-threonine RIPK1 TRCN0000000707 CCGGCAGGCCAATTCCAAGTCATATCTCGAGATATGACTTGGAATTGGCCTGTTTTT kinase 1 receptor (TNFRSF)-interacting serine-threonine RIPK1 TRCN0000000708 CCGGCCTTGTTGATAATGACTTCCACTCGAGTGGAAGTCATTATCAACAAGGTTTTT kinase 1 receptor (TNFRSF)-interacting serine-threonine RIPK1 TRCN0000000709 CCGGCTTACAACAGAGAGGAGGAAACTCGAGTTTCCTCCTCTCTGTTGTAAGTTTTT kinase 1 RIPK2 receptor-interacting serine-threonine kinase 2 TRCN0000006347 CCGGCCAGGCTTAATTGCCCTACAACTCGAGTTGTAGGGCAATTAAGCCTGGTTTTT RIPK2 receptor-interacting serine-threonine kinase 2 TRCN0000006348 CCGGGCCAGTATCAAGCACGATATACTCGAGTATATCGTGCTTGATACTGGCTTTTT RIPK2 receptor-interacting serine-threonine kinase 2 TRCN0000006349 CCGGGCACCATTTCTGGATCTCAAACTCGAGTTTGAGATCCAGAAATGGTGCTTTTT RIPK2 receptor-interacting serine-threonine kinase 2 TRCN0000006350 CCGGGCACAATATGACTCCTCCTTTCTCGAGAAAGGAGGAGTCATATTGTGCTTTTT RIPK2 receptor-interacting serine-threonine kinase 2 TRCN0000006351 CCGGGCTGTTATTCAGCTAAAGAAACTCGAGTTTCTTTAGCTGAATAACAGCTTTTT RIPK3 receptor-interacting serine-threonine kinase 3 TRCN0000002257 CCGGCTGAGAGACAAGGCATGAACTCTCGAGAGTTCATGCCTTGTCTCTCAGTTTTT RIPK3 receptor-interacting serine-threonine kinase 3 TRCN0000002258 CCGGGTGGCTAAACAAACTGAATCTCTCGAGAGATTCAGTTTGTTTAGCCACTTTTT RIPK3 receptor-interacting serine-threonine kinase 3 TRCN0000002259 CCGGCACAGGGTTGGTATAATCATACTCGAGTATGATTATACCAACCCTGTGTTTTT RIPK3 receptor-interacting serine-threonine kinase 3 TRCN0000002260 CCGGGCACTCTCGTAATGATGTCATCTCGAGATGACATCATTACGAGAGTGCTTTTT RIPK3 receptor-interacting serine-threonine kinase 3 TRCN0000002261 CCGGCTACAGCTTCGGGATCCTAATCTCGAGATTAGGATCCCGAAGCTGTAGTTTTT RIPK4 receptor-interacting serine-threonine kinase 4 TRCN0000007133 CCGGGCTCATGATCTGGACGTGAAACTCGAGTTTCACGTCCAGATCATGAGCTTTTT RIPK4 receptor-interacting serine-threonine kinase 4 TRCN0000007134 CCGGCCACGTCAAGATTTCTGATTTCTCGAGAAATCAGAAATCTTGACGTGGTTTTT RIPK4 receptor-interacting serine-threonine kinase 4 TRCN0000007132 CCGGCGTTCGTTTCTCGTTGCCTAACTCGAGTTAGGCAACGAGAAACGAACGTTTTT RIPK4 receptor-interacting serine-threonine kinase 4 TRCN0000007135 CCGGCGACACCAAGCACGATGTATACTCGAGTATACATCGTGCTTGGTGTCGTTTTT RIPK4 receptor-interacting serine-threonine kinase 4 TRCN0000007136 CCGGCGCCGATGTCATTGACCTGTTCTCGAGAACAGGTCAATGACATCGGCGTTTTT ribonuclease L (2',5'-oligoisoadenylate synthetase- RNASEL TRCN0000000924 CCGGCCGGAATTTGGGAGAACACATCTCGAGATGTGTTCTCCCAAATTCCGGTTTTT dependent) ribonuclease L (2',5'-oligoisoadenylate synthetase- RNASEL TRCN0000000925 CCGGGCTGGTCCTCTATGTGGTAAACTCGAGTTTACCACATAGAGGACCAGCTTTTT dependent) ribonuclease L (2',5'-oligoisoadenylate synthetase- RNASEL TRCN0000000926 CCGGCAAGAGCACATAGAGATTAATCTCGAGATTAATCTCTATGTGCTCTTGTTTTT dependent) ribonuclease L (2',5'-oligoisoadenylate synthetase- RNASEL TRCN0000000927 CCGGTCCACAGAATATACCGCCCTACTCGAGTAGGGCGGTATATTCTGTGGATTTTT dependent) ribonuclease L (2',5'-oligoisoadenylate synthetase- RNASEL TRCN0000194843 CCGGCTGAAGGATCTCCACAGAATACTCGAGTATTCTGTGGAGATCCTTCAGTTTTTTG dependent) Rho-associated, coiled-coil containing protein kinase ROCK1 TRCN0000002159 CCGGGAGGTAAATGAACACAAAGTACTCGAGTACTTTGTGTTCATTTACCTCTTTTT 1 Rho-associated, coiled-coil containing protein kinase ROCK1 TRCN0000002160 CCGGCCCGATTTAAGTAGTGACATTCTCGAGAATGTCACTACTTAAATCGGGTTTTT 1

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Rho-associated, coiled-coil containing protein kinase ROCK1 TRCN0000002162 CCGGGCTCGAATTACATCTTTACAACTCGAGTTGTAAAGATGTAATTCGAGCTTTTT 1 Rho-associated, coiled-coil containing protein kinase ROCK1 TRCN0000002163 CCGGGCCAGCAAAGAGAGTGATATTCTCGAGAATATCACTCTCTTTGCTGGCTTTTT 1 Rho-associated, coiled-coil containing protein kinase ROCK1 TRCN0000121092 CCGGCGGGTTGTTCAGATTGAGAAACTCGAGTTTCTCAATCTGAACAACCCGTTTTTG 1 Rho-associated, coiled-coil containing protein kinase ROCK2 TRCN0000000977 CCGGCCTGTGTACCTGATGGAAGTTCTCGAGAACTTCCATCAGGTACACAGGTTTTT 2 Rho-associated, coiled-coil containing protein kinase ROCK2 TRCN0000000978 CCGGGCACAGTTTGAGAAGCAGCTACTCGAGTAGCTGCTTCTCAAACTGTGCTTTTT 2 Rho-associated, coiled-coil containing protein kinase ROCK2 TRCN0000000979 CCGGGCCTTGCATATTGGTCTGGATCTCGAGATCCAGACCAATATGCAAGGCTTTTT 2 Rho-associated, coiled-coil containing protein kinase ROCK2 TRCN0000194836 CCGGCCTTGATGTCTGTCTATTATTCTCGAGAATAATAGACAGACATCAAGGTTTTTTG 2 Rho-associated, coiled-coil containing protein kinase ROCK2 TRCN0000194874 CCGGCCTTTCAAGATGATAGGTATCCTCGAGGATACCTATCATCTTGAAAGGTTTTTTG 2 ROR1 receptor tyrosine kinase-like orphan receptor 1 TRCN0000002024 CCGGCTTTACTAGGAGACGCCAATACTCGAGTATTGGCGTCTCCTAGTAAAGTTTTT ROR1 receptor tyrosine kinase-like orphan receptor 1 TRCN0000002025 CCGGCTCATTTAGCAGACATCGCAACTCGAGTTGCGATGTCTGCTAAATGAGTTTTT ROR1 receptor tyrosine kinase-like orphan receptor 1 TRCN0000002026 CCGGGCACCGTCTATATGGAGTCTTCTCGAGAAGACTCCATATAGACGGTGCTTTTT ROR1 receptor tyrosine kinase-like orphan receptor 1 TRCN0000002027 CCGGCATTGCTTTACTCTTCTTCTTCTCGAGAAGAAGAAGAGTAAAGCAATGTTTTT ROR1 receptor tyrosine kinase-like orphan receptor 1 TRCN0000002028 CCGGCGGAGAGCAACTTCATGTAAACTCGAGTTTACATGAAGTTGCTCTCCGTTTTT ROR2 receptor tyrosine kinase-like orphan receptor 2 TRCN0000001490 CCGGGCAGCTTCACTCCATGTCATACTCGAGTATGACATGGAGTGAAGCTGCTTTTT ROR2 receptor tyrosine kinase-like orphan receptor 2 TRCN0000001491 CCGGCCGCTACCATCAGTGCTATAACTCGAGTTATAGCACTGATGGTAGCGGTTTTT ROR2 receptor tyrosine kinase-like orphan receptor 2 TRCN0000001492 CCGGCGACAAGCTGAACGTGAAGATCTCGAGATCTTCACGTTCAGCTTGTCGTTTTT ROR2 receptor tyrosine kinase-like orphan receptor 2 TRCN0000001493 CCGGCCTCATTAACCAGCACAAACACTCGAGTGTTTGTGCTGGTTAATGAGGTTTTT ROR2 receptor tyrosine kinase-like orphan receptor 2 TRCN0000010625 CCGGGCACAGCCCAAATCATAACTTCTCGAGAAGTTATGATTTGGGCTGTGCTTTTT ROS1 c-ros oncogene 1 , receptor tyrosine kinase TRCN0000000956 CCGGCCACAGCTACAAACCAACAAACTCGAGTTTGTTGGTTTGTAGCTGTGGTTTTT ROS1 c-ros oncogene 1 , receptor tyrosine kinase TRCN0000000953 CCGGTGGGAAATAGAGAGTTGAGATCTCGAGATCTCAACTCTCTATTTCCCATTTTT ROS1 c-ros oncogene 1 , receptor tyrosine kinase TRCN0000000954 CCGGGCTGCCTAAAGTCGTGTGTAACTCGAGTTACACACGACTTTAGGCAGCTTTTT ROS1 c-ros oncogene 1 , receptor tyrosine kinase TRCN0000000955 CCGGGCTTGGAGTTTGTCTGCTGAACTCGAGTTCAGCAGACAAACTCCAAGCTTTTT ROS1 c-ros oncogene 1 , receptor tyrosine kinase TRCN0000000957 CCGGCCTCACCTCATAACTCTTCTTCTCGAGAAGAAGAGTTATGAGGTGAGGTTTTT RPS6KA1 ribosomal protein S6 kinase, 90kDa, polypeptide 1 TRCN0000001384 CCGGAGCGATTCACTGTATAAACTTCTCGAGAAGTTTATACAGTGAATCGCTTTTTT RPS6KA1 ribosomal protein S6 kinase, 90kDa, polypeptide 1 TRCN0000001385 CCGGGCTCTATCTCATTCTGGACTTCTCGAGAAGTCCAGAATGAGATAGAGCTTTTT RPS6KA1 ribosomal protein S6 kinase, 90kDa, polypeptide 1 TRCN0000001386 CCGGGAAGGAGACCATGACACTGATCTCGAGATCAGTGTCATGGTCTCCTTCTTTTT RPS6KA1 ribosomal protein S6 kinase, 90kDa, polypeptide 1 TRCN0000001387 CCGGACACAGTTTCAGAGACAGCCACTCGAGTGGCTGTCTCTGAAACTGTGTTTTTT RPS6KA1 ribosomal protein S6 kinase, 90kDa, polypeptide 1 TRCN0000001388 CCGGGACCATGACACTGATTCTGAACTCGAGTTCAGAATCAGTGTCATGGTCTTTTT RPS6KA2 ribosomal protein S6 kinase, 90kDa, polypeptide 2 TRCN0000006354 CCGGCGCCACCTACTTTGCTCTAAACTCGAGTTTAGAGCAAAGTAGGTGGCGTTTTT RPS6KA2 ribosomal protein S6 kinase, 90kDa, polypeptide 2 TRCN0000006355 CCGGGCAAGTTTGTGTACCTGGTAACTCGAGTTACCAGGTACACAAACTTGCTTTTT RPS6KA2 ribosomal protein S6 kinase, 90kDa, polypeptide 2 TRCN0000195208 CCGGCAAACGCTCATCACCTGTTTACTCGAGTAAACAGGTGATGAGCGTTTGTTTTTTG RPS6KA2 ribosomal protein S6 kinase, 90kDa, polypeptide 2 TRCN0000196388 CCGGGCCGTGAAGATCATTGATAAGCTCGAGCTTATCAATGATCTTCACGGCTTTTTTG RPS6KA2 ribosomal protein S6 kinase, 90kDa, polypeptide 2 TRCN0000199744 CCGGGCGTGTGACATCTGGAGTTTGCTCGAGCAAACTCCAGATGTCACACGCTTTTTTG RPS6KA3 ribosomal protein S6 kinase, 90kDa, polypeptide 3 TRCN0000001396 CCGGACTGCCACAATACCAACTAAACTCGAGTTTAGTTGGTATTGTGGCAGTTTTTT RPS6KA3 ribosomal protein S6 kinase, 90kDa, polypeptide 3 TRCN0000001397 CCGGTCAACGATAGACTGGAATAAACTCGAGTTTATTCCAGTCTATCGTTGATTTTT RPS6KA3 ribosomal protein S6 kinase, 90kDa, polypeptide 3 TRCN0000010428 CCGGCAGAAGAAGATGTCAAATTCTCTCGAGAGAATTTGACATCTTCTTCTGTTTTTG RPS6KA3 ribosomal protein S6 kinase, 90kDa, polypeptide 3 TRCN0000040143 CCGGCCATCTACATAGCCTGGGAATCTCGAGATTCCCAGGCTATGTAGATGGTTTTTG RPS6KA3 ribosomal protein S6 kinase, 90kDa, polypeptide 3 TRCN0000040144 CCGGCGCTGAGAATGGACAGCAAATCTCGAGATTTGCTGTCCATTCTCAGCGTTTTTG RPS6KA4 ribosomal protein S6 kinase, 90kDa, polypeptide 4 TRCN0000021514 CCGGCCAGACAGAGCAGAAGTATTTCTCGAGAAATACTTCTGCTCTGTCTGGTTTTT RPS6KA4 ribosomal protein S6 kinase, 90kDa, polypeptide 4 TRCN0000021515 CCGGCCGAAATCATCCGTAGCAAGACTCGAGTCTTGCTACGGATGATTTCGGTTTTT RPS6KA4 ribosomal protein S6 kinase, 90kDa, polypeptide 4 TRCN0000021517 CCGGACCCTCCATTCTCTTTGACCACTCGAGTGGTCAAAGAGAATGGAGGGTTTTTT RPS6KA4 ribosomal protein S6 kinase, 90kDa, polypeptide 4 TRCN0000021518 CCGGCGAAATCATCCGTAGCAAGACCTCGAGGTCTTGCTACGGATGATTTCGTTTTT RPS6KA4 ribosomal protein S6 kinase, 90kDa, polypeptide 4 TRCN0000195726 CCGGCCTCACTTTATGTCATCTGCTCTCGAGAGCAGATGACATAAAGTGAGGTTTTTTG RPS6KA5 ribosomal protein S6 kinase, 90kDa, polypeptide 5 TRCN0000001494 CCGGACCTATGACTTGTTTGGAAATCTCGAGATTTCCAAACAAGTCATAGGTTTTTT RPS6KA5 ribosomal protein S6 kinase, 90kDa, polypeptide 5 TRCN0000001495 CCGGGCACCATTTAAGCCAGTCATTCTCGAGAATGACTGGCTTAAATGGTGCTTTTT RPS6KA5 ribosomal protein S6 kinase, 90kDa, polypeptide 5 TRCN0000001496 CCGGGCAGATTTATGTTGGAGAGATCTCGAGATCTCTCCAACATAAATCTGCTTTTT RPS6KA5 ribosomal protein S6 kinase, 90kDa, polypeptide 5 TRCN0000001497 CCGGGCTGAGAAGGTGGGAATAGAACTCGAGTTCTATTCCCACCTTCTCAGCTTTTT RPS6KA5 ribosomal protein S6 kinase, 90kDa, polypeptide 5 TRCN0000001498 CCGGCGCGGTGGAAATCATGAAGAACTCGAGTTCTTCATGATTTCCACCGCGTTTTT RPS6KA6 ribosomal protein S6 kinase, 90kDa, polypeptide 6 TRCN0000002264 CCGGGAGTTGTTAAAGAAATCCCTACTCGAGTAGGGATTTCTTTAACAACTCTTTTT RPS6KA6 ribosomal protein S6 kinase, 90kDa, polypeptide 6 TRCN0000196549 CCGGGCTTGTGATATCTGGAGTTTACTCGAGTAAACTCCAGATATCACAAGCTTTTTTG RPS6KA6 ribosomal protein S6 kinase, 90kDa, polypeptide 6 TRCN0000196585 CCGGGTCCACAATATTCATACTATGCTCGAGCATAGTATGAATATTGTGGACTTTTTTG RPS6KA6 ribosomal protein S6 kinase, 90kDa, polypeptide 6 TRCN0000002262 CCGGGTATATGAATTGAAGGAGGATCTCGAGATCCTCCTTCAATTCATATACTTTTT RPS6KA6 ribosomal protein S6 kinase, 90kDa, polypeptide 6 TRCN0000002263 CCGGGCAGTAGTGTTCAAGTGTTTACTCGAGTAAACACTTGAACACTACTGCTTTTT RPS6KB1 ribosomal protein S6 kinase, 70kDa, polypeptide 1 TRCN0000003158 CCGGCCCATGATCTCCAAACGGCCACTCGAGTGGCCGTTTGGAGATCATGGGTTTTT RPS6KB1 ribosomal protein S6 kinase, 70kDa, polypeptide 1 TRCN0000003159 CCGGAGCACAGCAAATCCTCAGACACTCGAGTGTCTGAGGATTTGCTGTGCTTTTTT RPS6KB1 ribosomal protein S6 kinase, 70kDa, polypeptide 1 TRCN0000003160 CCGGGCGACATCTTTCTCAACCTTACTCGAGTAAGGTTGAGAAAGATGTCGCTTTTT RPS6KB1 ribosomal protein S6 kinase, 70kDa, polypeptide 1 TRCN0000195109 CCGGCCGGAGAATATCATGCTTAATCTCGAGATTAAGCATGATATTCTCCGGTTTTTTG RPS6KB1 ribosomal protein S6 kinase, 70kDa, polypeptide 1 TRCN0000003161 CCGGTATTTGCCATGAAGGTGCTTACTCGAGTAAGCACCTTCATGGCAAATATTTTT RPS6KB2 ribosomal protein S6 kinase, 70kDa, polypeptide 2 TRCN0000010539 CCGGCACATGAATTGGGACGACCTTCTCGAGAAGGTCGTCCCAATTCATGTGTTTTT

