A High-Throughput Integrated Microfluidics Method Enables
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Gene Symbol Gene Description ACVR1B Activin a Receptor, Type IB
Table S1. Kinase clones included in human kinase cDNA library for yeast two-hybrid screening Gene Symbol Gene Description ACVR1B activin A receptor, type IB ADCK2 aarF domain containing kinase 2 ADCK4 aarF domain containing kinase 4 AGK multiple substrate lipid kinase;MULK AK1 adenylate kinase 1 AK3 adenylate kinase 3 like 1 AK3L1 adenylate kinase 3 ALDH18A1 aldehyde dehydrogenase 18 family, member A1;ALDH18A1 ALK anaplastic lymphoma kinase (Ki-1) ALPK1 alpha-kinase 1 ALPK2 alpha-kinase 2 AMHR2 anti-Mullerian hormone receptor, type II ARAF v-raf murine sarcoma 3611 viral oncogene homolog 1 ARSG arylsulfatase G;ARSG AURKB aurora kinase B AURKC aurora kinase C BCKDK branched chain alpha-ketoacid dehydrogenase kinase BMPR1A bone morphogenetic protein receptor, type IA BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) BRAF v-raf murine sarcoma viral oncogene homolog B1 BRD3 bromodomain containing 3 BRD4 bromodomain containing 4 BTK Bruton agammaglobulinemia tyrosine kinase BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) C9orf98 chromosome 9 open reading frame 98;C9orf98 CABC1 chaperone, ABC1 activity of bc1 complex like (S. pombe) CALM1 calmodulin 1 (phosphorylase kinase, delta) CALM2 calmodulin 2 (phosphorylase kinase, delta) CALM3 calmodulin 3 (phosphorylase kinase, delta) CAMK1 calcium/calmodulin-dependent protein kinase I CAMK2A calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha CAMK2B calcium/calmodulin-dependent -
Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells
Published OnlineFirst January 30, 2013; DOI: 10.1158/1541-7786.MCR-12-0378 Molecular Cancer Oncogenes and Tumor Suppressors Research Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells Natalie Ludyga1, Natasa Anastasov2, Michael Rosemann2, Jana Seiler1, Nadine Lohmann1, Herbert Braselmann3, Karin Mengele4, Manfred Schmitt4, Heinz Ho€fler1,5, and Michaela Aubele1 Abstract Breast cancer is the most common malignancy in women of the Western world. One prominent feature of breast cancer is the co- and overexpression of HER2 and protein tyrosine kinase 6 (PTK6). According to the current clinical cancer therapy guidelines, HER2-overexpressing tumors are routinely treated with trastuzumab, a humanized monoclonal antibody targeting HER2. Approximately, 30% of HER2-overexpressing breast tumors at least initially respond to the anti-HER2 therapy, but a subgroup of these tumors develops resistance shortly after the administration of trastuzumab. A PTK6-targeted therapy does not yet exist. Here, we show for the first time that the simultaneous knockdown in vitro, compared with the single knockdown of HER2 and PTK6, in particular in the trastuzumab-resistant JIMT-1 cells, leads to a significantly decreased phosphorylation of crucial signaling proteins: mitogen-activated protein kinase 1/3 (MAPK 1/3, ERK 1/2) and p38 MAPK, and (phosphatase and tensin homologue deleted on chromosome ten) PTEN that are involved in tumorigenesis. In addition, dual knockdown strongly reduced the migration and invasion of the JIMT-1 cells. Moreover, the downregulation of HER2 and PTK6 led to an induction of p27, and the dual knockdown significantly diminished cell proliferation in JIMT-1 and T47D cells. -
LY2801653 Is an Orally Bioavailable Multi-Kinase Inhibitor with Potent
Invest New Drugs (2013) 31:833–844 DOI 10.1007/s10637-012-9912-9 PRECLINICAL STUDIES LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models S. Betty Yan & Victoria L. Peek & Rose Ajamie & Sean G. Buchanan & Jeremy R. Graff & Steven A. Heidler & Yu-Hua Hui & Karen L. Huss & Bruce W. Konicek & Jason R. Manro & Chuan Shih & Julie A. Stewart & Trent R. Stewart & Stephanie L. Stout & Mark T. Uhlik & Suzane L. Um & Yong Wang & Wenjuan Wu & Lei Yan & Wei J. Yang & Boyu Zhong & Richard A. Walgren Received: 19 October 2012 /Accepted: 3 December 2012 /Published online: 29 December 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com Summary The HGF/MET signaling