And Systems-Based Re-Engineering of Dendritic Cells with Non-Coding Rnas for Cancer Immunotherapy

Supplementary Materials

Network- and systems-based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy

Xin Lai1,5,6,*, Florian S. Dreyer1,5,6, Martina Cantone1,5,6, Martin Eberhardt1,5,6, Kerstin F. Gerer2,5,6, Tanushree Jaitly1,5,6, Steffen Uebe3, Christopher Lischer1,5,6, Arif Ekici3, Jürgen Wittmann4, Hans-Martin Jäck4, Niels Schaft2,5,6, Jan Dörrie2,5,6, Julio Vera1,5,6,* 1. Laboratory of Systems Tumor Immunology, Department of Dermatology, Friedrich-Alexander- Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany 2. RNA Group, Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany 3. Department of Human Genetics, Universitätsklinikum Erlangen, Erlangen, Germany 4. Division of Molecular Immunology, Department of Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany 5. Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany 6. Comprehensive Cancer Center (CCC) Erlangen, Erlangen, Germany

* To whom correspondence should be addressed. Xin Lai, Tel: +49(0)91318545888, E-mail: xin.lai@uk- erlangen.de; Julio Vera, Tel: +49(0)91318545876, E-mail: [email protected].

Contents

SUPPLEMENTARY TEXT ...... 2 MicroRNA quantification ...... 2 Reactome pathway hierarchy ...... 2 Gene set enrichment analysis ...... 2 Gene prioritization in regulatory networks ...... 3 References ...... 3 SUPPLEMENTARY FIGURES ...... 5 SUPPLEMENTARY TABLE CAPTIONS ...... 14 SUPPLEMENTARY FIGURE S2 AND S4 ...... 16

SUPPLEMENTARY TEXT

MicroRNA quantification After using FastQC [1] to verify the quality of the samples (N and GC content, sequence quality score, and sequence duplication level), neither trimming nor adapter removal was performed. As observed in the FastQC report, a high N content is noticed towards the end of the sequences, and given the presence of the adaptor sequence at the beginning of the read, a hard-trimming procedure would have created sequences with too few remaining nucleotides, hence causing the loss of information. As consequence, the mapping step was performed with BWA [2]. The “BWA mem” function is capable of compensating for the presence of adapters and handling short reads, thus aligning only the sequence of the read containing the miRNA. Reads were mapped to the human reference genome hg19. The obtained SAM files were split according to chromosomal location of the mapped read in order to parallelize and speed up the quantification procedure. Each chromosome-specific file was used as input for bedtools genomecov [3], specifying a GFF annotation file containing miRNAs only as reference. This function produces per-base counts on the reference. To further quantify the miRNA content, a customized pipeline was designed. For characterizing the expression value for pri-miRNAs and mature miRNAs separately, the positions annotated in the miRNA- specific GFF file were extracted and then accessed in the per-base counts. The GFF file was taken from miRBase (version 21, genome id GRCh38, genome accession NCBI_Assembly:GCA_000001405.15, release 06/2014). For each interval (from start to end position of each pre- and mature-miRNA) given in the GFF file, the average count (or pseudo-count) was calculated and assigned to the annotated miRNA or pri-miRNA.

Reactome pathway hierarchy We downloaded the Reactome pathway relation data (release 68) and created a Homo sapiens pathway relation network that was used to retrace pathways’ hierarchy. Specifically, pathways that appear at the top of the directional network (i.e., the pathways have only outgoing edges and no ingoing edges) were regarded as root categories. Pathways belonging to a root category were identified by manual searching. We started by searching the first-neighbour terms of a root category and continued until no more first- neighbour terms could be added into the category. This resulted in a pathway category with its associated pathways. By doing so, we successfully reproduced 26 root categories from Reactome.

Gene set enrichment analysis We applied a competitive gene set test to perform gene set enrichment analyses for Reactome pathways. The algorithm CAMERA tests whether the genes in the set are lowly or highly ranked in terms of differential expression relative to genes not in the set [4]. Specifically, genes were sorted based on their weighted log2 fold-change (i.e., log2 fold-change divided by the standard error of the log2 fold-change) from differential expression analysis to create a background gene list. The enrichment score of a gene set 2 was calculated by walking down the background list, increasing a local enrichment score when members of the gene set are frequently encountered and decreasing it when the associated genes are less encountered [5,6]. The maximum local enrichment score was used as an enrichment score of a gene set. A positive score means that the pathway-specific genes are more likely to be highly ranked in the gene list (i.e., their corresponding expressions tend to be upregulated in caIKK-DCs), while a negative score means that the genes are more likely to be lowly ranked (i.e., their corresponding expressions tend to be downregulated in caIKK-DCs). The corresponding p-value of a pathway was estimated after adjusting the variance of gene-wise statistics using a factor that estimates gene-wise correlation and the number of genes in the tested gene set. All obtained p-values were corrected using the Benjamini-Hochberg method. Pathways with FDR ≤ 0.05 were regarded as significantly up- (positive score) or down-regulated (negative score) in our comparison of caIKK-DCs with controls.