189 Supplement

RPS6KB2 ribosomal protein S6 kinase, 70kDa, polypeptide 2 TRCN0000010540 CCGGAGGACGTGAGCCAGTTTGATACTCGAGTATCAAACTGGCTCACGTCCTTTTTT RPS6KB2 ribosomal protein S6 kinase, 70kDa, polypeptide 2 TRCN0000199878 CCGGGCCATGAAAGTCCTAAGGAAGCTCGAGCTTCCTTAGGACTTTCATGGCTTTTTTG RPS6KB2 ribosomal protein S6 kinase, 70kDa, polypeptide 2 TRCN0000204908 CCGGCGGTGGACAGTCCTGATGACACTCGAGTGTCATCAGGACTGTCCACCGTTTTTTG RPS6KB2 ribosomal protein S6 kinase, 70kDa, polypeptide 2 TRCN0000000729 CCGGTGCGTATGAAAGTGTGTGTCTCTCGAGAGACACACACTTTCATACGCATTTTT RPS6KC1 ribosomal protein S6 kinase, 52kDa, polypeptide 1 TRCN0000003261 CCGGCCAAGGTGTGATCTGAATTTACTCGAGTAAATTCAGATCACACCTTGGTTTTT RPS6KC1 ribosomal protein S6 kinase, 52kDa, polypeptide 1 TRCN0000003263 CCGGCCCAGCTCAGATCCTAAGTTTCTCGAGAAACTTAGGATCTGAGCTGGGTTTTT RPS6KC1 ribosomal protein S6 kinase, 52kDa, polypeptide 1 TRCN0000003259 CCGGGCTTTACATAGAGAGGGAATTCTCGAGAATTCCCTCTCTATGTAAAGCTTTTT RPS6KC1 ribosomal protein S6 kinase, 52kDa, polypeptide 1 TRCN0000003260 CCGGGCAATGAATATGGGCAAGAAACTCGAGTTTCTTGCCCATATTCATTGCTTTTT RPS6KC1 ribosomal protein S6 kinase, 52kDa, polypeptide 1 TRCN0000003262 CCGGGCTCACTCAGATTCCCTCATTCTCGAGAATGAGGGAATCTGAGTGAGCTTTTT RPS6KL1 ribosomal protein S6 kinase-like 1 TRCN0000007082 CCGGAGTGGTTACCTCAAAGACAATCTCGAGATTGTCTTTGAGGTAACCACTTTTTT RPS6KL1 ribosomal protein S6 kinase-like 1 TRCN0000007083 CCGGGCCTTCAACCACTATCAGAATCTCGAGATTCTGATAGTGGTTGAAGGCTTTTT RPS6KL1 ribosomal protein S6 kinase-like 1 TRCN0000007085 CCGGGACTCATCTCAGGACACTGATCTCGAGATCAGTGTCCTGAGATGAGTCTTTTT RPS6KL1 ribosomal protein S6 kinase-like 1 TRCN0000007086 CCGGAGGTGGTGTCAGCAAACTCAACTCGAGTTGAGTTTGCTGACACCACCTTTTTT RPS6KL1 ribosomal protein S6 kinase-like 1 TRCN0000007084 CCGGCGCGATGTTAGTGAGGACTATCTCGAGATAGTCCTCACTAACATCGCGTTTTT RYK RYK receptor-like tyrosine kinase TRCN0000001572 CCGGCAACGCCAACAGAAGCACATTCTCGAGAATGTGCTTCTGTTGGCGTTGTTTTT RYK RYK receptor-like tyrosine kinase TRCN0000001573 CCGGGCAAGTTAGTAGAGGCCAATACTCGAGTATTGGCCTCTACTAACTTGCTTTTT RYK RYK receptor-like tyrosine kinase TRCN0000001575 CCGGGCTCTATCCTTTAATCTGTTACTCGAGTAACAGATTAAAGGATAGAGCTTTTT RYK RYK receptor-like tyrosine kinase TRCN0000001576 CCGGCAAGTTAAGATCACAGACAATCTCGAGATTGTCTGTGATCTTAACTTGTTTTT RYK RYK receptor-like tyrosine kinase TRCN0000195387 CCGGCGGATAGAGAAGAACGACTTGCTCGAGCAAGTCGTTCTTCTCTATCCGTTTTTTG SBK1 SH3-binding domain kinase 1 TRCN0000037394 CCGGGTCACCAAGCACTACGAACTACTCGAGTAGTTCGTAGTGCTTGGTGACTTTTTG SBK1 SH3-binding domain kinase 1 TRCN0000037395 CCGGCGACGCCTTCTTCGAGGAGTTCTCGAGAACTCCTCGAAGAAGGCGTCGTTTTTG SBK1 SH3-binding domain kinase 1 TRCN0000037396 CCGGCAAGGTCTTTGACGTGGTCTTCTCGAGAAGACCACGTCAAAGACCTTGTTTTTG SBK1 SH3-binding domain kinase 1 TRCN0000037397 CCGGCCGCGTAAAGCTGGCCGACTTCTCGAGAAGTCGGCCAGCTTTACGCGGTTTTTG SBK1 SH3-binding domain kinase 1 TRCN0000037398 CCGGCCCTTCATCATCAAGGTCTTTCTCGAGAAAGACCTTGATGATGAAGGGTTTTTG SCYL1 SCY1-like 1 (S. cerevisiae) TRCN0000007122 CCGGGCTGGACTGAACCGTGGCGGTCTCGAGACCGCCACGGTTCAGTCCAGCTTTTT SCYL1 SCY1-like 1 (S. cerevisiae) TRCN0000007124 CCGGCTTTGTAGAAACCAACCTCTTCTCGAGAAGAGGTTGGTTTCTACAAAGTTTTT SCYL1 SCY1-like 1 (S. cerevisiae) TRCN0000007126 CCGGCCCGTGTCCATCTTCGTCTATCTCGAGATAGACGAAGATGGACACGGGTTTTT SCYL1 SCY1-like 1 (S. cerevisiae) TRCN0000199039 CCGGCGGAGCTTCCTGTCCAAATTGCTCGAGCAATTTGGACAGGAAGCTCCGTTTTTTG SCYL1 SCY1-like 1 (S. cerevisiae) TRCN0000199176 CCGGCGCCTTCGAGTTCGGCAATGCCTCGAGGCATTGCCGAACTCGAAGGCGTTTTTTG SCYL2 SCY1-like 2 (S. cerevisiae) TRCN0000007148 CCGGGCCCGTTAATACAAACCAGAACTCGAGTTCTGGTTTGTATTAACGGGCTTTTT SCYL2 SCY1-like 2 (S. cerevisiae) TRCN0000007149 CCGGGCCACCAACTACTATGACCAACTCGAGTTGGTCATAGTAGTTGGTGGCTTTTT SCYL2 SCY1-like 2 (S. cerevisiae) TRCN0000007150 CCGGGCGGTTCGTGTAAATTCATTACTCGAGTAATGAATTTACACGAACCGCTTTTT SCYL2 SCY1-like 2 (S. cerevisiae) TRCN0000007151 CCGGGCCCTCAGAAACCCAAAGTTACTCGAGTAACTTTGGGTTTCTGAGGGCTTTTT SCYL2 SCY1-like 2 (S. cerevisiae) TRCN0000007147 CCGGCCGTTATGTTTAGAGTAGAAACTCGAGTTTCTACTCTAAACATAACGGTTTTT SCYL3 SCY1-like 3 (S. cerevisiae) TRCN0000002386 CCGGCCTGTTCTCTAAATGTCAAATCTCGAGATTTGACATTTAGAGAACAGGTTTTT SCYL3 SCY1-like 3 (S. cerevisiae) TRCN0000002390 CCGGCTCCAGTTGTTTGAAGTTCATCTCGAGATGAACTTCAAACAACTGGAGTTTTT SCYL3 SCY1-like 3 (S. cerevisiae) TRCN0000199443 CCGGGCCTTGGAAATCAAGCTTACCCTCGAGGGTAAGCTTGATTTCCAAGGCTTTTTTG SCYL3 SCY1-like 3 (S. cerevisiae) TRCN0000199556 CCGGCCTCTGGACTTGCTGTTTATCCTCGAGGATAAACAGCAAGTCCAGAGGTTTTTTG SCYL3 SCY1-like 3 (S. cerevisiae) TRCN0000002387 CCGGGTCTGTTTATCATCTGTGTTTCTCGAGAAACACAGATGATAAACAGACTTTTT SGK1 serum/glucocorticoid regulated kinase 1 TRCN0000009866 CCGGAAATGTACGACAACATTCTGCTCGAGCAGAATGTTGTCGTACATTTCTTTTTG SGK1 serum/glucocorticoid regulated kinase 1 TRCN0000010432 CCGGCAATTCTCATCGCTTTCATGACTCGAGTCATGAAAGCGATGAGAATTGTTTTTG SGK1 serum/glucocorticoid regulated kinase 1 TRCN0000040175 CCGGCGGAATGTTCTGTTGAAGAATCTCGAGATTCTTCAACAGAACATTCCGTTTTTG SGK1 serum/glucocorticoid regulated kinase 1 TRCN0000040177 CCGGCATGTCTTCTTCTCCTTAATTCTCGAGAATTAAGGAGAAGAAGACATGTTTTTG SGK1 serum/glucocorticoid regulated kinase 1 TRCN0000194957 CCGGCTGGAAGCTTAGCAATCTTATCTCGAGATAAGATTGCTAAGCTTCCAGTTTTTTG SGK196 protein kinase-like protein SgK196 TRCN0000001540 CCGGGAAGGGCTGAATGGAAGTTACCTCGAGGTAACTTCCATTCAGCCCTTCTTTTT SGK196 protein kinase-like protein SgK196 TRCN0000001541 CCGGCCTGATGAATACTCTACTCTACTCGAGTAGAGTAGAGTATTCATCAGGTTTTT SGK196 protein kinase-like protein SgK196 TRCN0000001542 CCGGGACAACACTATGCTTACTGAACTCGAGTTCAGTAAGCATAGTGTTGTCTTTTT SGK196 protein kinase-like protein SgK196 TRCN0000001543 CCGGGTCCGATTCCATTTGTTTGATCTCGAGATCAAACAAATGGAATCGGACTTTTT SGK196 protein kinase-like protein SgK196 TRCN0000001544 CCGGAGCCTGGAGATGAAAGATGATCTCGAGATCATCTTTCATCTCCAGGCTTTTTT SGK2 serum/glucocorticoid regulated kinase 2 TRCN0000002110 CCGGACTCCACCCTTCAACCCAAATCTCGAGATTTGGGTTGAAGGGTGGAGTTTTTT SGK2 serum/glucocorticoid regulated kinase 2 TRCN0000002111 CCGGTGAAGACACCACATCCACATTCTCGAGAATGTGGATGTGGTGTCTTCATTTTT SGK2 serum/glucocorticoid regulated kinase 2 TRCN0000002112 CCGGGCACTCCCTCAACATCATTTACTCGAGTAAATGATGTTGAGGGAGTGCTTTTT SGK2 serum/glucocorticoid regulated kinase 2 TRCN0000002113 CCGGGCTGGGAGATGTGGCTTATTTCTCGAGAAATAAGCCACATCTCCCAGCTTTTT SGK2 serum/glucocorticoid regulated kinase 2 TRCN0000010682 CCGGCTCAAGTGCATTCCTGGGATTCTCGAGAATCCCAGGAATGCACTTGAGTTTTT SGK223 homolog of rat pragma of Rnd2 TRCN0000037424 CCGGGCACAACTGGATCGACATGAACTCGAGTTCATGTCGATCCAGTTGTGCTTTTTG SGK223 homolog of rat pragma of Rnd2 TRCN0000037425 CCGGCGGAGGATGACAGTGATCAAACTCGAGTTTGATCACTGTCATCCTCCGTTTTTG SGK223 homolog of rat pragma of Rnd2 TRCN0000037428 CCGGGTACCGCAAGTTCGATGAGTTCTCGAGAACTCATCGAACTTGCGGTACTTTTTG SGK223 homolog of rat pragma of Rnd2 TRCN0000199835 CCGGGAGTCGTCAGTGCCGGATAGACTCGAGTCTATCCGGCACTGACGACTCTTTTTTG SGK223 homolog of rat pragma of Rnd2 TRCN0000037426 CCGGCGCTCTTCAAGCTGACTTGTACTCGAGTACAAGTCAGCTTGAAGAGCGTTTTTG SGK269 KIAA2002 protein TRCN0000196723 CCGGGCATAGAACATGTGCACATAACTCGAGTTATGTGCACATGTTCTATGCTTTTTTG SGK269 KIAA2002 protein TRCN0000199724 CCGGGCCATGTTCCTAAGCCTTATGCTCGAGCATAAGGCTTAGGAACATGGCTTTTTTG SGK269 KIAA2002 protein TRCN0000195001 CCGGCCCTGTTAAGTCACCTAATTTCTCGAGAAATTAGGTGACTTAACAGGGTTTTTTG

190 Supplement

SGK269 KIAA2002 protein TRCN0000195688 CCGGCCTAAGCGCTGGATATCATTTCTCGAGAAATGATATCCAGCGCTTAGGTTTTTTG SGK269 KIAA2002 protein TRCN0000197185 CCGGGAAGATCTCTTCCAGACTTTCCTCGAGGAAAGTCTGGAAGAGATCTTCTTTTTTG serum/glucocorticoid regulated kinase family, SGK3 TRCN0000001517 CCGGGCGAGACCCTAGTTAAGAGAACTCGAGTTCTCTTAACTAGGGTCTCGCTTTTT member 3 serum/glucocorticoid regulated kinase family, SGK3 TRCN0000001518 CCGGGCAGGACTAAACGAATTCATTCTCGAGAATGAATTCGTTTAGTCCTGCTTTTT member 3 serum/glucocorticoid regulated kinase family, SGK3 TRCN0000001519 CCGGGAACGTAATGTGCTCTTGAAACTCGAGTTTCAAGAGCACATTACGTTCTTTTT member 3 serum/glucocorticoid regulated kinase family, SGK3 TRCN0000001520 CCGGGCATTCGTTGGTTTCTCTTATCTCGAGATAAGAGAAACCAACGAATGCTTTTT member 3 serum/glucocorticoid regulated kinase family, SGK3 TRCN0000001521 CCGGGCCGAGATGTTGCTGAAATGTCTCGAGACATTTCAGCAACATCTCGGCTTTTT member 3 uncharacterized serine/threonine-protein kinase SGK494 TRCN0000002410 CCGGGAGATGTGAAGATGGAGAATACTCGAGTATTCTCCATCTTCACATCTCTTTTT SgK494 uncharacterized serine/threonine-protein kinase SGK494 TRCN0000002411 CCGGTAATTGCTGTGGATACTGTAACTCGAGTTACAGTATCCACAGCAATTATTTTT SgK494 uncharacterized serine/threonine-protein kinase SGK494 TRCN0000002412 CCGGAGTTTCCCATTAGGCCCATTACTCGAGTAATGGGCCTAATGGGAAACTTTTTT SgK494 uncharacterized serine/threonine-protein kinase SGK494 TRCN0000002413 CCGGGAGTTTCCCATTAGGCCCATTCTCGAGAATGGGCCTAATGGGAAACTCTTTTT SgK494 uncharacterized serine/threonine-protein kinase SGK494 TRCN0000194930 CCGGCACTAAATATTCAGCTGATTGCTCGAGCAATCAGCTGAATATTTAGTGTTTTTTG SgK494 SIK1 salt-inducible kinase 1 TRCN0000199404 CCGGCTGACAGTTGTCTGACCTTCTCTCGAGAGAAGGTCAGACAACTGTCAGTTTTTTG SIK1 salt-inducible kinase 1 TRCN0000199588 CCGGGCGCGTGCATTGATTACTATCCTCGAGGATAGTAATCAATGCACGCGCTTTTTTG SIK1 salt-inducible kinase 1 TRCN0000199637 CCGGGTTCAGCTGATGAAGCTTCTGCTCGAGCAGAAGCTTCATCAGCTGAACTTTTTTG SIK1 salt-inducible kinase 1 TRCN0000001362 CCGGGAGAAATGTATGCCAAATGATCTCGAGATCATTTGGCATACATTTCTCTTTTT SIK1 salt-inducible kinase 1 TRCN0000001363 CCGGCCATCCACACATCATAAAGCTCTCGAGAGCTTTATGATGTGTGGATGGTTTTT SIK2 salt-inducible kinase 2 TRCN0000037494 CCGGCCCTCACATAATCAAACTTTACTCGAGTAAAGTTTGATTATGTGAGGGTTTTTG SIK2 salt-inducible kinase 2 TRCN0000037495 CCGGGCTGGATAACAACATGAATATCTCGAGATATTCATGTTGTTATCCAGCTTTTTG SIK2 salt-inducible kinase 2 TRCN0000037496 CCGGGCTCATGCCTTTGAGGCATTTCTCGAGAAATGCCTCAAAGGCATGAGCTTTTTG SIK2 salt-inducible kinase 2 TRCN0000037497 CCGGCCGTATTTCATGTCAGAAGATCTCGAGATCTTCTGACATGAAATACGGTTTTTG SIK2 salt-inducible kinase 2 TRCN0000037498 CCGGGCAGTTGTTGTATGAACAAATCTCGAGATTTGTTCATACAACAACTGCTTTTTG SIK3 SIK family kinase 3 TRCN0000037449 CCGGCCCAACTTTGACAGGTTAATACTCGAGTATTAACCTGTCAAAGTTGGGTTTTTG SIK3 SIK family kinase 3 TRCN0000037450 CCGGCGGAACATTGTTCATCGTGATCTCGAGATCACGATGAACAATGTTCCGTTTTTG SIK3 SIK family kinase 3 TRCN0000037451 CCGGGCTATCCATCTACGTGTATTACTCGAGTAATACACGTAGATGGATAGCTTTTTG SIK3 SIK family kinase 3 TRCN0000037452 CCGGGCCAGGCTTTATCTTATCAAACTCGAGTTTGATAAGATAAAGCCTGGCTTTTTG SIK3 SIK family kinase 3 TRCN0000194845 CCGGCAGATGCCTATGATCACTATACTCGAGTATAGTGATCATAGGCATCTGTTTTTTG SLK STE20-like kinase (yeast) TRCN0000000894 CCGGTGGCTCTTTCAGTATGTCATTCTCGAGAATGACATACTGAAAGAGCCATTTTT SLK STE20-like kinase (yeast) TRCN0000000895 CCGGCCACCACTGATGAACCTGAAACTCGAGTTTCAGGTTCATCAGTGGTGGTTTTT SLK STE20-like kinase (yeast) TRCN0000000896 CCGGCGAGAAGGAAACAGAGCAAATCTCGAGATTTGCTCTGTTTCCTTCTCGTTTTT SLK STE20-like kinase (yeast) TRCN0000000897 CCGGCCATGACAGAACAGCAGTAATCTCGAGATTACTGCTGTTCTGTCATGGTTTTT SLK STE20-like kinase (yeast) TRCN0000000898 CCGGGCGTTACAATCAAAGACTTATCTCGAGATAAGTCTTTGATTGTAACGCTTTTT SMG1 homolog, phosphatidylinositol 3-kinase-related SMG1 TRCN0000037413 CCGGGCACTGTAACTACGGCTACAACTCGAGTTGTAGCCGTAGTTACAGTGCTTTTTG kinase (C. elegans) SMG1 homolog, phosphatidylinositol 3-kinase-related SMG1 TRCN0000037409 CCGGGCCGAGATGTTGATCCGAATACTCGAGTATTCGGATCAACATCTCGGCTTTTTG kinase (C. elegans) SMG1 homolog, phosphatidylinositol 3-kinase-related SMG1 TRCN0000037410 CCGGGCCATGACTAACACTGAAATTCTCGAGAATTTCAGTGTTAGTCATGGCTTTTTG kinase (C. elegans) SMG1 homolog, phosphatidylinositol 3-kinase-related SMG1 TRCN0000037411 CCGGCCCAATTAGAAGCCATCTCATCTCGAGATGAGATGGCTTCTAATTGGGTTTTTG kinase (C. elegans) SMG1 homolog, phosphatidylinositol 3-kinase-related SMG1 TRCN0000037412 CCGGCGGCAAATCATATTTCCAGAACTCGAGTTCTGGAAATATGATTTGCCGTTTTTG kinase (C. elegans) SNRK SNF related kinase TRCN0000001953 CCGGCACTGAATTGGAACGGATAAACTCGAGTTTATCCGTTCCAATTCAGTGTTTTT SNRK SNF-1 related kinase TRCN0000195348 CCGGCCCAAGTTGAGCAGGTTAAAGCTCGAGCTTTAACCTGCTCAACTTGGGTTTTTTG SNRK SNF related kinase TRCN0000001951 CCGGGAGCAGGTTAAAGATGAATATCTCGAGATATTCATCTTTAACCTGCTCTTTTT SNRK SNF related kinase TRCN0000001952 CCGGGCACTTAACCTAGAGAGAGAACTCGAGTTCTCTCTCTAGGTTAAGTGCTTTTT SNRK SNF related kinase TRCN0000001954 CCGGGCAATATCAAGGCCCAGTTTACTCGAGTAAACTGGGCCTTGATATTGCTTTTT v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene SRC TRCN0000038149 CCGGGCTCGGCTCATTGAAGACAATCTCGAGATTGTCTTCAATGAGCCGAGCTTTTTG homolog (avian) v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene SRC TRCN0000038150 CCGGGACAGACCTGTCCTTCAAGAACTCGAGTTCTTGAAGGACAGGTCTGTCTTTTTG homolog (avian) v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene SRC TRCN0000038151 CCGGGTCATGAAGAAGCTGAGGCATCTCGAGATGCCTCAGCTTCTTCATGACTTTTTG homolog (avian) v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene SRC TRCN0000038152 CCGGTCAGAGCGGTTACTGCTCAATCTCGAGATTGAGCAGTAACCGCTCTGATTTTTG homolog (avian) v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene SRC TRCN0000195339 CCGGCATCCTCAGGAACCAACAATTCTCGAGAATTGTTGGTTCCTGAGGATGTTTTTTG homolog (avian) src-related kinase lacking C-terminal regulatory SRMS TRCN0000000938 CCGGCGGCCAATTATCGTGTCTTCTCTCGAGAGAAGACACGATAATTGGCCGTTTTT tyrosine and N-terminal myristylation sites src-related kinase lacking C-terminal regulatory SRMS TRCN0000000939 CCGGCTACTACAAGGCCAACTGGAACTCGAGTTCCAGTTGGCCTTGTAGTAGTTTTT tyrosine and N-terminal myristylation sites src-related kinase lacking C-terminal regulatory SRMS TRCN0000000940 CCGGAGGTCATCAAGTCAGCCAACACTCGAGTGTTGGCTGACTTGATGACCTTTTTT tyrosine and N-terminal myristylation sites src-related kinase lacking C-terminal regulatory SRMS TRCN0000000941 CCGGCTATGAAGGGATGACCAACCACTCGAGTGGTTGGTCATCCCTTCATAGTTTTT tyrosine and N-terminal myristylation sites src-related kinase lacking C-terminal regulatory SRMS TRCN0000000942 CCGGCAATTATCGTGTCTTCTCCCACTCGAGTGGGAGAAGACACGATAATTGTTTTT tyrosine and N-terminal myristylation sites SRPK1 SFRS protein kinase 1 TRCN0000001232 CCGGGAACAACACATTAGCCAACTTCTCGAGAAGTTGGCTAATGTGTTGTTCTTTTT