pathway regulates a of a potent, orally bioavailable, small-molecule inhibitor wide variety of normal cellular functions that can be subverted LY2801653 targeting MET kinase. LY2801653 is a type-II to support neoplasia, including cell proliferation, survival, ATP competitive, slow-off inhibitor of MET tyrosine kinase apoptosis, scattering and motility, invasion, and angiogenesis. with a dissociation constant (Ki) of 2 nM, a pharmacodynamic −1 MET over-expression (with or without gene amplification), residence time (Koff) of 0.00132 min and t1/2 of 525 min. aberrant autocrine or paracrine ligand production, and mis- LY2801653 demonstrated in vitro effects on MET pathway- sense MET mutations are mechanisms that lead to activation dependent cell scattering and cell proliferation; in vivo anti- of the MET pathway in tumors and are associated with poor tumor effects in MET amplified (MKN45), MET autocrine prognostic outcome. -
Profiling Data
Compound Name DiscoveRx Gene Symbol Entrez Gene Percent Compound Symbol Control Concentration (nM) JNK-IN-8 AAK1 AAK1 69 1000 JNK-IN-8 ABL1(E255K)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317I)-nonphosphorylated ABL1 87 1000 JNK-IN-8 ABL1(F317I)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317L)-nonphosphorylated ABL1 65 1000 JNK-IN-8 ABL1(F317L)-phosphorylated ABL1 61 1000 JNK-IN-8 ABL1(H396P)-nonphosphorylated ABL1 42 1000 JNK-IN-8 ABL1(H396P)-phosphorylated ABL1 60 1000 JNK-IN-8 ABL1(M351T)-phosphorylated ABL1 81 1000 JNK-IN-8 ABL1(Q252H)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(Q252H)-phosphorylated ABL1 56 1000 JNK-IN-8 ABL1(T315I)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(T315I)-phosphorylated ABL1 92 1000 JNK-IN-8 ABL1(Y253F)-phosphorylated ABL1 71 1000 JNK-IN-8 ABL1-nonphosphorylated ABL1 97 1000 JNK-IN-8 ABL1-phosphorylated ABL1 100 1000 JNK-IN-8 ABL2 ABL2 97 1000 JNK-IN-8 ACVR1 ACVR1 100 1000 JNK-IN-8 ACVR1B ACVR1B 88 1000 JNK-IN-8 ACVR2A ACVR2A 100 1000 JNK-IN-8 ACVR2B ACVR2B 100 1000 JNK-IN-8 ACVRL1 ACVRL1 96 1000 JNK-IN-8 ADCK3 CABC1 100 1000 JNK-IN-8 ADCK4 ADCK4 93 1000 JNK-IN-8 AKT1 AKT1 100 1000 JNK-IN-8 AKT2 AKT2 100 1000 JNK-IN-8 AKT3 AKT3 100 1000 JNK-IN-8 ALK ALK 85 1000 JNK-IN-8 AMPK-alpha1 PRKAA1 100 1000 JNK-IN-8 AMPK-alpha2 PRKAA2 84 1000 JNK-IN-8 ANKK1 ANKK1 75 1000 JNK-IN-8 ARK5 NUAK1 100 1000 JNK-IN-8 ASK1 MAP3K5 100 1000 JNK-IN-8 ASK2 MAP3K6 93 1000 JNK-IN-8 AURKA AURKA 100 1000 JNK-IN-8 AURKA AURKA 84 1000 JNK-IN-8 AURKB AURKB 83 1000 JNK-IN-8 AURKB AURKB 96 1000 JNK-IN-8 AURKC AURKC 95 1000 JNK-IN-8 -
Crystal Structure of the Kinase Domain of Mertk in Complex with AZD7762 Provides Clues for Structure-Based Drug Development
International Journal of Molecular Sciences Article Crystal Structure of the Kinase Domain of MerTK in Complex with AZD7762 Provides Clues for Structure-Based Drug Development Tae Hyun Park 1,2 , Seung-Hyun Bae 1,3 , Seoung Min Bong 1, Seong Eon Ryu 2, Hyonchol Jang 1,3 and Byung Il Lee 1,3,* 1 Research Institute, National Cancer Center, Goyang, 10408 Gyeonggi, Korea; [email protected] (T.H.P.); [email protected] (S.-H.B.); [email protected] (S.M.B.); [email protected] (H.J.) 2 Department of Bioengineering, Hanyang University, 04763 Seoul, Korea; [email protected] 3 Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, 10408 Gyeonggi, Korea * Correspondence: [email protected]; Tel.: +82-31-920-2223; Fax: +82-31-920-2006 Received: 29 August 2020; Accepted: 21 October 2020; Published: 23 October 2020 Abstract: Aberrant tyrosine-protein kinase Mer (MerTK) expression triggers prosurvival signaling and contributes to cell survival, invasive motility, and chemoresistance in many kinds of cancers. In addition, recent reports suggested that MerTK could be a primary target for abnormal platelet aggregation. Consequently, MerTK inhibitors may promote cancer cell death, sensitize cells to chemotherapy, and act as new antiplatelet agents. We screened an inhouse chemical library to discover novel small-molecule MerTK inhibitors, and identified AZD7762, which is known as a checkpoint-kinase (Chk) inhibitor. The inhibition of MerTK by AZD7762 was validated using an in vitro homogeneous time-resolved fluorescence (HTRF) assay and through monitoring the decrease in phosphorylated MerTK in two lung cancer cell lines. -