191 Supplement

SRPK1 SFRS protein kinase 1 TRCN0000001228 CCGGCCATAACTAAAGGATCAGGATCTCGAGATCCTGATCCTTTAGTTATGGTTTTT SRPK1 SFRS protein kinase 1 TRCN0000001229 CCGGCCAGGCAGAATTACTAGAGAACTCGAGTTCTCTAGTAATTCTGCCTGGTTTTT SRPK1 SFRS protein kinase 1 TRCN0000001230 CCGGGTGGCAATGAAAGTAGTTAAACTCGAGTTTAACTACTTTCATTGCCACTTTTT SRPK1 SFRS protein kinase 1 TRCN0000001231 CCGGCAGACCCTAATGATCCAAATACTCGAGTATTTGGATCATTAGGGTCTGTTTTT SRPK2 SFRS protein kinase 2 TRCN0000006274 CCGGGCACCCTGTAAATGTTACTTTCTCGAGAAAGTAACATTTACAGGGTGCTTTTT SRPK2 SFRS protein kinase 2 TRCN0000006277 CCGGCGTTGTGTGAAGAGTATCATTCTCGAGAATGATACTCTTCACACAACGTTTTT SRPK2 SFRS protein kinase 2 TRCN0000006278 CCGGGCAACGGGAGATTATTTGTTTCTCGAGAAACAAATAATCTCCCGTTGCTTTTT SRPK2 SFRS protein kinase 2 TRCN0000006275 CCGGGCCGGTATCATGTTATTAGAACTCGAGTTCTAATAACATGATACCGGCTTTTT SRPK2 SFRS protein kinase 2 TRCN0000006276 CCGGCCTGAGGAATATAATCTTGATCTCGAGATCAAGATTATATTCCTCAGGTTTTT SRPK3 SFRS protein kinase 3 TRCN0000007066 CCGGCCACACCAAGTGCAAGATCATCTCGAGATGATCTTGCACTTGGTGTGGTTTTT SRPK3 SFRS protein kinase 3 TRCN0000007067 CCGGGAGACCATTGTCCAGCTCATTCTCGAGAATGAGCTGGACAATGGTCTCTTTTT SRPK3 SFRS protein kinase 3 TRCN0000007068 CCGGTGCAGATAAGATCAAGATCAACTCGAGTTGATCTTGATCTTATCTGCATTTTT SRPK3 SFRS protein kinase 3 TRCN0000011066 CCGGCTCCAGCTCTCCGTGCCTTAACTCGAGTTAAGGCACGGAGAGCTGGAGTTTTT SRPK3 SFRS protein kinase 3 TRCN0000011067 CCGGGCCACACAGTTCAGCGCCTTTCTCGAGAAAGGCGCTGAACTGTGTGGCTTTTT STK10 serine/threonine kinase 10 TRCN0000003135 CCGGGTAGAGCACGAAACCCAGAAACTCGAGTTTCTGGGTTTCGTGCTCTACTTTTT STK10 serine/threonine kinase 10 TRCN0000003136 CCGGACAGGAAATCAACGCCAAGAACTCGAGTTCTTGGCGTTGATTTCCTGTTTTTT STK10 serine/threonine kinase 10 TRCN0000003137 CCGGAGTCCTCTCCTGTTTGCGAAACTCGAGTTTCGCAAACAGGAGAGGACTTTTTT STK10 serine/threonine kinase 10 TRCN0000003139 CCGGCCTGAAGATAGCCCTGGATAACTCGAGTTATCCAGGGCTATCTTCAGGTTTTT STK10 serine/threonine kinase 10 TRCN0000196974 CCGGGCAGCTCAAAGACCAGTACTTCTCGAGAAGTACTGGTCTTTGAGCTGCTTTTTTG STK11 serine/threonine kinase 11 TRCN0000000408 CCGGGCCAACGTGAAGAAGGAAATTCTCGAGAATTTCCTTCTTCACGTTGGCTTTTT STK11 serine/threonine kinase 11 TRCN0000000409 CCGGGATCCTCAAGAAGAAGAAGTTCTCGAGAACTTCTTCTTCTTGAGGATCTTTTT STK11 serine/threonine kinase 11 TRCN0000000410 CCGGGAAGAAGAAGTTGCGAAGGATCTCGAGATCCTTCGCAACTTCTTCTTCTTTTT STK11 serine/threonine kinase 11 TRCN0000000411 CCGGCATCTACACTCAGGACTTCACCTCGAGGTGAAGTCCTGAGTGTAGATGTTTTT STK11 serine/threonine kinase 11 TRCN0000000407 CCGGGAGTGTGCGGTCAATATTTATCTCGAGATAAATATTGACCGCACACTCTTTTT STK16 serine/threonine kinase 16 TRCN0000000695 CCGGGAGCAGGAGAATGTGTAACAACTCGAGTTGTTACACATTCTCCTGCTCTTTTT STK16 serine/threonine kinase 16 TRCN0000000697 CCGGCTGCGTGCTATATGCCATGATCTCGAGATCATGGCATATAGCACGCAGTTTTT STK16 serine/threonine kinase 16 TRCN0000000698 CCGGCTAGTGGAAGGGTTACATGATCTCGAGATCATGTAACCCTTCCACTAGTTTTT STK16 serine/threonine kinase 16 TRCN0000000699 CCGGAGGTACGCTGTGGAATGAGATCTCGAGATCTCATTCCACAGCGTACCTTTTTT STK16 serine/threonine kinase 16 TRCN0000000696 CCGGGCTGCTGCTACCATTCTTCAACTCGAGTTGAAGAATGGTAGCAGCAGCTTTTT STK17A serine/threonine kinase 17a TRCN0000000974 CCGGCCTATAAGCATGGCAACAGATCTCGAGATCTGTTGCCATGCTTATAGGTTTTT STK17A serine/threonine kinase 17a TRCN0000000975 CCGGGAGATTGCTGTACTTGAACTACTCGAGTAGTTCAAGTACAGCAATCTCTTTTT STK17A serine/threonine kinase 17a TRCN0000000976 CCGGCAGAGCAGTATTCAAGAGCCTCTCGAGAGGCTCTTGAATACTGCTCTGTTTTT STK17A serine/threonine kinase 17a TRCN0000010569 CCGGTGTGGAGCATTGGAGTGTTAACTCGAGTTAACACTCCAATGCTCCACATTTTT STK17A serine/threonine kinase 17a TRCN0000000973 CCGGCTAGTAAGAGAGGTGGTAATTCTCGAGAATTACCACCTCTCTTACTAGTTTTT STK17B serine/threonine kinase 17b TRCN0000000780 CCGGCCAGTGAGATTATGATTTGTACTCGAGTACAAATCATAATCTCACTGGTTTTT STK17B serine/threonine kinase 17b TRCN0000000781 CCGGGATAGAGAAGACAAAGAGAATCTCGAGATTCTCTTTGTCTTCTCTATCTTTTT STK17B serine/threonine kinase 17b TRCN0000000782 CCGGACTTCTAAATCCTCCTGTAATCTCGAGATTACAGGAGGATTTAGAAGTTTTTT STK17B serine/threonine kinase 17b TRCN0000010155 CCGGGATAGAGAAGACAAAGAGAATCTCGAGATTCTCTTTGTCTTCTCTATCTTTTT STK17B serine/threonine kinase 17b TRCN0000010156 CCGGCTACTAACTACAACTCCTCAACTCGAGTTGAGGAGTTGTAGTTAGTAGTTTTT STK19 serine/threonine kinase 19 TRCN0000010139 CCGGCCCGGAGACCTTTGGAGTTAACTCGAGTTAACTCCAAAGGTCTCCGGGTTTTT STK19 serine/threonine kinase 19 TRCN0000010140 CCGGTGTGATGGCCGACCGTATGCTCTCGAGAGCATACGGTCGGCCATCACATTTTT STK19 serine/threonine kinase 19 TRCN0000010141 CCGGGGACCAAATGACACAGACCTTCTCGAGAAGGTCTGTGTCATTTGGTCCTTTTT STK19 serine/threonine kinase 19 TRCN0000010149 CCGGGCATCTCTACCACTTCAGGAACTCGAGTTCCTGAAGTGGTAGAGATGCTTTTT STK19 serine/threonine kinase 19 TRCN0000010150 CCGGGCCTGGAGCTGGGAGATTCATCTCGAGATGAATCTCCCAGCTCCAGGCTTTTT STK24 serine/threonine kinase 24 (STE20 homolog, yeast) TRCN0000000641 CCGGGCAGGGTTTGTCATTAATAATCTCGAGATTATTAATGACAAACCCTGCTTTTT STK24 serine/threonine kinase 24 (STE20 homolog, yeast) TRCN0000000643 CCGGGACAGGTACAAGAGATGGAAGCTCGAGCTTCCATCTCTTGTACCTGTCTTTTT STK24 serine/threonine kinase 24 (STE20 homolog, yeast) TRCN0000000644 CCGGTGGACAGAAATAAGATGAAAGCTCGAGCTTTCATCTTATTTCTGTCCATTTTT STK24 serine/threonine kinase 24 (STE20 homolog, yeast) TRCN0000000645 CCGGTGCAGAGTTGAAGGAGAAGAGCTCGAGCTCTTCTCCTTCAACTCTGCATTTTT STK24 serine/threonine kinase 24 (STE20 homolog, yeast) TRCN0000194713 CCGGCAATTATTTCTCCTCTGTTTGCTCGAGCAAACAGAGGAGAAATAATTGTTTTTTG STK25 serine/threonine kinase 25 (STE20 homolog, yeast) TRCN0000006269 CCGGGCTCATAAGTACTTGTGTCATCTCGAGATGACACAAGTACTTATGAGCTTTTT STK25 serine/threonine kinase 25 (STE20 homolog, yeast) TRCN0000006270 CCGGGCAGATTAAGAGGAACACATTCTCGAGAATGTGTTCCTCTTAATCTGCTTTTT STK25 serine/threonine kinase 25 (STE20 homolog, yeast) TRCN0000006272 CCGGCTGGATTATCTGCACTCCGAACTCGAGTTCGGAGTGCAGATAATCCAGTTTTT STK25 serine/threonine kinase 25 (STE20 homolog, yeast) TRCN0000006273 CCGGGCTCCTGAAGCACAAGTTCATCTCGAGATGAACTTGTGCTTCAGGAGCTTTTT STK25 serine/threonine kinase 25 (STE20 homolog, yeast) TRCN0000199175 CCGGCCTGAGGAGCTCTTCACCAAGCTCGAGCTTGGTGAAGAGCTCCTCAGGTTTTTTG STK3 serine/threonine kinase 3 (STE20 homolog, yeast) TRCN0000002173 CCGGGTCATTTCCTAAGCTACATATCTCGAGATATGTAGCTTAGGAAATGACTTTTT STK3 serine/threonine kinase 3 (STE20 homolog, yeast) TRCN0000002175 CCGGGAATGCCAAACCTGTATCAATCTCGAGATTGATACAGGTTTGGCATTCTTTTT STK3 serine/threonine kinase 3 (STE20 homolog, yeast) TRCN0000002177 CCGGCGGATGAAGATGAGCTGGATTCTCGAGAATCCAGCTCATCTTCATCCGTTTTT STK3 serine/threonine kinase 3 (STE20 homolog, yeast) TRCN0000002174 CCGGGCAATACACAAGGAATCCGGTCTCGAGACCGGATTCCTTGTGTATTGCTTTTT STK3 serine/threonine kinase 3 (STE20 homolog, yeast) TRCN0000002176 CCGGCCACAAATCCACCACCAACATCTCGAGATGTTGGTGGTGGATTTGTGGTTTTT STK31 serine/threonine kinase 31 TRCN0000003275 CCGGGCAGGATTTGTCAGTCTCTTTCTCGAGAAAGAGACTGACAAATCCTGCTTTTT STK31 serine/threonine kinase 31 TRCN0000003276 CCGGCCTCTGTAGCTTGATATGTTACTCGAGTAACATATCAAGCTACAGAGGTTTTT STK31 serine/threonine kinase 31 TRCN0000003277 CCGGGCTATCCATTAAGAAGACATTCTCGAGAATGTCTTCTTAATGGATAGCTTTTT

192 Supplement

STK31 serine/threonine kinase 31 TRCN0000196555 CCGGGACTTTAATTTAGGGTCTAACCTCGAGGTTAGACCCTAAATTAAAGTCTTTTTTG STK31 serine/threonine kinase 31 TRCN0000196648 CCGGGCAGGCAATCTTATAACATTTCTCGAGAAATGTTATAAGATTGCCTGCTTTTTTG STK32A serine/threonine kinase 32A TRCN0000007127 CCGGGCACCCTTTCCTGGTTAATTTCTCGAGAAATTAACCAGGAAAGGGTGCTTTTT STK32A serine/threonine kinase 32A TRCN0000007128 CCGGGAGCGCAATGAAGTGAGAAATCTCGAGATTTCTCACTTCATTGCGCTCTTTTT STK32A serine/threonine kinase 32A TRCN0000007129 CCGGGAAGAATGATACCAAGAAGATCTCGAGATCTTCTTGGTATCATTCTTCTTTTT STK32A serine/threonine kinase 32A TRCN0000007130 CCGGGCAACAGAACGTCCACTTCAACTCGAGTTGAAGTGGACGTTCTGTTGCTTTTT STK32A serine/threonine kinase 32A TRCN0000007131 CCGGTCCTGGTTAATTTGTGGTATTCTCGAGAATACCACAAATTAACCAGGATTTTT STK32B serine/threonine kinase 32B TRCN0000002273 CCGGCCAAAGCAATCAAACCGTCATCTCGAGATGACGGTTTGATTGCTTTGGTTTTT STK32B serine/threonine kinase 32B TRCN0000002274 CCGGCAGAAGCGAGACACTAAGAAACTCGAGTTTCTTAGTGTCTCGCTTCTGTTTTT STK32B serine/threonine kinase 32B TRCN0000002275 CCGGGATCCCACATTTGAGCTTGAACTCGAGTTCAAGCTCAAATGTGGGATCTTTTT STK32B serine/threonine kinase 32B TRCN0000002276 CCGGCGGTAGTGAAAGGAGCAGAAACTCGAGTTTCTGCTCCTTTCACTACCGTTTTT STK32B serine/threonine kinase 32B TRCN0000194905 CCGGCCATGTCATCTCTTAGATTTCCTCGAGGAAATCTAAGAGATGACATGGTTTTTTG STK32C serine/threonine kinase 32C TRCN0000007043 CCGGCGACTTCAACATTGCCACCATCTCGAGATGGTGGCAATGTTGAAGTCGTTTTT STK32C serine/threonine kinase 32C TRCN0000007044 CCGGCAGTCCGAGAATGACTATCTTCTCGAGAAGATAGTCATTCTCGGACTGTTTTT STK32C serine/threonine kinase 32C TRCN0000007045 CCGGCCTGACAACATTCTCCTGGATCTCGAGATCCAGGAGAATGTTGTCAGGTTTTT STK32C serine/threonine kinase 32C TRCN0000007046 CCGGGCACAAGAAGAAGAAGCGTCTCTCGAGAGACGCTTCTTCTTCTTGTGCTTTTT STK32C serine/threonine kinase 32C TRCN0000199340 CCGGCCTGTTTCAGTGGAGCAAGTGCTCGAGCACTTGCTCCACTGAAACAGGTTTTTTG STK33 serine/threonine kinase 33 TRCN0000002077 CCGGCCAAGGAACAGCAACCAAGTACTCGAGTACTTGGTTGCTGTTCCTTGGTTTTT STK33 serine/threonine kinase 33 TRCN0000002078 CCGGGCAGTTCAAGTTTCACATCTACTCGAGTAGATGTGAAACTTGAACTGCTTTTT STK33 serine/threonine kinase 33 TRCN0000002079 CCGGGAACACATCATACATCTGGAACTCGAGTTCCAGATGTATGATGTGTTCTTTTT STK33 serine/threonine kinase 33 TRCN0000195277 CCGGCGTCGTAATGTACATGTTATTCTCGAGAATAACATGTACATTACGACGTTTTTTG STK33 serine/threonine kinase 33 TRCN0000196452 CCGGGCTAAGGAACTACTAGATAACCTCGAGGTTATCTAGTAGTTCCTTAGCTTTTTTG STK35 serine/threonine kinase 35 TRCN0000002091 CCGGGTGAATGTGAATAAGTACTGGCTCGAGCCAGTACTTATTCACATTCACTTTTT STK35 serine/threonine kinase 35 TRCN0000002092 CCGGCCTGCTATCTCTGGTTTGTCACTCGAGTGACAAACCAGAGATAGCAGGTTTTT STK35 serine/threonine kinase 35 TRCN0000002094 CCGGTGAACTTGAAACCAGAATGGACTCGAGTCCATTCTGGTTTCAAGTTCATTTTT STK35 serine/threonine kinase 35 TRCN0000002095 CCGGGAGGGCAATCAAGACAACAAACTCGAGTTTGTTGTCTTGATTGCCCTCTTTTT STK35 serine/threonine kinase 35 TRCN0000199133 CCGGCGGCGTGGTTTATGAGGCAGTCTCGAGACTGCCTCATAAACCACGCCGTTTTTTG serine/threonine kinase 36, fused homolog STK36 TRCN0000006986 CCGGGCCAGAGAAGAGTCCTTTCTTCTCGAGAAGAAAGGACTCTTCTCTGGCTTTTT (Drosophila) serine/threonine kinase 36, fused homolog STK36 TRCN0000006988 CCGGCGGGATCTTAGCCTCAGAATTCTCGAGAATTCTGAGGCTAAGATCCCGTTTTT (Drosophila) serine/threonine kinase 36, fused homolog STK36 TRCN0000006987 CCGGCCGAGATATGAAGCCTCAGAACTCGAGTTCTGAGGCTTCATATCTCGGTTTTT (Drosophila) serine/threonine kinase 36, fused homolog STK36 TRCN0000006990 CCGGCCCAGAACTTCAGGTCCTAAACTCGAGTTTAGGACCTGAAGTTCTGGGTTTTT (Drosophila) STK38 serine/threonine kinase 38 TRCN0000010215 CCGGGCTCATCGGCTACCCACCTTTCTCGAGAAAGGTGGGTAGCCGATGAGCTTTTT STK38 serine/threonine kinase 38 TRCN0000010216 CCGGGAGACTGACTACAAGAACAAACTCGAGTTTGTTCTTGTAGTCAGTCTCTTTTT STK38 serine/threonine kinase 38 TRCN0000196524 CCGGGTATTAGCCATAGACTCTATTCTCGAGAATAGAGTCTATGGCTAATACTTTTTTG STK38 serine/threonine kinase 38 TRCN0000199774 CCGGGCCTGCAACTTAGGCGGATTGCTCGAGCAATCCGCCTAAGTTGCAGGCTTTTTTG STK38 serine/threonine kinase 38 TRCN0000010214 CCGGCAGCAAGGGCCATGTGAAACTCTCGAGAGTTTCACATGGCCCTTGCTGTTTTT STK38L serine/threonine kinase 38 like TRCN0000002053 CCGGGAAGAAGGATTAGCAGATGAACTCGAGTTCATCTGCTAATCCTTCTTCTTTTT STK38L serine/threonine kinase 38 like TRCN0000002054 CCGGAGAAGAAAGATACAGGCCATACTCGAGTATGGCCTGTATCTTTCTTCTTTTTT STK38L serine/threonine kinase 38 like TRCN0000002055 CCGGCCAGCAGCAATCCCTATAGAACTCGAGTTCTATAGGGATTGCTGCTGGTTTTT STK38L serine/threonine kinase 38 like TRCN0000002056 CCGGTGGGAGTGATTATGTATGAAACTCGAGTTTCATACATAATCACTCCCATTTTT STK38L serine/threonine kinase 38 like TRCN0000002057 CCGGCCCTGGAGTTAATAGAGTGATCTCGAGATCACTCTATTAACTCCAGGGTTTTT serine threonine kinase 39 (STE20/SPS1 homolog, STK39 TRCN0000001004 CCGGCCCTGCTTGACTGTATATTATCTCGAGATAATATACAGTCAAGCAGGGTTTTT yeast) serine threonine kinase 39 (STE20/SPS1 homolog, STK39 TRCN0000001005 CCGGCCTGATGAAGTGAAGCTGATTCTCGAGAATCAGCTTCACTTCATCAGGTTTTT yeast) serine threonine kinase 39 (STE20/SPS1 homolog, STK39 TRCN0000001006 CCGGCGGTCAGATTCACAGGGATTTCTCGAGAAATCCCTGTGAATCTGACCGTTTTT yeast) serine threonine kinase 39 (STE20/SPS1 homolog, STK39 TRCN0000001008 CCGGCTACACAGAAACGGTCAGATTCTCGAGAATCTGACCGTTTCTGTGTAGTTTTT yeast) serine threonine kinase 39 (STE20/SPS1 homolog, STK39 TRCN0000194826 CCGGCCAGTATGGATGAACTATTAACTCGAGTTAATAGTTCATCCATACTGGTTTTTTG yeast) STK4 serine/threonine kinase 4 TRCN0000001622 CCGGAGTTGAGTGATAGCTGGGAAACTCGAGTTTCCCAGCTATCACTCAACTTTTTT STK4 serine/threonine kinase 4 TRCN0000001623 CCGGCCGGCCAGATTGTTGCTATTACTCGAGTAATAGCAACAATCTGGCCGGTTTTT STK4 serine/threonine kinase 4 TRCN0000001624 CCGGGCCCTCATGTAGTCAAATATTCTCGAGAATATTTGACTACATGAGGGCTTTTT STK4 serine/threonine kinase 4 TRCN0000194840 CCGGCCACAACATCTACCAGATATACTCGAGTATATCTGGTAGATGTTGTGGTTTTTTG STK4 serine/threonine kinase 4 TRCN0000195454 CCGGCCAGAGCTATGGTCAGATAACCTCGAGGTTATCTGACCATAGCTCTGGTTTTTTG STK40 serine/threonine kinase 40 TRCN0000001816 CCGGCCGGATGGTTAAGAAGATGAACTCGAGTTCATCTTCTTAACCATCCGGTTTTT STK40 serine/threonine kinase 40 TRCN0000194815 CCGGCCTAGATAACTAATCTGCTTTCTCGAGAAAGCAGATTAGTTATCTAGGTTTTTTG STK40 serine/threonine kinase 40 TRCN0000195360 CCGGCAGTGCCCTTGCCTCATAATACTCGAGTATTATGAGGCAAGGGCACTGTTTTTTG STK40 serine/threonine kinase 40 TRCN0000199941 CCGGGCAGGAGCTCTTCCGCAAGATCTCGAGATCTTGCGGAAGAGCTCCTGCTTTTTTG STK40 serine/threonine kinase 40 TRCN0000001815 CCGGCCTATTGTAAAGAAACGGAAACTCGAGTTTCCGTTTCTTTACAATAGGTTTTT STRADA STE20-related kinase adaptor alpha TRCN0000007047 CCGGGCTGACTGATTGGGAAAGAAACTCGAGTTTCTTTCCCAATCAGTCAGCTTTTT STRADA STE20-related kinase adaptor alpha TRCN0000007049 CCGGCGTGACTGTACGGAGGATTAACTCGAGTTAATCCTCCGTACAGTCACGTTTTT STRADA STE20-related kinase adaptor alpha TRCN0000007050 CCGGCAGCAGAATCTCCAGGGTTATCTCGAGATAACCCTGGAGATTCTGCTGTTTTT

193 Supplement

STRADA protein kinase LYK5 TRCN0000195518 CCGGCAGCAACCTCAGCATGATAAGCTCGAGCTTATCATGCTGAGGTTGCTGTTTTTTG STRADA protein kinase LYK5 TRCN0000195667 CCGGCAAGTACAGTGTCAAGGTTCTCTCGAGAGAACCTTGACACTGTACTTGTTTTTTG STRADB STE20-related kinase adaptor beta TRCN0000007072 CCGGGCACTGGAGAATCTATTATTTCTCGAGAAATAATAGATTCTCCAGTGCTTTTT STRADB STE20-related kinase adaptor beta TRCN0000007073 CCGGCCAGTGGAACTCACACAGTAACTCGAGTTACTGTGTGAGTTCCACTGGTTTTT STRADB STE20-related kinase adaptor beta TRCN0000007074 CCGGGCCGTGATTCTATCCCACTTTCTCGAGAAAGTGGGATAGAATCACGGCTTTTT STRADB STE20-related kinase adaptor beta TRCN0000007076 CCGGGCTTTGGGTTATTTCTCCATTCTCGAGAATGGAGAAATAACCCAAAGCTTTTT amyotrophic lateral sclerosis 2 (juvenile) chromosome STRADB TRCN0000194701 CCGGCAGAGTACTATGACAAGGAAACTCGAGTTTCCTTGTCATAGTACTCTGTTTTTTG region, candidate 2 STYK1 serine/threonine/tyrosine kinase 1 TRCN0000001743 CCGGGTTGGTTACTATCTTCCTCATCTCGAGATGAGGAAGATAGTAACCAACTTTTT STYK1 serine/threonine/tyrosine kinase 1 TRCN0000001744 CCGGCGGGATGTGATGACTATGGATCTCGAGATCCATAGTCATCACATCCCGTTTTT STYK1 serine/threonine/tyrosine kinase 1 TRCN0000001746 CCGGCGCCTAGAAGCTGCCATTAAACTCGAGTTTAATGGCAGCTTCTAGGCGTTTTT STYK1 protein kinase STYK1 TRCN0000195207 CCGGCCAACTTTGTTGGTTACTATCCTCGAGGATAGTAACCAACAAAGTTGGTTTTTTG STYK1 protein kinase STYK1 TRCN0000195740 CCGGCAAGTATATCACATCGGAAAGCTCGAGCTTTCCGATGTGATATACTTGTTTTTTG SYK spleen tyrosine kinase TRCN0000003163 CCGGGCAGGCCATCATCAGTCAGAACTCGAGTTCTGACTGATGATGGCCTGCTTTTT SYK spleen tyrosine kinase TRCN0000003164 CCGGCGACAAAGACAAGACAGGGAACTCGAGTTCCCTGTCTTGTCTTTGTCGTTTTT SYK spleen tyrosine kinase TRCN0000003165 CCGGGCGCAATTACTACTATGACGTCTCGAGACGTCATAGTAGTAATTGCGCTTTTT SYK spleen tyrosine kinase TRCN0000003166 CCGGCGGGTGGAATAATCTCAAGAACTCGAGTTCTTGAGATTATTCCACCCGTTTTT SYK spleen tyrosine kinase TRCN0000003167 CCGGCCTTAGCATGTGACTCCTGAACTCGAGTTCAGGAGTCACATGCTAAGGTTTTT TAF1 RNA polymerase II, TATA box binding protein TAF1 TRCN0000006284 CCGGGTACAGTATCTGATCCTGAAACTCGAGTTTCAGGATCAGATACTGTACTTTTT (TBP)-associated factor, 250kDa TAF1 RNA polymerase II, TATA box binding protein TAF1 TRCN0000006285 CCGGCCTTCTAGCATGACTAGGAATCTCGAGATTCCTAGTCATGCTAGAAGGTTTTT (TBP)-associated factor, 250kDa TAF1 RNA polymerase II, TATA box binding protein TAF1 TRCN0000006286 CCGGGCTGCAAGCATTTGAGAACAACTCGAGTTGTTCTCAAATGCTTGCAGCTTTTT (TBP)-associated factor, 250kDa TAF1 RNA polymerase II, TATA box binding protein TAF1 TRCN0000006287 CCGGCCAATGGATTTAGAGACCATACTCGAGTATGGTCTCTAAATCCATTGGTTTTT (TBP)-associated factor, 250kDa TAF1 RNA polymerase II, TATA box binding protein TAF1 TRCN0000006288 CCGGGCCACTCTTGATGATGACAAACTCGAGTTTGTCATCATCAAGAGTGGCTTTTT (TBP)-associated factor, 250kDa TAF1 RNA polymerase II, TATA box binding protein TAF1L TRCN0000196373 CCGGGTTACTATATTCGGGAATTAGCTCGAGCTAATTCCCGAATATAGTAACTTTTTTG (TBP)-associated factor, 210kDa-like TAF1 RNA polymerase II, TATA box binding protein TAF1L TRCN0000037499 CCGGCCTTCTATTAAGACTAGGAATCTCGAGATTCCTAGTCTTAATAGAAGGTTTTTG (TBP)-associated factor, 210kDa-like TAF1 RNA polymerase II, TATA box binding protein TAF1L TRCN0000037500 CCGGCCCATTTACTTTAGCGGGTATCTCGAGATACCCGCTAAAGTAAATGGGTTTTTG (TBP)-associated factor, 210kDa-like TAF1 RNA polymerase II, TATA box binding protein TAF1L TRCN0000037501 CCGGCCACTGTTCATTGTGACTATTCTCGAGAATAGTCACAATGAACAGTGGTTTTTG (TBP)-associated factor, 210kDa-like TAF1 RNA polymerase II, TATA box binding protein TAF1L TRCN0000037502 CCGGCCAGCATTCAATTCCTGCTATCTCGAGATAGCAGGAATTGAATGCTGGTTTTTG (TBP)-associated factor, 210kDa-like TAOK1 TAO kinase 1 TRCN0000037524 CCGGCCCAAGTATCTCGTCACAAATCTCGAGATTTGTGACGAGATACTTGGGTTTTTG TAOK1 TAO kinase 1 TRCN0000037526 CCGGCGCCTCAGATTAGACAAAGATCTCGAGATCTTTGTCTAATCTGAGGCGTTTTTG TAOK1 TAO kinase 1 TRCN0000037527 CCGGGCCTAAGAGTTTGAAGTCTAACTCGAGTTAGACTTCAAACTCTTAGGCTTTTTG TAOK1 TAO kinase 1 TRCN0000037528 CCGGCGAGTGTCACTTCACAAATATCTCGAGATATTTGTGAAGTGACACTCGTTTTTG TAOK1 TAO kinase 1 TRCN0000194926 CCGGCGAGAACACTTTGCTACTATACTCGAGTATAGTAGCAAAGTGTTCTCGTTTTTTG TAOK2 TAO kinase 2 TRCN0000195627 CCGGCCATCAAGAAGATGTCCTACACTCGAGTGTAGGACATCTTCTTGATGGTTTTTTG TAOK2 TAO kinase 2 TRCN0000001932 CCGGCCACCGCTCTTTAACATGAATCTCGAGATTCATGTTAAAGAGCGGTGGTTTTT TAOK2 TAO kinase 2 TRCN0000001933 CCGGACTCCCACAACATGATCCATACTCGAGTATGGATCATGTTGTGGGAGTTTTTT TAOK2 TAO kinase 2 TRCN0000001934 CCGGCACCTCTCACAGCTCCATTATCTCGAGATAATGGAGCTGTGAGAGGTGTTTTT TAOK2 TAO kinase 2 TRCN0000001935 CCGGTACCACATTGCACAGAACGAACTCGAGTTCGTTCTGTGCAATGTGGTATTTTT TAOK3 TAO kinase 3 TRCN0000001525 CCGGCCGTCTCTTCTATTCACAGTACTCGAGTACTGTGAATAGAAGAGACGGTTTTT TAOK3 TAO kinase 3 TRCN0000001528 CCGGGAAAGGCAAGAGCGAGAGATTCTCGAGAATCTCTCGCTCTTGCCTTTCTTTTT TAOK3 TAO kinase 3 TRCN0000001529 CCGGAGCGAGAGAATAAAGAACCTACTCGAGTAGGTTCTTTATTCTCTCGCTTTTTT TAOK3 TAO kinase 3 TRCN0000001526 CCGGGCAGCAACCATTCCATTCCAACTCGAGTTGGAATGGAATGGTTGCTGCTTTTT TAOK3 TAO kinase 3 TRCN0000001527 CCGGGAGTACAATAAGAGGCGAGAACTCGAGTTCTCGCCTCTTATTGTACTCTTTTT TBCK TBC1 domain containing kinase TRCN0000195579 CCGGGCCACATAAAGCCCAAGAAATCTCGAGATTTCTTGGGCTTTATGTGGCTTTTTTG TBCK TBC1 domain containing kinase TRCN0000007077 CCGGGCAAGAAACTTGACTCTACATCTCGAGATGTAGAGTCAAGTTTCTTGCTTTTT TBCK TBC1 domain containing kinase TRCN0000007078 CCGGGCATGGTTGTTTGGACATTATCTCGAGATAATGTCCAAACAACCATGCTTTTT TBCK TBC1 domain containing kinase TRCN0000007079 CCGGCCAGCTAAGAAATAGATTGAACTCGAGTTCAATCTATTTCTTAGCTGGTTTTT TBCK TBC1 domain containing kinase TRCN0000007080 CCGGCGGAATAGTGAAGACTTTATTCTCGAGAATAAAGTCTTCACTATTCCGTTTTT TBK1 TANK-binding kinase 1 TRCN0000003182 CCGGGCAGAACGTAGATTAGCTTATCTCGAGATAAGCTAATCTACGTTCTGCTTTTT TBK1 TANK-binding kinase 1 TRCN0000003184 CCGGCCAGGAAATATCATGCGTGTTCTCGAGAACACGCATGATATTTCCTGGTTTTT TBK1 TANK-binding kinase 1 TRCN0000003185 CCGGGCGGCAGAGTTAGGTGAAATTCTCGAGAATTTCACCTAACTCTGCCGCTTTTT TBK1 TANK-binding kinase 1 TRCN0000003186 CCGGCGGGAACCTCTGAATACCATACTCGAGTATGGTATTCAGAGGTTCCCGTTTTT TBK1 TANK-binding kinase 1 TRCN0000003183 CCGGGTATTTGATGTGGTCGTGTAACTCGAGTTACACGACCACATCAAATACTTTTT TEC tec protein tyrosine kinase TRCN0000009982 CCGGGCACCCAGCAGAAACCAATATCTCGAGATATTGGTTTCTGCTGGGTGCTTTTT TEC tec protein tyrosine kinase TRCN0000009983 CCGGAGTATCCATTTCAGGTTGTTCCTCGAGGAACAACCTGAAATGGATACTTTTTT TEC tec protein tyrosine kinase TRCN0000009992 CCGGGAGCCCAGTACAAAGTCGCAACTCGAGTTGCGACTTTGTACTGGGCTCTTTTT TEC tec protein tyrosine kinase TRCN0000195027 CCGGCCTGAGACATTGTCTACAATTCTCGAGAATTGTAGACAATGTCTCAGGTTTTTTG TEC tec protein tyrosine kinase TRCN0000195240 CCGGCCCTTTGACTTCTACAGAAATCTCGAGATTTCTGTAGAAGTCAAAGGGTTTTTTG TEK TEK tyrosine kinase, endothelial TRCN0000000412 CCGGTGGGTGACATTTGGGAGACATCTCGAGATGTCTCCCAAATGTCACCCATTTTT