Supplementary Table 1. in Vitro Side Effect Profiling Study for LDN/OSU-0212320. Neurotransmitter Related Steroids
Supplementary Table 1. In vitro side effect profiling study for LDN/OSU-0212320. Percent Inhibition Receptor 10 µM Neurotransmitter Related Adenosine, Non-selective 7.29% Adrenergic, Alpha 1, Non-selective 24.98% Adrenergic, Alpha 2, Non-selective 27.18% Adrenergic, Beta, Non-selective -20.94% Dopamine Transporter 8.69% Dopamine, D1 (h) 8.48% Dopamine, D2s (h) 4.06% GABA A, Agonist Site -16.15% GABA A, BDZ, alpha 1 site 12.73% GABA-B 13.60% Glutamate, AMPA Site (Ionotropic) 12.06% Glutamate, Kainate Site (Ionotropic) -1.03% Glutamate, NMDA Agonist Site (Ionotropic) 0.12% Glutamate, NMDA, Glycine (Stry-insens Site) 9.84% (Ionotropic) Glycine, Strychnine-sensitive 0.99% Histamine, H1 -5.54% Histamine, H2 16.54% Histamine, H3 4.80% Melatonin, Non-selective -5.54% Muscarinic, M1 (hr) -1.88% Muscarinic, M2 (h) 0.82% Muscarinic, Non-selective, Central 29.04% Muscarinic, Non-selective, Peripheral 0.29% Nicotinic, Neuronal (-BnTx insensitive) 7.85% Norepinephrine Transporter 2.87% Opioid, Non-selective -0.09% Opioid, Orphanin, ORL1 (h) 11.55% Serotonin Transporter -3.02% Serotonin, Non-selective 26.33% Sigma, Non-Selective 10.19% Steroids Estrogen 11.16% 1 Percent Inhibition Receptor 10 µM Testosterone (cytosolic) (h) 12.50% Ion Channels Calcium Channel, Type L (Dihydropyridine Site) 43.18% Calcium Channel, Type N 4.15% Potassium Channel, ATP-Sensitive -4.05% Potassium Channel, Ca2+ Act., VI 17.80% Potassium Channel, I(Kr) (hERG) (h) -6.44% Sodium, Site 2 -0.39% Second Messengers Nitric Oxide, NOS (Neuronal-Binding) -17.09% Prostaglandins Leukotriene, -
Structure, Function, and Regulation of the SRMS Tyrosine Kinase
International Journal of Molecular Sciences Review Structure, Function, and Regulation of the SRMS Tyrosine Kinase Chakia J. McClendon 1 and W. Todd Miller 1,2,* 1 Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794-8661, USA; [email protected] 2 Department of Veterans Affairs Medical Center, Northport, NY 11768, USA * Correspondence: [email protected] Received: 21 May 2020; Accepted: 12 June 2020; Published: 14 June 2020 Abstract: Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (SRMS) is a tyrosine kinase that was discovered in 1994. It is a member of a family of nonreceptor tyrosine kinases that also includes Brk (PTK6) and Frk. Compared with other tyrosine kinases, there is relatively little information about the structure, function, and regulation of SRMS. In this review, we summarize the current state of knowledge regarding SRMS, including recent results aimed at identifying downstream signaling partners. We also present a structural model for the enzyme and discuss the potential involvement of SRMS in cancer cell signaling. Keywords: tyrosine kinase; signal transduction; phosphorylation; SH3 domains; SH2 domains; Src family kinases 1. Introduction Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (SRMS) is a 53 kDa nonreceptor tyrosine kinase that was first discovered in mouse neural precursor cells [1]. Studies of the expression pattern of SRMS mRNA showed that the highest levels were present in lung, testes, and liver tissues. Full-length cDNA encoding SRMS was isolated from a murine lung cDNA library, with the predicted SRMS protein containing all of the conserved amino acid residues expected for a nonreceptor tyrosine kinase. -
MERTK Antibody Catalog Number: MKT-101AP Lot Number: General Information
FabGennix International, Inc. 9191 Kyser Way Bldg. 4 Suite 402 Frisco, TX 75033 Tel: (214)-387-8105, 1-800-786-1236 Fax: (214)-387-8105 Email: [email protected] Web: www.FabGennix.com Rabbit Polyclonal Anti-MERTK antibody Catalog Number: MKT-101AP Lot Number: General Information Product MERTK Antibody Description Affinity Purified Human cellular proto-oncogene (c- mer) mRNA Antibody C-epitope Accession # Uniprot: Q12866 GenBank: U08023.1 Verified Applications CM, ELISA, ICC, IF, IHC, IP, WB Species Cross Reactivity Human, Mouse, Rat Host Rabbit Immunogen Synthetic peptide taken within amino acid region 900-994 on MerTK protein. Alternative Nomenclature c mer proto oncogene tyrosine kinase antibody, cMER antibody, Eyk antibody, MER antibody, MER receptor tyrosine kinase antibody, MERK antibody, MERPEN antibody, Mertk antibody, MERTK c-mer proto-oncogene tyrosine kinase antibody, MGC133349 antibody, nmf12 antibody, Nyk antibody, Proto oncogene tyrosine protein kinase MER antibody, Receptor tyrosine kinase MerTK antibody, RP38 antibody, STK kinase antibody, Tyrosine-protein kinase Mer antibody Physical Properties Quantity 100 µg Volume 200 µl Form Affinity Purified Immunoglobulins Determinant C-epitope Immunoglobulin & Concentration 0.75 mg/ml IgG in antibody stabilization buffer Storage Store at -20⁰C for long term storage. Related Products Catalog # BIOTIN-Conjugated MKT100-BIOTIN FITC-Conjugated MKT100-FITC Antigenic Blocking Peptide P-MKT100 Western Blot Positive Control PC-MKT Tel: (214)-387-8105, 1-800-786-1236 Fax: (214)-387-8105 Email: [email protected] Web: www.FabGennix.com Recommended Dilutions DOT Blot 1:10,000 ELISA 1:10,000 Immunocytochemistry 1:200 Immunofluorescence 1:200 Immunohistochemistry 1:200 Immunoprecipitation 1:200 Western Blot 1:750 Application Verification: WB using MKT-101AP and human RPE cells. -
Amanda Harvey Institute for Environment Health and Societies
PROTEIN TYROSINE KINASE-6 (PTK6) Amanda Harvey Institute for Environment Health and Societies Brunel University London United Kingdom [email protected] Synonyms Breast Tumor Kinase (Brk) Historical Background The intracellular protein tyrosine kinase, PTK6 (also known as the breast tumor kinase, Brk), has been implicated in the development and progression of a number of different tumor types. First identified in 3 separate studies in the early 1990s, it was initially found in a study to determine which tyrosine kinases were expressed in human melanocytes and then the full-length sequence was subsequently cloned from metastatic breast cancer using a screen to identify novel kinases that were expressed in tumors, but not normal breast tissue. Identification of the murine orthologue, sik, in mouse intestinal cells was achieved by the generation of a library of kinase catalytic domains. PTK6 is related to the Src family of protein kinases and belongs to a distinct class of enzymes which includes Frk and SRMS (reviewed Harvey and Burmi 2011) and expression produces two different isoforms as a result of alternative splicing (reviewed in Hussain and Harvey 2014) (Figure 1). Figure 1 –– PTK6 Figure 1.tif Figure 1: PTK6 domain structure. Schematic representation of the PTK6 gene structure and its products. All 8 exons are contained in the PTK6 transcript, resulting in production of a full length, fully functional protein. ALT-PTK6 arises as a result of alternative splicing, excluding exon 2. The subsequent protein shares the amino-terminus and the SH3 domain with its full length isoform and a frameshift results in the carboxy-terminus being truncated and proline rich (PR) Under normal physiological conditions, PTK6 expression is highly controlled and is usually limited to differentiating cells of epithelial origin. -
Effects of Fyn-Related-Kinase Activity on Breast
EFFECTS OF FYN-RELATED-KINASE ACTIVITY ON BREAST CANCER CELL PROLIFERATION, MIGRATION, INVASION AND COLONY FORMATION A Thesis Submitted to the College of Graduate Studies and Research In Partial Fulfillment of the Requirements For the Degree of Master of Science In the Department of Biochemistry University of Saskatchewan Saskatoon By Chenlu Dai Copyright Chenlu Dai, January, 2015. All rights reserved. Permission to Use In presenting this thesis in partial fulfilment of the requirements for a Postgraduate degree from the University of Saskatchewan, I agree that the Libraries of this University may make it freely available for inspection. I further agree that permission for copying of this thesis in any manner, in whole or in part, for scholarly purposes may be granted by the professor or