194 Supplement

TEK TEK tyrosine kinase, endothelial TRCN0000000413 CCGGGCTACCTACTAATGAAGAAATCTCGAGATTTCTTCATTAGTAGGTAGCTTTTT TEK TEK tyrosine kinase, endothelial TRCN0000000414 CCGGCGCTACCTACTAATGAAGAAACTCGAGTTTCTTCATTAGTAGGTAGCGTTTTT TEK TEK tyrosine kinase, endothelial TRCN0000000415 CCGGGCTTCTATACAAACCCGTTAACTCGAGTTAACGGGTTTGTATAGAAGCTTTTT TEK TEK tyrosine kinase, endothelial TRCN0000000416 CCGGCCTACCAGCTACTTTAACTATCTCGAGATAGTTAAAGTAGCTGGTAGGTTTTT TESK1 testis-specific kinase 1 TRCN0000002247 CCGGCAGACAACTTCATCAGCACCTCTCGAGAGGTGCTGATGAAGTTGTCTGTTTTT TESK1 testis-specific kinase 1 TRCN0000002248 CCGGCTAAGGTTCATGGGAGTCTGTCTCGAGACAGACTCCCATGAACCTTAGTTTTT TESK1 testis-specific kinase 1 TRCN0000002249 CCGGCATGAGACTAACACGTGCAATCTCGAGATTGCACGTGTTAGTCTCATGTTTTT TESK1 testis-specific kinase 1 TRCN0000002250 CCGGCTGTATGATGAGAAGGCTGATCTCGAGATCAGCCTTCTCATCATACAGTTTTT TESK1 testis-specific kinase 1 TRCN0000002251 CCGGGATGTCTTTGCCTTCGGGATTCTCGAGAATCCCGAAGGCAAAGACATCTTTTT TESK2 testis-specific kinase 2 TRCN0000001432 CCGGGCTAACCTATTCAAAGACCTTCTCGAGAAGGTCTTTGAATAGGTTAGCTTTTT TESK2 testis-specific kinase 2 TRCN0000001433 CCGGCCATCCCAACATCCTTAGGTACTCGAGTACCTAAGGATGTTGGGATGGTTTTT TESK2 testis-specific kinase 2 TRCN0000001434 CCGGCCTCAGCTACCTTCACTTCAACTCGAGTTGAAGTGAAGGTAGCTGAGGTTTTT TESK2 testis-specific kinase 2 TRCN0000001435 CCGGGAGTTAAAGAGATCCCACCATCTCGAGATGGTGGGATCTCTTTAACTCTTTTT TESK2 testis-specific kinase 2 TRCN0000001436 CCGGCTGATAAAGAGGGATGAGAATCTCGAGATTCTCATCCCTCTTTATCAGTTTTT TEX14 testis expressed 14 TRCN0000037469 CCGGGCAGACAATAATGCACGAGAACTCGAGTTCTCGTGCATTATTGTCTGCTTTTTG TEX14 testis expressed 14 TRCN0000037470 CCGGCGGATATTCAAGACCTGTCTACTCGAGTAGACAGGTCTTGAATATCCGTTTTTG TEX14 testis expressed 14 TRCN0000037471 CCGGCCGAAACCTTACTATGATATTCTCGAGAATATCATAGTAAGGTTTCGGTTTTTG TEX14 testis expressed 14 TRCN0000037472 CCGGCCTACCAAGATTTCCAAGAATCTCGAGATTCTTGGAAATCTTGGTAGGTTTTTG TEX14 testis expressed 14 TRCN0000037473 CCGGGCTGGAGTCATTTCTGCTCAACTCGAGTTGAGCAGAAATGACTCCAGCTTTTTG TGFBR1 transforming growth factor, beta receptor 1 TRCN0000010441 CCGGCACAACAGCATGTGTATAGCTCTCGAGAGCTATACACATGCTGTTGTGTTTTTG TGFBR1 transforming growth factor, beta receptor 1 TRCN0000039773 CCGGGCTGGTCTTAACTTTAGGTAACTCGAGTTACCTAAAGTTAAGACCAGCTTTTTG TGFBR1 transforming growth factor, beta receptor 1 TRCN0000039777 CCGGCGATGTTCCATTGGTGGAATTCTCGAGAATTCCACCAATGGAACATCGTTTTTG TGFBR1 transforming growth factor, beta receptor 1 TRCN0000194693 CCGGCTCATGTTGATGGTCTATATCCTCGAGGATATAGACCATCAACATGAGTTTTTTG TGFBR1 transforming growth factor, beta receptor 1 TRCN0000195626 CCGGCCCTTCATTAGATCGCCCTTTCTCGAGAAAGGGCGATCTAATGAAGGGTTTTTTG transforming growth factor, beta receptor II TGFBR2 TRCN0000000831 CCGGGAAGAATATAACACCAGCAATCTCGAGATTGCTGGTGTTATATTCTTCTTTTT (70/80kDa) transforming growth factor, beta receptor II TGFBR2 TRCN0000000834 CCGGCTTCTACTGCTACCGCGTTAACTCGAGTTAACGCGGTAGCAGTAGAAGTTTTT (70/80kDa) transforming growth factor, beta receptor II TGFBR2 TRCN0000010445 CCGGAATGACGAGAACATAACACTCTCGAGAGTGTTATGTTCTCGTCATTCTTTTTG (70/80kDa) transforming growth factor, beta receptor II TGFBR2 TRCN0000010446 CCGGAGTATGCCTCTTGGAAGACACTCGAGTGTCTTCCAAGAGGCATACTCTTTTTG (70/80kDa) transforming growth factor, beta receptor II TGFBR2 TRCN0000040008 CCGGCCTGACTTGTTGCTAGTCATACTCGAGTATGACTAGCAACAAGTCAGGTTTTTG (70/80kDa) tyrosine kinase with immunoglobulin-like and EGF- TIE1 TRCN0000001603 CCGGCGATGAAGTGTACGAGCTGATCTCGAGATCAGCTCGTACACTTCATCGTTTTT like domains 1 tyrosine kinase with immunoglobulin-like and EGF- TIE1 TRCN0000121267 CCGGCTCTGACTTAAGCTGCCTCAACTCGAGTTGAGGCAGCTTAAGTCAGAGTTTTTG like domains 1 tyrosine kinase with immunoglobulin-like and EGF- TIE1 TRCN0000121268 CCGGGCCACGACCATGACGGCGAATCTCGAGATTCGCCGTCATGGTCGTGGCTTTTTG like domains 1 tyrosine kinase with immunoglobulin-like and EGF- TIE1 TRCN0000001602 CCGGCAGCACTCACACCACTAACATCTCGAGATGTTAGTGGTGTGAGTGCTGTTTTT like domains 1 tyrosine kinase with immunoglobulin-like and EGF- TIE1 TRCN0000001604 CCGGCTTTGGGAGATAGTGAGCCTTCTCGAGAAGGCTCACTATCTCCCAAAGTTTTT like domains 1 TLK1 tousled-like kinase 1 TRCN0000007056 CCGGGCTGAAATTGTAGAGAGTATACTCGAGTATACTCTCTACAATTTCAGCTTTTT TLK1 tousled-like kinase 1 TRCN0000007057 CCGGCGGAGAAGAAACAATCGGAATCTCGAGATTCCGATTGTTTCTTCTCCGTTTTT TLK1 tousled-like kinase 1 TRCN0000007058 CCGGGCCACCAAAGATTTCCAACAACTCGAGTTGTTGGAAATCTTTGGTGGCTTTTT TLK1 tousled-like kinase 1 TRCN0000007059 CCGGCGGTCTATTGTAATGCAGATTCTCGAGAATCTGCATTACAATAGACCGTTTTT TLK1 tousled-like kinase 1 TRCN0000007060 CCGGCCCACACATGAGAAGATCAAACTCGAGTTTGATCTTCTCATGTGTGGGTTTTT TLK2 tousled-like kinase 2 TRCN0000002361 CCGGGCAAGACATCCTACAAGAGAACTCGAGTTCTCTTGTAGGATGTCTTGCTTTTT TLK2 tousled-like kinase 2 TRCN0000002362 CCGGTCTACATATCAGGGAACTAAACTCGAGTTTAGTTCCCTGATATGTAGATTTTT TLK2 tousled-like kinase 2 TRCN0000002363 CCGGCGGATTCATAAAGAGCTGGATCTCGAGATCCAGCTCTTTATGAATCCGTTTTT TLK2 tousled-like kinase 2 TRCN0000002364 CCGGCAGTGAAGTTTACAAGGCATTCTCGAGAATGCCTTGTAAACTTCACTGTTTTT TLK2 tousled-like kinase 2 TRCN0000002365 CCGGTGGTGTTTGACTTCGGAGGAACTCGAGTTCCTCCGAAGTCAAACACCATTTTT TNIK TRAF2 and NCK interacting kinase TRCN0000037517 CCGGGCCTCAAAGAACAACTTCTATCTCGAGATAGAAGTTGTTCTTTGAGGCTTTTTG TNIK TRAF2 and NCK interacting kinase TRCN0000037518 CCGGCCATCTCATATTCAGGGCAATCTCGAGATTGCCCTGAATATGAGATGGTTTTTG TNIK TRAF2 and NCK interacting kinase TRCN0000037514 CCGGCGGTAGAAGAAGGTCAAAGATCTCGAGATCTTTGACCTTCTTCTACCGTTTTTG TNIK TRAF2 and NCK interacting kinase TRCN0000037515 CCGGCCAGAAGTTATTGCCTGTGATCTCGAGATCACAGGCAATAACTTCTGGTTTTTG TNIK TRAF2 and NCK interacting kinase TRCN0000196440 CCGGGCTATTGTCATCTTGCCTAAACTCGAGTTTAGGCAAGATGACAATAGCTTTTTTG TNIK TRAF2 and NCK interacting kinase TRCN0000199940 CCGGGCGAACTTCTTAGGCAAGAACCTCGAGGTTCTTGCCTAAGAAGTTCGCTTTTTTG TNK1 tyrosine kinase, non-receptor, 1 TRCN0000000740 CCGGGCCCACTACATTCTCAAACAACTCGAGTTGTTTGAGAATGTAGTGGGCTTTTT TNK1 tyrosine kinase, non-receptor, 1 TRCN0000000741 CCGGCAGGGCACTTCGACTTTGTAACTCGAGTTACAAAGTCGAAGTGCCCTGTTTTT TNK1 tyrosine kinase, non-receptor, 1 TRCN0000000742 CCGGCCACCTTTATCCTCTAGCTCTCTCGAGAGAGCTAGAGGATAAAGGTGGTTTTT TNK1 tyrosine kinase, non-receptor, 1 TRCN0000000743 CCGGGAAGCATGTTGTGTGAGGGATCTCGAGATCCCTCACACAACATGCTTCTTTTT TNK2 tyrosine kinase, non-receptor, 2 TRCN0000002038 CCGGGTCGTGGATGAGTAAGGTGTTCTCGAGAACACCTTACTCATCCACGACTTTTT TNK2 tyrosine kinase, non-receptor, 2 TRCN0000002039 CCGGTGCTTCCTCTTCCACCCAATTCTCGAGAATTGGGTGGAAGAGGAAGCATTTTT TNK2 tyrosine kinase, non-receptor, 2 TRCN0000002040 CCGGTGACGAACTGTATCTGGGAAACTCGAGTTTCCCAGATACAGTTCGTCATTTTT TNK2 tyrosine kinase, non-receptor, 2 TRCN0000002041 CCGGCTGCATAAGATCGACAAGGAGCTCGAGCTCCTTGTCGATCTTATGCAGTTTTT

195 Supplement

TNK2 tyrosine kinase, non-receptor, 2 TRCN0000002042 CCGGCAACTTCTCCACCAACAACAGCTCGAGCTGTTGTTGGTGGAGAAGTTGTTTTT TNNI3K TNNI3 interacting kinase TRCN0000002192 CCGGCCATTCCCAAGCCCATATCATCTCGAGATGATATGGGCTTGGGAATGGTTTTT TNNI3K TNNI3 interacting kinase TRCN0000002193 CCGGACTCCATTTCTGTTCTCGATTCTCGAGAATCGAGAACAGAAATGGAGTTTTTT TNNI3K TNNI3 interacting kinase TRCN0000002194 CCGGGCTCAATCATCCCTGCGTAATCTCGAGATTACGCAGGGATGATTGAGCTTTTT TNNI3K TNNI3 interacting kinase TRCN0000002195 CCGGGCCAATTATACATCGTGACTTCTCGAGAAGTCACGATGTATAATTGGCTTTTT TNNI3K TNNI3 interacting kinase TRCN0000002196 CCGGTGGGCTGAATTATGTAGACTTCTCGAGAAGTCTACATAATTCAGCCCATTTTT TP53RK TP53 regulating kinase TRCN0000037520 CCGGCCCAACACTGAAACTGTGTTTCTCGAGAAACACAGTTTCAGTGTTGGGTTTTTG TP53RK TP53 regulating kinase TRCN0000037522 CCGGCAGTCCACTATGGAGACTGAACTCGAGTTCAGTCTCCATAGTGGACTGTTTTTG TP53RK TP53 regulating kinase TRCN0000195649 CCGGCTTTCTGAAGAGCTACTCCACCTCGAGGTGGAGTAGCTCTTCAGAAAGTTTTTTG TP53RK TP53 regulating kinase TRCN0000196427 CCGGGATCTAAGTAAAGGTGTTAAGCTCGAGCTTAACACCTTTACTTAGATCTTTTTTG TP53RK TP53 regulating kinase TRCN0000196805 CCGGGAAGACCTCATTCATGGTGATCTCGAGATCACCATGAATGAGGTCTTCTTTTTTG serine/threonine kinase with Dbl- and pleckstrin TRAD TRCN0000001427 CCGGGCACAATTAGATGACAAGTTTCTCGAGAAACTTGTCATCTAATTGTGCTTTTT homology domains serine/threonine kinase with Dbl- and pleckstrin TRAD TRCN0000001428 CCGGGCAAAGATGTGGCTGTGAAATCTCGAGATTTCACAGCCACATCTTTGCTTTTT homology domains serine/threonine kinase with Dbl- and pleckstrin TRAD TRCN0000001429 CCGGGTGGAGTTAATGTGCCTTGTTCTCGAGAACAAGGCACATTAACTCCACTTTTT homology domains serine/threonine kinase with Dbl- and pleckstrin TRAD TRCN0000001430 CCGGCAAAGATTACTATGCACTGAACTCGAGTTCAGTGCATAGTAATCTTTGTTTTT homology domains serine/threonine kinase with Dbl- and pleckstrin TRAD TRCN0000001431 CCGGCAACGTATGCAGGGTGGATTTCTCGAGAAATCCACCCTGCATACGTTGTTTTT homology domains TRIB1 tribbles homolog 1 (Drosophila) TRCN0000001535 CCGGCCGGTGGTCAAGTGTGTAATACTCGAGTATTACACACTTGACCACCGGTTTTT TRIB1 tribbles homolog 1 (Drosophila) TRCN0000001536 CCGGCGGGTACATCGACTCAGAAATCTCGAGATTTCTGAGTCGATGTACCCGTTTTT TRIB1 tribbles homolog 1 (Drosophila) TRCN0000001537 CCGGCAGTGACATTAGTTCCTTCTTCTCGAGAAGAAGGAACTAATGTCACTGTTTTT TRIB1 tribbles homolog 1 (Drosophila) TRCN0000001538 CCGGAGAACCCAGCTTAGACTAGAACTCGAGTTCTAGTCTAAGCTGGGTTCTTTTTT TRIB1 tribbles homolog 1 (Drosophila) TRCN0000001539 CCGGCCATTAAACACTACCAGGACACTCGAGTGTCCTGGTAGTGTTTAATGGTTTTT TRIB2 tribbles homolog 2 (Drosophila) TRCN0000007142 CCGGCGTGGACTCTAGTATGTAAATCTCGAGATTTACATACTAGAGTCCACGTTTTT TRIB2 tribbles homolog 2 (Drosophila) TRCN0000007145 CCGGGCGTTTCTTGTATCGGGAAATCTCGAGATTTCCCGATACAAGAAACGCTTTTT TRIB2 tribbles homolog 2 (Drosophila) TRCN0000007146 CCGGCGTCAACATGGAAGAGAACTTCTCGAGAAGTTCTCTTCCATGTTGACGTTTTT TRIB2 tribbles homolog 2 (Drosophila) TRCN0000007143 CCGGGCTCATAGTAACATCAACCAACTCGAGTTGGTTGATGTTACTATGAGCTTTTT TRIB2 tribbles homolog 2 (Drosophila) TRCN0000007144 CCGGGCTGCGGAAATTCATCTTTAACTCGAGTTAAAGATGAATTTCCGCAGCTTTTT TRIB3 tribbles homolog 3 (Drosophila) TRCN0000037404 CCGGCCAGGTCCATACTCTAGGTTTCTCGAGAAACCTAGAGTATGGACCTGGTTTTTG TRIB3 tribbles homolog 3 (Drosophila) TRCN0000037408 CCGGTGGATGACAACTTAGATACCGCTCGAGCGGTATCTAAGTTGTCATCCATTTTTG TRIB3 tribbles homolog 3 (Drosophila) TRCN0000196756 CCGGGCTAGTTCTTGTCTAACTCAACTCGAGTTGAGTTAGACAAGAACTAGCTTTTTTG TRIB3 tribbles homolog 3 (Drosophila) TRCN0000197212 CCGGGATCTCAAGCTGTGTCGCTTTCTCGAGAAAGCGACACAGCTTGAGATCTTTTTTG TRIB3 tribbles homolog 3 (Drosophila) TRCN0000199148 CCGGCCCAACCCGATCCCATCTCTGCTCGAGCAGAGATGGGATCGGGTTGGGTTTTTTG TRIM24 tripartite motif-containing 24 TRCN0000021260 CCGGCCATGAAATGAGCCTGGCTTTCTCGAGAAAGCCAGGCTCATTTCATGGTTTTT TRIM24 tripartite motif-containing 24 TRCN0000021259 CCGGCGCATGAAACTTATGCAACAACTCGAGTTGTTGCATAAGTTTCATGCGTTTTT TRIM24 tripartite motif-containing 24 TRCN0000021261 CCGGCCTGTTGTTATAGTGAAGCAACTCGAGTTGCTTCACTATAACAACAGGTTTTT TRIM24 tripartite motif-containing 24 TRCN0000021262 CCGGGCAGCAGTACAGCATTACTTTCTCGAGAAAGTAATGCTGTACTGCTGCTTTTT TRIM24 tripartite motif-containing 24 TRCN0000021263 CCGGCGAGACTTATCTAAACCAGAACTCGAGTTCTGGTTTAGATAAGTCTCGTTTTT TRIM28 tripartite motif-containing 28 TRCN0000017998 CCGGCCTGGCTCTGTTCTCTGTCCTCTCGAGAGGACAGAGAACAGAGCCAGGTTTTT TRIM28 tripartite motif-containing 28 TRCN0000017999 CCGGGAGAATTATTTCATGCGTGATCTCGAGATCACGCATGAAATAATTCTCTTTTT TRIM28 tripartite motif-containing 28 TRCN0000018001 CCGGCTGAGACCAAACCTGTGCTTACTCGAGTAAGCACAGGTTTGGTCTCAGTTTTT TRIM28 tripartite motif-containing 28 TRCN0000018002 CCGGGACCACCAGTACCAGTTCTTACTCGAGTAAGAACTGGTACTGGTGGTCTTTTT TRIM28 tripartite motif-containing 28 TRCN0000018000 CCGGGAGGACTACAACCTTATTGTTCTCGAGAACAATAAGGTTGTAGTCCTCTTTTT TRIM33 tripartite motif-containing 33 TRCN0000022004 CCGGGCGACTGATTACTTTCCAGTTCTCGAGAACTGGAAAGTAATCAGTCGCTTTTT TRIM33 tripartite motif-containing 33 TRCN0000022006 CCGGGCTCCTGGTTATACTCCTAATCTCGAGATTAGGAGTATAACCAGGAGCTTTTT TRIM33 tripartite motif-containing 33 TRCN0000022007 CCGGCCCTCAGTTACCAATCCAGAACTCGAGTTCTGGATTGGTAACTGAGGGTTTTT TRIM33 tripartite motif-containing 33 TRCN0000022005 CCGGGCAGTTGCATTGTACTTTGAACTCGAGTTCAAAGTACAATGCAACTGCTTTTT TRIM33 tripartite motif-containing 33 TRCN0000022008 CCGGCGGCCCTCAATATTCCATGATCTCGAGATCATGGAATATTGAGGGCCGTTTTT TRIO triple functional domain (PTPRF interacting) TRCN0000000871 CCGGCAAGCAAACATAACTGATCAGCTCGAGCTGATCAGTTATGTTTGCTTGTTTTT TRIO triple functional domain (PTPRF interacting) TRCN0000000872 CCGGGCACAGAACACATACACCAATCTCGAGATTGGTGTATGTGTTCTGTGCTTTTT TRIO triple functional domain (PTPRF interacting) TRCN0000000874 CCGGGCTTCTCAATCCCAACTACATCTCGAGATGTAGTTGGGATTGAGAAGCTTTTT TRIO triple functional domain (PTPRF interacting) TRCN0000195292 CCGGCCACGAAGAATGGATTGAAATCTCGAGATTTCAATCCATTCTTCGTGGTTTTTTG TRIO triple functional domain (PTPRF interacting) TRCN0000196250 CCGGGCATTGCTGTATCACAGTATTCTCGAGAATACTGTGATACAGCAATGCTTTTTTG transient receptor potential cation channel, subfamily TRPM6 TRCN0000021584 CCGGCCTGGCATAAAGAATGTATATCTCGAGATATACATTCTTTATGCCAGGTTTTT M, member 6 transient receptor potential cation channel, subfamily TRPM6 TRCN0000021585 CCGGCCCTCTAATCTAAAGCGAGTTCTCGAGAACTCGCTTTAGATTAGAGGGTTTTT M, member 6 transient receptor potential cation channel, subfamily TRPM6 TRCN0000021586 CCGGCCGGAAGTATAACAACAACAACTCGAGTTGTTGTTGTTATACTTCCGGTTTTT M, member 6 transient receptor potential cation channel, subfamily TRPM6 TRCN0000021587 CCGGCCAAATTCTAATGGAGTGTATCTCGAGATACACTCCATTAGAATTTGGTTTTT M, member 6 transient receptor potential cation channel, subfamily TRPM6 TRCN0000021588 CCGGGCTCCCTATCTGATAACTCAACTCGAGTTGAGTTATCAGATAGGGAGCTTTTT M, member 6 transient receptor potential cation channel, subfamily TRPM7 TRCN0000021561 CCGGGCCAATATGTTCTACATTGTACTCGAGTACAATGTAGAACATATTGGCTTTTT M, member 7 transient receptor potential cation channel, subfamily TRPM7 TRCN0000021559 CCGGCGGGAGGAAATTGTTTGGTAACTCGAGTTACCAAACAATTTCCTCCCGTTTTT M, member 7

196 Supplement

transient receptor potential cation channel, subfamily TRPM7 TRCN0000021560 CCGGGCCCGATATTATTTCCACTATCTCGAGATAGTGGAAATAATATCGGGCTTTTT M, member 7 transient receptor potential cation channel, subfamily TRPM7 TRCN0000021562 CCGGCCACCAAAGAATCAGAATCAACTCGAGTTGATTCTGATTCTTTGGTGGTTTTT M, member 7 transient receptor potential cation channel, subfamily TRPM7 TRCN0000021563 CCGGCGGATGCTTATGGAGTCATAACTCGAGTTATGACTCCATAAGCATCCGTTTTT M, member 7 transformation/transcription domain-associated TRRAP TRCN0000005363 CCGGCGCTACTTTGAGAACCCTCAACTCGAGTTGAGGGTTCTCAAAGTAGCGTTTTT protein transformation/transcription domain-associated TRRAP TRCN0000005361 CCGGCGTGTAAGAAAGGGAGAATATCTCGAGATATTCTCCCTTTCTTACACGTTTTT protein transformation/transcription domain-associated TRRAP TRCN0000005362 CCGGGCCCTGTTCTTTCGCTTTGTACTCGAGTACAAAGCGAAAGAACAGGGCTTTTT protein transformation/transcription domain-associated TRRAP TRCN0000005364 CCGGCGAGAGCAAATCGAGGAAATACTCGAGTATTTCCTCGATTTGCTCTCGTTTTT protein transformation/transcription domain-associated TRRAP TRCN0000195159 CCGGCCTTTACGAATTGCGGCATTACTCGAGTAATGCCGCAATTCGTAAAGGTTTTTTG protein TSSK1B testis-specific serine kinase 1B TRCN0000037464 CCGGGTAGCATGGCAACTGGAGAAACTCGAGTTTCTCCAGTTGCCATGCTACTTTTTG TSSK1B testis-specific serine kinase 1B TRCN0000037465 CCGGCTACGACGACTCCAACATCAACTCGAGTTGATGTTGGAGTCGTCGTAGTTTTTG TSSK1B testis-specific serine kinase 1B TRCN0000037466 CCGGTGGCAAGGTCTACATCGTCATCTCGAGATGACGATGTAGACCTTGCCATTTTTG TSSK1B testis-specific serine kinase 1B TRCN0000037467 CCGGTGCTCCATCATTAAGACCTACCTCGAGGTAGGTCTTAATGATGGAGCATTTTTG TSSK1B testis-specific serine kinase 1B TRCN0000037468 CCGGACTGCTCCATCATTAAGACCTCTCGAGAGGTCTTAATGATGGAGCAGTTTTTTG TSSK2 testis-specific serine kinase 2 TRCN0000003219 CCGGTGTCAACCACGGCTCCATCATCTCGAGATGATGGAGCCGTGGTTGACATTTTT TSSK2 testis-specific serine kinase 2 TRCN0000003220 CCGGACGGCTCCATCATCAAGACTTCTCGAGAAGTCTTGATGATGGAGCCGTTTTTT TSSK2 testis-specific serine kinase 2 TRCN0000003221 CCGGCTACTGACTTTGTGGAGAGATCTCGAGATCTCTCCACAAAGTCAGTAGTTTTT TSSK2 testis-specific serine kinase 2 TRCN0000003222 CCGGCCTACTGACTTTGTGGAGAGACTCGAGTCTCTCCACAAAGTCAGTAGGTTTTT TSSK2 testis-specific serine kinase 2 TRCN0000003223 CCGGGACCTCTGACGGACGGATCTACTCGAGTAGATCCGTCCGTCAGAGGTCTTTTT TSSK3 testis-specific serine kinase 3 TRCN0000002207 CCGGGAAGAAGTTAGTTGGCATCCACTCGAGTGGATGCCAACTAACTTCTTCTTTTT TSSK3 testis-specific serine kinase 3 TRCN0000002208 CCGGCAGAAGAGTTTATCCAGAGATCTCGAGATCTCTGGATAAACTCTTCTGTTTTT TSSK3 testis-specific serine kinase 3 TRCN0000002209 CCGGCAAGTGCTCTCCAATAAAGTACTCGAGTACTTTATTGGAGAGCACTTGTTTTT TSSK3 testis-specific serine kinase 3 TRCN0000002210 CCGGAGGGCCAGAAGAGTTTATCCACTCGAGTGGATAAACTCTTCTGGCCCTTTTTT TSSK3 testis-specific serine kinase 3 TRCN0000002211 CCGGCCAGAAGAGTTTATCCAGAGACTCGAGTCTCTGGATAAACTCTTCTGGTTTTT TSSK4 testis-specific serine kinase 4 TRCN0000002414 CCGGCGTCATCCTTTACACTCTAGTCTCGAGACTAGAGTGTAAAGGATGACGTTTTT TSSK4 testis-specific serine kinase 4 TRCN0000002415 CCGGTCTCTACCTTGTGCCCTCATACTCGAGTATGAGGGCACAAGGTAGAGATTTTT TSSK4 testis-specific serine kinase 4 TRCN0000002416 CCGGCAGCTCCACAACACCACTAAACTCGAGTTTAGTGGTGTTGTGGAGCTGTTTTT TSSK4 testis-specific serine kinase 4 TRCN0000002417 CCGGACACCACTAAACAGCACCAATCTCGAGATTGGTGCTGTTTAGTGGTGTTTTTT TSSK4 testis-specific serine kinase 4 TRCN0000010698 CCGGTGCTGCTGGTAGGGACTTAAACTCGAGTTTAAGTCCCTACCAGCAGCATTTTT TSSK6 testis-specific serine kinase 6 TRCN0000037460 CCGGAGAAGTACGATGTGTGGAGCACTCGAGTGCTCCACACATCGTACTTCTTTTTTG TSSK6 testis-specific serine kinase 6 TRCN0000037459 CCGGGAACCTGCAATAAACTCGCTGCTCGAGCAGCGAGTTTATTGCAGGTTCTTTTTG TSSK6 testis-specific serine kinase 6 TRCN0000037461 CCGGGTGCAACGGGAAACTGTACATCTCGAGATGTACAGTTTCCCGTTGCACTTTTTG TSSK6 testis-specific serine kinase 6 TRCN0000037462 CCGGCAAGAAGTACGATGTGTGGAGCTCGAGCTCCACACATCGTACTTCTTGTTTTTG TSSK6 testis-specific serine kinase 6 TRCN0000037463 CCGGCCACATCCAAGAAGTACAAGGCTCGAGCCTTGTACTTCTTGGATGTGGTTTTTG TTBK1 tau tubulin kinase 1 TRCN0000037534 CCGGCCAGTTGATCATGTCAGTGTTCTCGAGAACACTGACATGATCAACTGGTTTTTG TTBK1 tau tubulin kinase 1 TRCN0000037535 CCGGGACAGATGTCAACCGGAACAACTCGAGTTGTTCCGGTTGACATCTGTCTTTTTG TTBK1 tau tubulin kinase 1 TRCN0000037536 CCGGTGGGAAGTTATTTCATCCCAACTCGAGTTGGGATGAAATAACTTCCCATTTTTG TTBK1 tau tubulin kinase 1 TRCN0000037537 CCGGGAGGAGGATTTCGACAGCAAACTCGAGTTTGCTGTCGAAATCCTCCTCTTTTTG TTBK1 tau tubulin kinase 1 TRCN0000037538 CCGGACCAAAGTTGAGAGGACCTTTCTCGAGAAAGGTCCTCTCAACTTTGGTTTTTTG TTBK2 tau tubulin kinase 2 TRCN0000003230 CCGGCTACGCAGATATAAAGTCCTACTCGAGTAGGACTTTATATCTGCGTAGTTTTT TTBK2 tau tubulin kinase 2 TRCN0000003232 CCGGTGCATGTGTGTCCCTGTACTTCTCGAGAAGTACAGGGACACACATGCATTTTT TTBK2 tau tubulin kinase 2 TRCN0000003233 CCGGCCAGATGAACAGCTTAGCGATCTCGAGATCGCTAAGCTGTTCATCTGGTTTTT TTBK2 tau tubulin kinase 2 TRCN0000195181 CCGGCTAGACCATATCTCTTCTTTGCTCGAGCAAAGAAGAGATATGGTCTAGTTTTTTG TTBK2 tau tubulin kinase 2 TRCN0000196284 CCGGGTCCCTGTACTTTCTATGTAACTCGAGTTACATAGAAAGTACAGGGACTTTTTTG TTK TTK protein kinase TRCN0000006356 CCGGCGGTATTAACTGCCCAAGAATCTCGAGATTCTTGGGCAGTTAATACCGTTTTT TTK TTK protein kinase TRCN0000006357 CCGGCCAGTTGTAAAGAATGACTTTCTCGAGAAAGTCATTCTTTACAACTGGTTTTT TTK TTK protein kinase TRCN0000006358 CCGGGCACAATTTGAACTGTCACAACTCGAGTTGTGACAGTTCAAATTGTGCTTTTT TTK TTK protein kinase TRCN0000011011 CCGGGCAACCACTTATGGTACTGTACTCGAGTACAGTACCATAAGTGGTTGCTTTTT TTK TTK protein kinase TRCN0000011012 CCGGGCCAACTTGTTGGTCTGAATTCTCGAGAATTCAGACCAACAAGTTGGCTTTTT TTN titin TRCN0000037479 CCGGCGCCCAATAAAGGACTTGAAACTCGAGTTTCAAGTCCTTTATTGGGCGTTTTTG TTN titin TRCN0000037480 CCGGGCCCAGAATAAATATGGCATTCTCGAGAATGCCATATTTATTCTGGGCTTTTTG TTN titin TRCN0000037481 CCGGCGCTGGATTAAATGCAACAAACTCGAGTTTGTTGCATTTAATCCAGCGTTTTTG TTN titin TRCN0000037482 CCGGGCCACCAAATTAGATGACATTCTCGAGAATGTCATCTAATTTGGTGGCTTTTTG TTN titin TRCN0000037483 CCGGCGCGCCTTACTTTATTACAAACTCGAGTTTGTAATAAAGTAAGGCGCGTTTTTG TXK TXK tyrosine kinase TRCN0000001577 CCGGGAAACAGAATGCCAACCCAAACTCGAGTTTGGGTTGGCATTCTGTTTCTTTTT TXK TXK tyrosine kinase TRCN0000001580 CCGGGCTGCCTGCTTAACTATCTCACTCGAGTGAGATAGTTAAGCAGGCAGCTTTTT TXK TXK tyrosine kinase TRCN0000009997 CCGGTACCTGATACTGGAGAAATACCTCGAGGTATTTCTCCAGTATCAGGTATTTTT TXK TXK tyrosine kinase TRCN0000009999 CCGGGACACGCCTTTCAATCAATCCCTCGAGGGATTGATTGAAAGGCGTGTCTTTTT TXK TXK tyrosine kinase TRCN0000121109 CCGGGCTTAACTATCTCAGGGAGAACTCGAGTTCTCCCTGAGATAGTTAAGCTTTTTG TYK2 tyrosine kinase 2 TRCN0000003120 CCGGGAGATCCACCACTTTAAGAATCTCGAGATTCTTAAAGTGGTGGATCTCTTTTT