professors who supervised my thesis work or, in their absence, by the Head of the Department or the Dean of the College in which my thesis work was completed. It is understood that any copying or publication or use of this thesis or parts thereof financial gain shall not be allowed without my written permission. It is also understood that due recognition shall be given to me and to the University of Saskatchewan in any scholarly use which may be made of any material in my thesis. Requests for permission to copy or to make other use of material in this thesis in whole or part should be addressed to: Head of the Department of Biochemistry University of Saskatchewan Saskatoon, Saskatchewan, S7N 5E5 i ABSTRACT The human Fyn-related kinase (FRK) is a member of subfamily of Src-related kinases family. -
Mammary Gland Specific Expression of Brk/PTK6 Promotes Delayed
Lofgren et al. Breast Cancer Research 2011, 13:R89 http://breast-cancer-research.com/content/13/5/R89 RESEARCHARTICLE Open Access Mammary gland specific expression of Brk/PTK6 promotes delayed involution and tumor formation associated with activation of p38 MAPK Kristopher A Lofgren1,2,3, Julie H Ostrander1,3, Daniel Housa1,3,4, Gregory K Hubbard1,3, Alessia Locatelli1,3, Robin L Bliss3, Kathryn L Schwertfeger2,3,5 and Carol A Lange1,2,3,6* Abstract Introduction: Protein tyrosine kinases (PTKs) are frequently overexpressed and/or activated in human malignancies, and regulate cancer cell proliferation, cellular survival, and migration. As such, they have become promising molecular targets for new therapies. The non-receptor PTK termed breast tumor kinase (Brk/PTK6) is overexpressed in approximately 86% of human breast tumors. The role of Brk in breast pathology is unclear. Methods: We expressed a WAP-driven Brk/PTK6 transgene in FVB/n mice, and analyzed mammary glands from wild-type (wt) and transgenic mice after forced weaning. Western blotting and immunohistochemistry (IHC) studies were conducted to visualize markers of mammary gland involution, cell proliferation and apoptosis, as well as Brk, STAT3, and activated p38 mitogen-activated protein kinase (MAPK) in mammary tissues and tumors from WAP-Brk mice. Human (HMEC) or mouse (HC11) mammary epithelial cells were stably or transiently transfected with Brk cDNA to assay p38 MAPK signaling and cell survival in suspension or in response to chemotherapeutic agents. Results: Brk-transgenic dams exhibited delayed mammary gland involution and aged mice developed infrequent tumors with reduced latency relative to wt mice. -
Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies Timothy M
Published OnlineFirst May 26, 2016; DOI: 10.1158/0008-5472.CAN-16-0058 Cancer Therapeutics, Targets, and Chemical Biology Research Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies Timothy M. Shaver1,2, Brian D. Lehmann1,2, J. Scott Beeler1,2, Chung-I Li3, Zhu Li1,2, Hailing Jin1,2, Thomas P. Stricker4, Yu Shyr5,6, and Jennifer A. Pietenpol1,2 Abstract Triple-negative breast cancer (TNBC) and other molecularly discovered a clinical occurrence and cell line model of the target- heterogeneous malignancies present a significant clinical chal- able FGFR3–TACC3 fusion in TNBC. Expanding our analysis to lenge due to a lack of high-frequency "driver" alterations amena- other malignancies, we identified a diverse array of novel and ble to therapeutic intervention. These cancers often exhibit geno- known hybrid transcripts, including rearrangements between mic instability, resulting in chromosomal rearrangements that noncoding regions and clinically relevant genes such as ALK, affect the structure and expression of protein-coding genes. How- CSF1R, and CD274/PD-L1. The over 1,000 genetic alterations ever, identification of these rearrangements remains technically we identified highlight the importance of considering noncod- challenging. Using a newly developed approach that quantita- ing gene rearrangement partners, and the targetable gene tively predicts gene rearrangements in tumor-derived genetic fusions identified in TNBC demonstrate the need to advance material, we identified