197 Supplement

TYK2 tyrosine kinase 2 TRCN0000003121 CCGGTGGTATCACTCCTCCTTGCTTCTCGAGAAGCAAGGAGGAGTGATACCATTTTT TYK2 tyrosine kinase 2 TRCN0000003122 CCGGGAGGCCATCATTCCGCACCATCTCGAGATGGTGCGGAATGATGGCCTCTTTTT TYK2 tyrosine kinase 2 TRCN0000003123 CCGGCGTGAGCCTAACCATGATCTTCTCGAGAAGATCATGGTTAGGCTCACGTTTTT TYK2 tyrosine kinase 2 TRCN0000003124 CCGGCGAGCACATCATCAAGTACAACTCGAGTTGTACTTGATGATGTGCTCGTTTTT TYRO3 TYRO3 protein tyrosine kinase TRCN0000002178 CCGGGAGTGTATGGAGGACGTGTATCTCGAGATACACGTCCTCCATACACTCTTTTT TYRO3 TYRO3 protein tyrosine kinase TRCN0000002179 CCGGGTGGAGAGGAACTACGAAGATCTCGAGATCTTCGTAGTTCCTCTCCACTTTTT TYRO3 TYRO3 protein tyrosine kinase TRCN0000002181 CCGGCCTTCTCCATACCCACAATCTCTCGAGAGATTGTGGGTATGGAGAAGGTTTTT TYRO3 TYRO3 protein tyrosine kinase TRCN0000010684 CCGGCGCTGAGATTTACAACTACCTCTCGAGAGGTAGTTGTAAATCTCAGCGTTTTT TYRO3 TYRO3 protein tyrosine kinase TRCN0000002180 CCGGCGAGCTTTACTTGTCTGCGAACTCGAGTTCGCAGACAAGTAAAGCTCGTTTTT UHMK1 U2AF homology motif (UHM) kinase 1 TRCN0000003279 CCGGGAGTGCAGAGAATGAATGTTTCTCGAGAAACATTCATTCTCTGCACTCTTTTT UHMK1 U2AF homology motif (UHM) kinase 1 TRCN0000003280 CCGGCCCATTCTTTAGCATTCCTTTCTCGAGAAAGGAATGCTAAAGAATGGGTTTTT UHMK1 U2AF homology motif (UHM) kinase 1 TRCN0000003281 CCGGGCCTATCACCTAAGAGACCTTCTCGAGAAGGTCTCTTAGGTGATAGGCTTTTT UHMK1 U2AF homology motif (UHM) kinase 1 TRCN0000003282 CCGGGAAATTACTGACTGGAAGGATCTCGAGATCCTTCCAGTCAGTAATTTCTTTTT UHMK1 U2AF homology motif (UHM) kinase 1 TRCN0000003283 CCGGCTGCTGAATGTGCTGGATGATCTCGAGATCATCCAGCACATTCAGCAGTTTTT ULK1 unc-51-like kinase 1 (C. elegans) TRCN0000000835 CCGGGCCCTTTGCGTTATATTGTATCTCGAGATACAATATAACGCAAAGGGCTTTTT ULK1 unc-51-like kinase 1 (C. elegans) TRCN0000000837 CCGGCCTGGTTATGGAGTACTGCAACTCGAGTTGCAGTACTCCATAACCAGGTTTTT ULK1 unc-51-like kinase 1 (C. elegans) TRCN0000000838 CCGGACATCGAGAACGTCACCAAGTCTCGAGACTTGGTGACGTTCTCGATGTTTTTT ULK1 unc-51-like kinase 1 (C. elegans) TRCN0000000839 CCGGTACACGCCATCTCCTCAAGTTCTCGAGAACTTGAGGAGATGGCGTGTATTTTT ULK1 unc-51-like kinase 1 (C. elegans) TRCN0000195477 CCGGCGCATGGACTTCGATGAGTTTCTCGAGAAACTCATCGAAGTCCATGCGTTTTTTG ULK2 unc-51-like kinase 2 (C. elegans) TRCN0000000891 CCGGGTCAGTGGTATTCGCATCAAACTCGAGTTTGATGCGAATACCACTGACTTTTT ULK2 unc-51-like kinase 2 (C. elegans) TRCN0000000892 CCGGGCAGACCGAAGATATTGTTTACTCGAGTAAACAATATCTTCGGTCTGCTTTTT ULK2 unc-51-like kinase 2 (C. elegans) TRCN0000000893 CCGGTCCCAGAGAAACATCACCTTACTCGAGTAAGGTGATGTTTCTCTGGGATTTTT ULK2 unc-51-like kinase 2 (C. elegans) TRCN0000195035 CCGGCCTGTGACCTTAGGTTTATTACTCGAGTAATAAACCTAAGGTCACAGGTTTTTTG ULK2 unc-51-like kinase 2 (C. elegans) TRCN0000195134 CCGGCCAATAGTCCTCAAGACTTAACTCGAGTTAAGTCTTGAGGACTATTGGTTTTTTG ULK3 unc-51-like kinase 3 (C. elegans) TRCN0000037419 CCGGCGTGTCTTCATGCAGCAATTACTCGAGTAATTGCTGCATGAAGACACGTTTTTG ULK3 unc-51-like kinase 3 (C. elegans) TRCN0000037420 CCGGGCAGACTTTGGTTTCGCACAACTCGAGTTGTGCGAAACCAAAGTCTGCTTTTTG ULK3 DKFZP434C131 protein TRCN0000195384 CCGGCACGGAGATTGAGATCCTCAACTCGAGTTGAGGATCTCAATCTCCGTGTTTTTTG ULK3 DKFZP434C131 protein TRCN0000199903 CCGGGCAAGGCTCTGGACTTCTTTGCTCGAGCAAAGAAGTCCAGAGCCTTGCTTTTTTG ULK3 unc-51-like kinase 3 (C. elegans) TRCN0000037421 CCGGACTCGTGAAGTGGTAGCCATACTCGAGTATGGCTACCACTTCACGAGTTTTTTG ULK4 unc-51-like kinase 4 (C. elegans) TRCN0000002202 CCGGGACCTGATTAGTGGATTACATCTCGAGATGTAATCCACTAATCAGGTCTTTTT ULK4 unc-51-like kinase 4 (C. elegans) TRCN0000002203 CCGGCCACTAGGTCACTCTTTCAGACTCGAGTCTGAAAGAGTGACCTAGTGGTTTTT ULK4 unc-51-like kinase 4 (C. elegans) TRCN0000002204 CCGGCAGGGCTTTATTACAGGAGAACTCGAGTTCTCCTGTAATAAAGCCCTGTTTTT ULK4 unc-51-like kinase 4 (C. elegans) TRCN0000002205 CCGGCGACGGAAGGGAACAATCAATCTCGAGATTGATTGTTCCCTTCCGTCGTTTTT ULK4 unc-51-like kinase 4 (C. elegans) TRCN0000002206 CCGGCAGAAGATGTTGTGAGAGAATCTCGAGATTCTCTCACAACATCTTCTGTTTTT VRK1 vaccinia related kinase 1 TRCN0000002129 CCGGCCTGGTGTTGAAGATACGGAACTCGAGTTCCGTATCTTCAACACCAGGTTTTT VRK1 vaccinia related kinase 1 TRCN0000002133 CCGGGAAGTAAGGATGATGGCAAATCTCGAGATTTGCCATCATCCTTACTTCTTTTT VRK1 vaccinia related kinase 1 TRCN0000197134 CCGGGAGATATCAAGGCCTCAAATCCTCGAGGATTTGAGGCCTTGATATCTCTTTTTTG VRK1 vaccinia related kinase 1 TRCN0000199332 CCGGCGAGCATCGATGCACACAATGCTCGAGCATTGTGTGCATCGATGCTCGTTTTTTG VRK1 vaccinia related kinase 1 TRCN0000002130 CCGGAGATAATAACTGACATGGCAACTCGAGTTGCCATGTCAGTTATTATCTTTTTT VRK2 vaccinia related kinase 2 TRCN0000010204 CCGGGCCAAACTATCAAGCCCTCAACTCGAGTTGAGGGCTTGATAGTTTGGCTTTTT VRK2 vaccinia related kinase 2 TRCN0000010205 CCGGGCACACAATAGGTTAATCGAACTCGAGTTCGATTAACCTATTGTGTGCTTTTT VRK2 vaccinia related kinase 2 TRCN0000010206 CCGGGGGAAGAAGTTACAGATTTATCTCGAGATAAATCTGTAACTTCTTCCCTTTTT VRK2 vaccinia related kinase 2 TRCN0000010207 CCGGGTTGGATGTACTGGAATATATCTCGAGATATATTCCAGTACATCCAACTTTTT VRK2 vaccinia related kinase 2 TRCN0000010208 CCGGACCACAAACAGTATCAGGAAACTCGAGTTTCCTGATACTGTTTGTGGTTTTTT VRK3 vaccinia related kinase 3 TRCN0000010235 CCGGGTATCCAAGCGGCATTCAAATCTCGAGATTTGAATGCCGCTTGGATACTTTTT VRK3 vaccinia related kinase 3 TRCN0000010563 CCGGACTCAGGACCACAGAAGCAAACTCGAGTTTGCTTCTGTGGTCCTGAGTTTTTT VRK3 vaccinia related kinase 3 TRCN0000199854 CCGGGCCACTGGTTTCAGGATACTCCTCGAGGAGTATCCTGAAACCAGTGGCTTTTTTG VRK3 vaccinia related kinase 3 TRCN0000000909 CCGGGATCTGCGTGTGTCTCCATATCTCGAGATATGGAGACACACGCAGATCTTTTT VRK3 vaccinia related kinase 3 TRCN0000000910 CCGGCTCACTCAAACTGGATGCCAACTCGAGTTGGCATCCAGTTTGAGTGAGTTTTT WEE1 WEE1 homolog (S. pombe) TRCN0000001700 CCGGCCACCCAGAGTAATAGAACATCTCGAGATGTTCTATTACTCTGGGTGGTTTTT WEE1 WEE1 homolog (S. pombe) TRCN0000001701 CCGGCTAGAAAGAGTGCAGAACAATCTCGAGATTGTTCTGCACTCTTTCTAGTTTTT WEE1 WEE1 homolog (S. pombe) TRCN0000001702 CCGGGCCTTGTGAATTTGCTGCTATCTCGAGATAGCAGCAAATTCACAAGGCTTTTT WEE1 WEE1 homolog (S. pombe) TRCN0000001703 CCGGAGATGAAACAAGACCTGCTAACTCGAGTTAGCAGGTCTTGTTTCATCTTTTTT WEE1 WEE1 homolog (S. pombe) TRCN0000001704 CCGGGCCAGTGATTATGAGCTTGAACTCGAGTTCAAGCTCATAATCACTGGCTTTTT WNK1 WNK lysine deficient protein kinase 1 TRCN0000000918 CCGGCCGAGGAGATAGCAACAATTACTCGAGTAATTGTTGCTATCTCCTCGGTTTTT WNK1 WNK lysine deficient protein kinase 1 TRCN0000000919 CCGGCCGCGATCTTAAATGTGACAACTCGAGTTGTCACATTTAAGATCGCGGTTTTT WNK1 WNK lysine deficient protein kinase 1 TRCN0000000920 CCGGGCGTAGTTTCAAGTATCACAACTCGAGTTGTGATACTTGAAACTACGCTTTTT WNK1 WNK lysine deficient protein kinase 1 TRCN0000196491 CCGGGCAGGAGTGTCTAGTTATATTCTCGAGAATATAACTAGACACTCCTGCTTTTTTG WNK1 WNK lysine deficient protein kinase 1 TRCN0000219718 CCGGTCTGCGGGAAGGCGGTTTATACTCGAGTATAAACCGCCTTCCCGCAGATTTTTG WNK2 WNK lysine deficient protein kinase 2 TRCN0000002252 CCGGCCAAGATTCAGCGCCCTATAACTCGAGTTATAGGGCGCTGAATCTTGGTTTTT WNK2 WNK lysine deficient protein kinase 2 TRCN0000002253 CCGGGAGGAAAGGTACGAGATCAAACTCGAGTTTGATCTCGTACCTTTCCTCTTTTT WNK2 WNK lysine deficient protein kinase 2 TRCN0000002254 CCGGCGAGACCTGAAATGTGACAATCTCGAGATTGTCACATTTCAGGTCTCGTTTTT

198 Supplement

WNK2 WNK lysine deficient protein kinase 2 TRCN0000002255 CCGGCCGATGAAATTGCCACGTATACTCGAGTATACGTGGCAATTTCATCGGTTTTT WNK2 WNK lysine deficient protein kinase 2 TRCN0000002256 CCGGGACGCTGAAGACATACCTGAACTCGAGTTCAGGTATGTCTTCAGCGTCTTTTT WNK3 WNK lysine deficient protein kinase 3 TRCN0000001532 CCGGGCAGCTCAAATATACCGGAAACTCGAGTTTCCGGTATATTTGAGCTGCTTTTT WNK3 WNK lysine deficient protein kinase 3 TRCN0000001530 CCGGCGGTCAATTAAAGATAGCAAACTCGAGTTTGCTATCTTTAATTGACCGTTTTT WNK3 WNK lysine deficient protein kinase 3 TRCN0000001531 CCGGCGGGACACATTGCTCACTATACTCGAGTATAGTGAGCAATGTGTCCCGTTTTT WNK3 WNK lysine deficient protein kinase 3 TRCN0000001533 CCGGGCCTCACGTTTGTCAGTATAACTCGAGTTATACTGACAAACGTGAGGCTTTTT WNK3 WNK lysine deficient protein kinase 3 TRCN0000001534 CCGGGCAGACTATATGGTTGAAGATCTCGAGATCTTCAACCATATAGTCTGCTTTTT WNK4 WNK lysine deficient protein kinase 4 TRCN0000007021 CCGGCCGATACCTCAAGTTTGACATCTCGAGATGTCAAACTTGAGGTATCGGTTTTT WNK4 WNK lysine deficient protein kinase 4 TRCN0000007022 CCGGGATGGATTTCTCAGACGGATTCTCGAGAATCCGTCTGAGAAATCCATCTTTTT WNK4 WNK lysine deficient protein kinase 4 TRCN0000219722 CCGGGGAGAGTGCAGCTCCATTATACTCGAGTATAATGGAGCTGCACTCTCCTTTTTG WNK4 WNK lysine deficient protein kinase 4 TRCN0000007020 CCGGCCGCTTCTATGATTCGTGGAACTCGAGTTCCACGAATCATAGAAGCGGTTTTT WNK4 WNK lysine deficient protein kinase 4 TRCN0000007023 CCGGGCTGCGTAAAGCAAGGGAATTCTCGAGAATTCCCTTGCTTTACGCAGCTTTTT YES1 v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1 TRCN0000001607 CCGGCCAGCCTACATTCACTTCTAACTCGAGTTAGAAGTGAATGTAGGCTGGTTTTT YES1 v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1 TRCN0000001608 CCGGGCAGTTAATTTCAGCAGTCTTCTCGAGAAGACTGCTGAAATTAACTGCTTTTT YES1 v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1 TRCN0000001609 CCGGCTGCACTGTATGGTCGGTTTACTCGAGTAAACCGACCATACAGTGCAGTTTTT YES1 v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1 TRCN0000001610 CCGGGTTACTATATTTGTGGCCTTACTCGAGTAAGGCCACAAATATAGTAACTTTTT YES1 v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1 TRCN0000001611 CCGGACCACGAAAGTAGCAATCAAACTCGAGTTTGATTGCTACTTTCGTGGTTTTTT YSK4 Sps1/Ste20-related kinase homolog (S. YSK4 TRCN0000002391 CCGGAGCATTGGTTGTACTGTGTTTCTCGAGAAACACAGTACAACCAATGCTTTTTT cerevisiae) YSK4 Sps1/Ste20-related kinase homolog (S. YSK4 TRCN0000002392 CCGGTCTGGCTATGGACGGAAATCACTCGAGTGATTTCCGTCCATAGCCAGATTTTT cerevisiae) YSK4 Sps1/Ste20-related kinase homolog (S. YSK4 TRCN0000002393 CCGGGAGCATTGGTTGTACTGTGTTCTCGAGAACACAGTACAACCAATGCTCTTTTT cerevisiae) YSK4 Sps1/Ste20-related kinase homolog (S. YSK4 TRCN0000002394 CCGGGATGGTGTTCTGTAAATATACCTCGAGGTATATTTACAGAACACCATCTTTTT cerevisiae) YSK4 Sps1/Ste20-related kinase homolog (S. YSK4 TRCN0000002395 CCGGCTAGTTAAAGTGTGTATCCATCTCGAGATGGATACACACTTTAACTAGTTTTT cerevisiae) sterile alpha motif and leucine zipper containing ZAK TRCN0000003264 CCGGACAGTAACAGAAGTGAGGAGACTCGAGTCTCCTCACTTCTGTTACTGTTTTTT kinase AZK sterile alpha motif and leucine zipper containing ZAK TRCN0000003265 CCGGGCTTCTCTGGGATCACTCTATCTCGAGATAGAGTGATCCCAGAGAAGCTTTTT kinase AZK sterile alpha motif and leucine zipper containing ZAK TRCN0000003266 CCGGCCTCAGTCACAGAAACATCATCTCGAGATGATGTTTCTGTGACTGAGGTTTTT kinase AZK sterile alpha motif and leucine zipper containing ZAK TRCN0000003267 CCGGACGAGAGATTAACCATTCCAACTCGAGTTGGAATGGTTAATCTCTCGTTTTTT kinase AZK sterile alpha motif and leucine zipper containing ZAK TRCN0000003268 CCGGCCATAACCATACAACACACATCTCGAGATGTGTGTTGTATGGTTATGGTTTTT kinase AZK sterile alpha motif and leucine zipper containing ZAK TRCN0000195071 CCGGCAGAAACTTGTGACACATATTCTCGAGAATATGTGTCACAAGTTTCTGTTTTTTG kinase AZK ZAP70 zeta-chain (TCR) associated protein kinase 70kDa TRCN0000000436 CCGGCAGGCGTAGATCACCAGAATACTCGAGTATTCTGGTGATCTACGCCTGTTTTT ZAP70 zeta-chain (TCR) associated protein kinase 70kDa TRCN0000000437 CCGGGAAGCCCTACAAGAAGATGAACTCGAGTTCATCTTCTTGTAGGGCTTCTTTTT ZAP70 zeta-chain (TCR) associated protein kinase 70kDa TRCN0000000438 CCGGCCCTCAACTCAGATGGATACACTCGAGTGTATCCATCTGAGTTGAGGGTTTTT ZAP70 zeta-chain (TCR) associated protein kinase 70kDa TRCN0000000439 CCGGTACCACTACCTCATCAGCCAACTCGAGTTGGCTGATGAGGTAGTGGTATTTTT ZAP70 zeta-chain (TCR) associated protein kinase 70kDa TRCN0000000440 CCGGCGATAACCTCCTCATAGCTGACTCGAGTCAGCTATGAGGAGGTTATCGTTTTT URI1 Unconventional prefoldin RPB5 interactor 1 TRCN0000074238 CCGGCCTCTGAATGTCATACTGTAACTCGAGTTACAGTATGACATTCAGAGGTTTTTG URI1 Unconventional prefoldin RPB5 interactor 1 TRCN0000074239 CCGGCCTTGCCTGATAAATTGTCTTCTCGAGAAGACAATTTATCAGGCAAGGTTTTTG URI1 Unconventional prefoldin RPB5 interactor 1 TRCN0000074240 CCGGCGAAAGGAAGTTCTGTTGGAACTCGAGTTCCAACAGAACTTCCTTTCGTTTTTG URI1 Unconventional prefoldin RPB5 interactor 1 TRCN0000074241 CCGGGCTCATAAACCGCATTCCAAACTCGAGTTTGGAATGCGGTTTATGAGCTTTTTG URI1 Unconventional prefoldin RPB5 interactor 1 TRCN0000074242 CCGGCCTAAGAGGGTCCGAATAAATCTCGAGATTTATTCGGACCCTCTTAGGTTTTTG CCNE1 Cyclin E TRCN0000045299 CCGGCCGAGCAAAGAAAGCCATGTTCTCGAGAACATGGCTTTCTTTGCTCGGTTTTTG CCNE1 Cyclin E TRCN0000045300 CCGGCCTTGTATCATTTCTCGTCATCTCGAGATGACGAGAAATGATACAAGGTTTTTG CCNE1 Cyclin E TRCN0000045301 CCGGGCAATTCTTCTGGATTGGTTACTCGAGTAACCAATCCAGAAGAATTGCTTTTTG CCNE1 Cyclin E TRCN0000045302 CCGGCGACATAGAGAACTGTGTCAACTCGAGTTGACACAGTTCTCTATGTCGTTTTTG CCNE1 Cyclin E TRCN0000045298 CCGGCCTCCAAAGTTGCACCAGTTTCTCGAGAAACTGGTGCAACTTTGGAGGTTTTTG ubiquinol-cytochrome c reductase, Rieske iron-sulfur UQCRFS1 TRCN0000046518 CCGGCGAAATCAAGTTATCCGATATCTCGAGATATCGGATAACTTGATTTCGTTTTTG polypeptide 1 ubiquinol-cytochrome c reductase, Rieske iron-sulfur UQCRFS1 TRCN0000046519 CCGGCCTATTTGGTAACTGGAGTAACTCGAGTTACTCCAGTTACCAAATAGGTTTTTG polypeptide 1 ubiquinol-cytochrome c reductase, Rieske iron-sulfur UQCRFS1 TRCN0000046520 CCGGAGTGACGATATGGTGATTGTTCTCGAGAACAATCACCATATCGTCACTTTTTTG polypeptide 1 ubiquinol-cytochrome c reductase, Rieske iron-sulfur UQCRFS1 TRCN0000046521 CCGGCCATTGCAAATGCAGGAGATTCTCGAGAATCTCCTGCATTTGCAATGGTTTTTG polypeptide 1 ubiquinol-cytochrome c reductase, Rieske iron-sulfur UQCRFS1 TRCN0000046522 CCGGCCCTGTTTGTGCGTCATAGAACTCGAGTTCTATGACGCACAAACAGGGTTTTTG polypeptide 1 PLEKHF1 pleckstrin homology and FYVE domain containing 1 TRCN0000163979 CCGGCTTTAACGACATCCTGGTGTACTCGAGTACACCAGGATGTCGTTAAAGTTTTTTG PLEKHF1 pleckstrin homology and FYVE domain containing 1 TRCN0000165370 CCGGGATGATCAAGACGGCCAAGAACTCGAGTTCTTGGCCGTCTTGATCATCTTTTTTG PLEKHF1 pleckstrin homology and FYVE domain containing 1 TRCN0000165241 CCGGGAATGGATTAGCCACATCGAGCTCGAGCTCGATGTGGCTAATCCATTCTTTTTTG PLEKHF1 pleckstrin homology and FYVE domain containing 1 TRCN0000166611 CCGGCCAAGAAGTCCTTTGTGGTGTCTCGAGACACCACAAAGGACTTCTTGGTTTTTTG PLEKHF1 pleckstrin homology and FYVE domain containing 1 TRCN0000163236 CCGGGCGCATCTTCTTCCTCTTTAACTCGAGTTAAAGAGGAAGAAGATGCGCTTTTTTG Pop4 POP4 homolog, ribonuclease P/MRP subunit TRCN0000049878 CCGGCCTACATTTACGGGAGCAAATCTCGAGATTTGCTCCCGTAAATGTAGGTTTTTG Pop4 POP4 homolog, ribonuclease P/MRP subunit TRCN0000049879 CCGGCCTCTCCATGAACTCTGGAAACTCGAGTTTCCAGAGTTCATGGAGAGGTTTTTG Pop4 POP4 homolog, ribonuclease P/MRP subunit TRCN0000049880 CCGGCGATGGCTTTATTTCCTACATCTCGAGATGTAGGAAATAAAGCCATCGTTTTTG

199 Supplement

Pop4 POP4 homolog, ribonuclease P/MRP subunit TRCN0000049881 CCGGCCCTCTTATGTGGGTATTACACTCGAGTGTAATACCCACATAAGAGGGTTTTTG Pop4 POP4 homolog, ribonuclease P/MRP subunit TRCN0000049882 CCGGCTGCGGCTCTTTGACATTAAACTCGAGTTTAATGTCAAAGAGCCGCAGTTTTTG C19orf12 Chromosome 19 Open Reading Frame 12 TRCN0000166351 CCGGCCGAGATCCAGTATGATGACTCTCGAGAGTCATCATACTGGATCTCGGTTTTTTG C19orf12 Chromosome 19 Open Reading Frame 12 TRCN0000163875 CCGGCGAGATCCAGTATGATGACTACTCGAGTAGTCATCATACTGGATCTCGTTTTTTG C19orf12 Chromosome 19 Open Reading Frame 12 TRCN0000160025 CCGGCCTTTAAATGACTCTGTGATTCTCGAGAATCACAGAGTCATTTAAAGGTTTTTTG C19orf12 Chromosome 19 Open Reading Frame 12 TRCN0000164358 CCGGCCAGTGCATCTAAGTCATGTTCTCGAGAACATGACTTAGATGCACTGGTTTTTTG C19orf12 Chromosome 19 Open Reading Frame 12 TRCN0000162497 CCGGCCACTAAATGTGCAATAGCATCTCGAGATGCTATTGCACATTTAGTGGTTTTTTG STAP1 SKP2-associated α- PFD 1 TRCN0000154852 CCGGGCTGTAACTTCTTCGTTGACACTCGAGTGTCAACGAAGAAGTTACAGCTTTTTTG STAP1 SKP2-associated α- PFD 1 TRCN0000151893 CCGGCCTTCAACTGAGAAATGTCATCTCGAGATGACATTTCTCAGTTGAAGGTTTTTTG STAP1 SKP2-associated α- PFD 1 TRCN0000155295 CCGGGCTAAGCACTCGGAGTTATATCTCGAGATATAACTCCGAGTGCTTAGCTTTTTTG STAP1 SKP2-associated α- PFD 1 TRCN0000157724 CCGGCAGCTGGCCAAATACCTTCAACTCGAGTTGAAGGTATTTGGCCAGCTGTTTTTTG STAP1 SKP2-associated α- PFD 1 TRCN0000151473 CCGGGAAGCTCTCAAGTTCATTGATCTCGAGATCAATGAACTTGAGAGCTTCTTTTTTG PDRG p53 and DNA damage-regulated protein 1 TRCN0000139239 CCGGCCTCTTTGTAGTGCTTGGCTACTCGAGTAGCCAAGCACTACAAAGAGGTTTTTTG PDRG p53 and DNA damage-regulated protein 1 TRCN0000139873 CCGGGATTGTGGACCTGGACACTAACTCGAGTTAGTGTCCAGGTCCACAATCTTTTTTG PDRG p53 and DNA damage-regulated protein 1 TRCN0000139874 CCGGGTCAGGAATCTGGCCATGAAACTCGAGTTTCATGGCCAGATTCCTGACTTTTTTG PDRG p53 and DNA damage-regulated protein 1 TRCN0000140611 CCGGGATGGTTTGCTTCGGGAACATCTCGAGATGTTCCCGAAGCAAACCATCTTTTTTG PDRG p53 and DNA damage-regulated protein 1 TRCN0000143250 CCGGGCTTCGGGAACATGTTTATCACTCGAGTGATAAACATGTTCCCGAAGCTTTTTTG PFD2 Prefoldin 2 TRCN0000152967 CCGGGAGAACAACAAGGAGCAGATACTCGAGTATCTGCTCCTTGTTGTTCTCTTTTTTG PFD2 Prefoldin 2 TRCN0000151225 CCGGGAGCAGATACAGAAGATCATTCTCGAGAATGATCTTCTGTATCTGCTCTTTTTTG PFD2 Prefoldin 2 TRCN0000155254 CCGGGAGTTGAATGAGCACAGCCTACTCGAGTAGGCTGTGCTCATTCAACTCTTTTTTG PFD2 Prefoldin 2 TRCN0000153025 CCGGGAGTTGGAGATGGAGTTGAATCTCGAGATTCAACTCCATCTCCAACTCTTTTTTG PFD2 Prefoldin 2 TRCN0000155946 CCGGCACAACATTCGTCTCATGGGACTCGAGTCCCATGAGACGAATGTTGTGTTTTTTG PFD6 Prefoldin 6 TRCN0000057283 CCGGGCTGAAATTAAGCGATACGAACTCGAGTTCGTATCGCTTAATTTCAGCTTTTTG PFD6 Prefoldin 6 TRCN0000057284 CCGGCAGAAACTTGAAGCACAACTACTCGAGTAGTTGTGCTTCAAGTTTCTGTTTTTG PFD6 Prefoldin 6 TRCN0000057285 CCGGGCTACAGAAGGACTTAAGTAACTCGAGTTACTTAAGTCCTTCTGTAGCTTTTTG PFD6 Prefoldin 6 TRCN0000057286 CCGGGAAATATCAACAGCTACAGAACTCGAGTTCTGTAGCTGTTGATATTTCTTTTTG PFD6 Prefoldin 6 TRCN0000057287 CCGGGTGGTCTTTAAACTTCTGGGTCTCGAGACCCAGAAGTTTAAAGACCACTTTTTG kif 11 Kinesin family member 11 TRCN0000116497 CCGGGCTTGAGCTTAACATAGGTAACTCGAGTTACCTATGTTAAGCTCAAGCTTTTTG kif 11 Kinesin family member 11 TRCN0000116498 CCGGGCGCCCATTCAATAGTAGAATCTCGAGATTCTACTATTGAATGGGCGCTTTTTG kif 11 Kinesin family member 11 TRCN0000116499 CCGGCCGATAAGATAGAAGATCAAACTCGAGTTTGATCTTCTATCTTATCGGTTTTTG kif 11 Kinesin family member 11 TRCN0000116500 CCGGGCGTACAAGAACATCTATAATCTCGAGATTATAGATGTTCTTGTACGCTTTTTG kif 11 Kinesin family member 11 TRCN0000116501 CCGGGCCAATGTTGTGAGGCTTCAACTCGAGTTGAAGCCTCACAACATTGGCTTTTTG INCENP Inner centromere protein TRCN0000074143 CCGGGCCTGCTGTTGATACCATGAACTCGAGTTCATGGTATCAACAGCAGGCTTTTTG INCENP Inner centromere protein TRCN0000074144 CCGGCGACATCAGATGAGGAATCAACTCGAGTTGATTCCTCATCTGATGTCGTTTTTG INCENP Inner centromere protein TRCN0000074146 CCGGCGGATTTCTTATGTTCAGGATCTCGAGATCCTGAACATAAGAAATCCGTTTTTG INCENP Inner centromere protein TRCN0000222568 CCGGCCGCATCATCTGTCACAGTTACTCGAGTAACTGTGACAGATGATGCGGTTTTTG POLR2E RNA Polymerase II Subunit E TRCN0000021834 CCGGGAAGCGAATCACCACACCATACTCGAGTATGGTGTGGTGATTCGCTTCTTTTT POLR2E RNA Polymerase II Subunit E TRCN0000021835 CCGGGATGACTTGGAGAATGCCGAACTCGAGTTCGGCATTCTCCAAGTCATCTTTTT POLR2E RNA Polymerase II Subunit E TRCN0000021836 CCGGGAAGGAACTCAAGGCCCGAAACTCGAGTTTCGGGCCTTGAGTTCCTTCTTTTT POLR2E RNA Polymerase II Subunit E TRCN0000021837 CCGGCACACCATACATGACCAAGTACTCGAGTACTTGGTCATGTATGGTGTGTTTTT POLR2E RNA Polymerase II Subunit E TRCN0000021838 CCGGCATCATCATTCGCCGTTACCTCTCGAGAGGTAACGGCGAATGATGATGTTTTT BRCA1 breast cancer 1, early onset TRCN0000009823 CCGGTATAAGACCTCTGGCATGAATCTCGAGATTCATGCCAGAGGTCTTATATTTTTG BRCA1 breast cancer 1, early onset TRCN0000009824 CCGGTATAGCTGTTGGAAGGACTAGCTCGAGCTAGTCCTTCCAACAGCTATATTTTTG BRCA1 breast cancer 1, early onset TRCN0000039833 CCGGCCCTAAGTTTACTTCTCTAAACTCGAGTTTAGAGAAGTAAACTTAGGGTTTTTG BRCA1 breast cancer 1, early onset TRCN0000039834 CCGGGCCCACCTAATTGTACTGAATCTCGAGATTCAGTACAATTAGGTGGGCTTTTTG BRCA1 breast cancer 1, early onset TRCN0000039835 CCGGCCCACCTAATTGTACTGAATTCTCGAGAATTCAGTACAATTAGGTGGGTTTTTG BRCA2 breast cancer 2, early onset TRCN0000040193 CCGGCGCTTAACCTTTCCAGTTTATCTCGAGATAAACTGGAAAGGTTAAGCGTTTTTG BRCA2 breast cancer 2, early onset TRCN0000040194 CCGGGCAGCCATTAAATTGTCCATACTCGAGTATGGACAATTTAATGGCTGCTTTTTG BRCA2 breast cancer 2, early onset TRCN0000040195 CCGGGCGTTTCTAAACATTGCATAACTCGAGTTATGCAATGTTTAGAAACGCTTTTTG BRCA2 breast cancer 2, early onset TRCN0000040196 CCGGCCTCTGAAAGTGGACTGGAAACTCGAGTTTCCAGTCCACTTTCAGAGGTTTTTG BRCA2 breast cancer 2, early onset TRCN0000009825 CCGGTACAATGTACACATGTAACACCTCGAGGTGTTACATGTGTACATTGTATTTTTG USP30 ubiquitin specific peptidase 30 TRCN0000038820 CCGGCCTAGTCAACACAACCCTAAACTCGAGTTTAGGGTTGTGTTGACTAGGTTTTTG USP30 ubiquitin specific peptidase 30 TRCN0000038819 CCGGCTGTTGTGTTAAGAAAGCATTCTCGAGAATGCTTTCTTAACACAACAGTTTTTG USP30 ubiquitin specific peptidase 30 TRCN0000038821 CCGGCCTGTTCGATTTGATACCTTTCTCGAGAAAGGTATCAAATCGAACAGGTTTTTG USP30 ubiquitin specific peptidase 30 TRCN0000038822 CCGGCCATGTCATTACCTCGTCATTCTCGAGAATGACGAGGTAATGACATGGTTTTTG USP30 ubiquitin specific peptidase 30 TRCN0000038823 CCGGCACACCAGTATTTATCCTTAACTCGAGTTAAGGATAAATACTGGTGTGTTTTTG USP15 ubiquitin specific peptidase 15 TRCN0000007565 CCGGCCGTAATCAATGTGGGCCTATCTCGAGATAGGCCCACATTGATTACGGTTTTT USP15 ubiquitin specific peptidase 15 TRCN0000007566 CCGGCCTTGGAAGTTTACTTAGTTACTCGAGTAACTAAGTAAACTTCCAAGGTTTTT USP15 ubiquitin specific peptidase 15 TRCN0000007567 CCGGCCCATTGATAACTCTGGACTTCTCGAGAAGTCCAGAGTTATCAATGGGTTTTT USP15 ubiquitin specific peptidase 15 TRCN0000007568 CCGGGCTCTTGAGAATGTGCCGATACTCGAGTATCGGCACATTCTCAAGAGCTTTTT USP15 ubiquitin specific peptidase 15 TRCN0000007569 CCGGGCTCACCAAGTGAAATGGAAACTCGAGTTTCCATTTCACTTGGTGAGCTTTTT DUSP16 dual specificity phosphatase 16 TRCN0000052013 CCGGCCGGCCATTTGTGGAATACAACTCGAGTTGTATTCCACAAATGGCCGGTTTTTG

200 Supplement

DUSP16 dual specificity phosphatase 16 TRCN0000052014 CCGGCCCGAATTCTTCCCAATCTTTCTCGAGAAAGATTGGGAAGAATTCGGGTTTTTG DUSP16 dual specificity phosphatase 16 TRCN0000052015 CCGGCATCAGAAGATGCTTTGGAATCTCGAGATTCCAAAGCATCTTCTGATGTTTTTG DUSP16 dual specificity phosphatase 16 TRCN0000052016 CCGGGCCTCCAATGGATGTGTTCTACTCGAGTAGAACACATCCATTGGAGGCTTTTTG DUSP16 dual specificity phosphatase 16 TRCN0000052017 CCGGGCAACAGGACAAAGTGTTAATCTCGAGATTAACACTTTGTCCTGTTGCTTTTTG HSF1 heat shock transcription factor 1 TRCN0000007480 CCGGGCAGGTTGTTCATAGTCAGAACTCGAGTTCTGACTATGAACAACCTGCTTTTT HSF1 heat shock transcription factor 1 TRCN0000007481 CCGGGCACATTCCATGCCCAAGTATCTCGAGATACTTGGGCATGGAATGTGCTTTTT HSF1 heat shock transcription factor 1 TRCN0000007482 CCGGCCAGCAACAGAAAGTCGTCAACTCGAGTTGACGACTTTCTGTTGCTGGTTTTT HSF1 heat shock transcription factor 1 TRCN0000007483 CCGGGCCCAAGTACTTCAAGCACAACTCGAGTTGTGCTTGAAGTACTTGGGCTTTTT HSF1 heat shock transcription factor 1 TRCN0000007484 CCGGCAGTGACCACTTGGATGCTATCTCGAGATAGCATCCAAGTGGTCACTGTTTTT UBA1 ubiquitin-like modifier activating enzyme 1 TRCN0000004000 CCGGCCACTGCCTTCTACCTTGTTTCTCGAGAAACAAGGTAGAAGGCAGTGGTTTTT UBA1 ubiquitin-like modifier activating enzyme 1 TRCN0000004001 CCGGCTCCAACTTCTCCGACTACATCTCGAGATGTAGTCGGAGAAGTTGGAGTTTTT UBA1 ubiquitin-like modifier activating enzyme 1 TRCN0000004002 CCGGGCACAAATTAGAGATCACCATCTCGAGATGGTGATCTCTAATTTGTGCTTTTT UBA1 ubiquitin-like modifier activating enzyme 1 TRCN0000004003 CCGGCCTGGGATGTCACGAAGTTAACTCGAGTTAACTTCGTGACATCCCAGGTTTTT UBA1 ubiquitin-like modifier activating enzyme 1 TRCN0000004004 CCGGGTGCTATGGTTTCTATGGTTACTCGAGTAACCATAGAAACCATAGCACTTTTT UBB ubiquitin B TRCN0000011102 CCGGCCTGCGTCTGAGAGGTGGTATCTCGAGATACCACCTCTCAGACGCAGGTTTTT UBB ubiquitin B TRCN0000011103 CCGGGTGAAGGCCAAGATCCAAGATCTCGAGATCTTGGATCTTGGCCTTCACTTTTT UBB ubiquitin B TRCN0000007735 CCGGCCGTACTCTTTCTGACTACAACTCGAGTTGTAGTCAGAAAGAGTACGGTTTTT UBB ubiquitin B TRCN0000007736 CCGGCCGCACTCTTTCTGACTACAACTCGAGTTGTAGTCAGAAAGAGTGCGGTTTTT UBB ubiquitin B TRCN0000007737 CCGGGCCAAGATCCAGGATAAAGAACTCGAGTTCTTTATCCTGGATCTTGGCTTTTT UBC ubiquitin C TRCN0000011107 CCGGCGAGAATGTCAAGGCAAAGATCTCGAGATCTTTGCCTTGACATTCTCGTTTTT UBC ubiquitin C TRCN0000011108 CCGGGCAAAGATCCAAGACAAGGAACTCGAGTTCCTTGTCTTGGATCTTTGCTTTTT UBC ubiquitin C TRCN0000011109 CCGGCGAGAACGTCAAAGCAAAGATCTCGAGATCTTTGCTTTGACGTTCTCGTTTTT UBC ubiquitin C TRCN0000011110 CCGGAGGTTGATCTTTGCTGGGAAACTCGAGTTTCCCAGCAAAGATCAACCTTTTTT UBC ubiquitin C TRCN0000011111 CCGGGAGGTTGATCTTTGCCGGAAACTCGAGTTTCCGGCAAAGATCAACCTCTTTTT FBXW7 F-box and WD repeat domain containing 7 TRCN0000006555 CCGGCCTAAAGAGTTGGCACTCTATCTCGAGATAGAGTGCCAACTCTTTAGGTTTTT FBXW7 F-box and WD repeat domain containing 7 TRCN0000006556 CCGGCCAGAGAAATTGCTTGCTTTACTCGAGTAAAGCAAGCAATTTCTCTGGTTTTT FBXW7 F-box and WD repeat domain containing 7 TRCN0000006557 CCGGCCAGTCGTTAACAAGTGGAATCTCGAGATTCCACTTGTTAACGACTGGTTTTT FBXW7 F-box and WD repeat domain containing 7 TRCN0000006558 CCGGCCAGAGACTGAAACCTGTCTACTCGAGTAGACAGGTTTCAGTCTCTGGTTTTT CUL3 cullin 3 TRCN0000073343 CCGGCCCTGTTGTAATTTGAGATTTCTCGAGAAATCTCAAATTACAACAGGGTTTTTG CUL3 cullin 3 TRCN0000073344 CCGGCCCAAATCAAAGGAAATAGAACTCGAGTTCTATTTCCTTTGATTTGGGTTTTTG CUL3 cullin 3 TRCN0000073345 CCGGCGTAAGAATAACAGTGGTCTTCTCGAGAAGACCACTGTTATTCTTACGTTTTTG CUL3 cullin 3 TRCN0000073346 CCGGCGTGTGCCAAATGGTTTGAAACTCGAGTTTCAAACCATTTGGCACACGTTTTTG CUL3 cullin 3 TRCN0000073347 CCGGGCGGATAATGAAATCTAGAAACTCGAGTTTCTAGATTTCATTATCCGCTTTTTG MISSION non internal control target control #1 pLKO-1 cloning internal control vector MISSION shRNA internal control TurboGFP pLKO1 shRNA TRC internal control control pLKO1 shRNA internal control scramble pLKO1 CMV- internal control TurboGFP pLKO1 UbC- internal control TurboGFP pLKO1 CMV-FP635 internal control pLKO1 UbC-FP635 internal control MISSON non internal control target control #3 pLKO1 shRNA internal control eGFP pLKO1 shRNA internal control Luciferase MISSION non internal control target control #2

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Curriculum Vitae

Rebekka Stark

ADDRESS: Eichholzstrasse 19e, 8808 Pfäffikon, Switzerland E-MAIL: [email protected] BORN: 21.07.1987, Sigmaringen, Germany NATIONALITY: German

EDUCATION

01.2013 – 05.2017 SWISS FEDERAL INSTITUTE OF TECHNOLOGY (ETH) ZÜRICH, SWITZERLAND Institute of Molecular Health Sciences, Prof. Wilhelm Krek PhD Student . Research Field: Cell Signaling and Disease Biology; Focus: Cancer Research

10.2010 – 10.2012 UNIVERSITY OF TÜBINGEN, GERMANY M.Sc. in Biology . Majors: Molecular Cell Biology, Immunology

10.2007 – 09.2010 UNIVERSITY OF TÜBINGEN, GERMANY B.Sc. in Biology . Major: Plant Biochemistry

09.1997 – 06.2006 HOHENZOLLERNGYMNASIUM SIGMARINGEN, GEMANY University entrance diploma (Abitur)

PROFESSIONAL EXPERIENCES

01.2013 – 05.2017 ETH ZÜRICH, SWITZERLAND Institute of Molecular Health Sciences Scientific associate, PhD student

06.2015 – 09.2016 ETH ZÜRICH, SWITZERLAND Telejob/ETH-gethired Vice President and Treasurer

03.2009 – 10.2012 UNIVERSITY OF TÜBINGEN, GERMANY Center for Plant Molecular Biology (ZMBP), Prof. Georg Felix Research assistant

EXTRACURRICULAR ACTIVITIES

06.2015 – 09.2016 BOAD MEMBER of THE ACADEMIC ASSOCIATION OF SCIENTIFIC STAFF AT ETH ZURICH (AVETH) Career Event Organization and Treasurer of the job-platform ETH-gethired

EDUCARE, PRINCETON/NJ, UNITED STATES OF AMERICA 08.2006 – 08.2007 Au Pair and part-time student

09.2003 – 10.2003 OVERLAND HIGH SCHOOL, DENVER/CO, UNITED STATES OF AMERICA Exchange student

SKILLS

Languages German (native), English (fluent), French,Latin (basic) Computer MS Office (Excel, Power Point, Word), CLC Workbench

HOBBIES

Ballet, Golf, Fitness, Skiing, Travelling

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