Gene prioritization in regulatory networks The following formula was used to score a gene in a network 𝑆 𝑑 𝐴𝑈𝐶 ∙ ∑ 𝑁𝑊 𝑁𝑊𝑰𝐷𝑛, 𝑚 𝑑), ∙ with 𝑁𝑊 log10adjp ∙ |log2fc | and 𝑁𝑊 ∑ 𝑁𝑊 . The node weights (NW) of a gene is calculated as the product of its absolute log2 fold change and the negative log10-transformation of the adjusted p-value, both of which were obtained through a differential gene expression analysis. 𝑁𝑊 is the average of the node weights of all network nodes. 𝑰𝐷𝑛, 𝑚 𝑑 is an indicator function, when the distance (D) between n and m is shorter than d it equals 1 otherwise it equals 0. The distance between two nodes was calculated and normalized using the equation D(n,m) = 1 – |𝑝|, where p represents the Pearson correlation coefficient between two interacting genes. The equation assigns an interaction with strong correlation a shorter distance, indicating that the perturbation of the source gene is more likely to activate or inhibit the expression of the target gene. d is a network- customized, topology-dependent distance threshold between pairs of nodes, and the distance is calculated using the diffusion kernel-based method that incorporates distances along multiple paths between pairs of genes [7]. Before calculation d is discretized into corresponding bins. Then, d increases from 0 to the diameter of the network (i.e., the maximum distance between nodes) by step 1, and for each step we computed a value, resulting in a curve that always ends at 0 when d reaches its maximum. The resulted area under the curve (AUC) is defined as the score of a node 𝑆𝑑 and the score is used to prioritize genes in a network.

References 1. Andrews S. Babraham Bioinformatics - FastQC A Quality Control tool for High Throughput Sequence Data. 2017. Available at: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/ 2. Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv:13033997. 2013. Available at: http://arxiv.org/abs/1303.3997 3. Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010; 26: 841–2. 3

4. Wu D, Smyth GK. Camera: a competitive gene set test accounting for inter-gene correlation. Nucleic Acids Res. 2012; 40: e133–e133. 5. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005; 102: 15545– 50. 6. Reimand J, Isserlin R, Voisin V, et al. Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, Cytoscape and EnrichmentMap. Nature Protocols. 2019; 14: 482–517. 7. Cornish AJ, Markowetz F. SANTA: quantifying the functional content of molecular networks. PLoS Comput Biol. 2014; 10: e1003808.

SUPPLEMENTARY FIGURES

Figure S1. Efficiency of electroporation of caIKK in DCs. DC were prepared identically to those used for RNA-sequencing: cocktail-matured DCs were electroporated with mRNA, encoding constitutively active IKKß (caIKK) or, as negative control, Melan-A (MelA). (A) After 24 h of incubation, supernatants were harvested and the concentrations of the indicated inflammatory cytokines were determined. The average + standard deviation of three independent experiments is shown. (B) Electroporated DCs were harvested 24 h, 48 h, and 72 h after electroporation, and the expression of the indicated surface markers was determined. Isotype background values were subtracted. The average + standard deviation of three independent experiments is shown. (C) From all DC-preparations, which were used for RNA sequencing, an aliquot was cultured for 24 h after electroporation. To confirm activation of NF-κB, CD25 and CD70 expression were measured. The left panel shows a representative histogram, and the right panel depicts data from the seven donors used in the study. The fold-induction was calculated by dividing the mean fluorescence intensity of the caIKK-transfected cells by that of the MelA-transfected ones. The black bar indicates the average.

Figure S2. Summary of a differential gene expression analysis for the complete transcriptome in caIKK-DCs (caIKK) and controls (Ctrl) obtained from seven donors. (A) The volcano plot shows significantly (FDR ≤ 0.05) up- (red) and down-regulated (blue) genes in caIKK-DCs. MLANA encoding Melan-A and IKBKB encoding IKKβ are identified as the most differentially expressed genes. (B) The PCA plot shows the distribution of DC samples in a principal component analysis using the complete transcriptome data (left) or only the miRNA expression data (right) as input. (C) The heat map shows a hierarchical clustering of the DC samples using the 44 differentially expressed miRNAs. The grid cells show the miRNA-wise z-score of expression. The hierarchical clustering was performed using Euclidean distance with the average linkage algorithm.

Figure S3. Overview of pathways in which the differentially expressed genes are enriched. Pathways from Reactome organized according to its pathway categories (labelled grey triangles) are shown as square nodes. The corresponding enrichment score is shown as the node’s fill colour (red: positive score; blue: negative score). Square grey nodes represent pathways that have no enrichment score because they do not contain genes but other molecules, such as chemical compounds and small molecules. Nodes with black borders are identified as significantly enriched pathways (FDR ≤ 0.05). The network was arranged using prefuse force-directed layout before manual adaptation. A support vector format of the figure can be found in the separated PDF file.

Figure S4. miRNA targeting profiles in enriched Reactome pathways. The heat map shows the number of protein-coding genes targeted by the DE miRNAs in the significantly enriched pathways (FDR ≤ 0.05). The pathways are clustered by the 26 primary Reactome categories (colour code on the left side). Each cluster begins with a category term followed by the enriched pathways belonging to this category. 8

Some pathways are associated with multiple categories, e.g., synthesis of DNA and DNA replication pre- initiation are can be found in cell cycle and DNA replication. The top annotation shows statistics of differential expression analysis of the miRNAs (i.e., log2 fold-change and FDR) and the number of the terms (including pathways and categories) regulated by the miRNA. The right annotation show the results of the gene set enrichment analysis (enrichment scores and FDR), excluding the 26 category terms (grey). On the right side, the number of genes that were found in our RNA-seq data and the total number of molecules of a category or a pathway are given. A support vector format of the figure can be found in the separated PDF file.

Figure S5. Illustration of gene prioritization results. The gene prioritization method was used to rank genes in a regulatory network that underlies the Toll-like Receptor 4 Cascade (R-HSA-166016) from the Reactome category immune system. The network contains three types of molecular species (i.e., miRNAs, protein-coding genes, and TFs) and two types of molecular interactions such as functional interactions (FI) among protein-coding genes and post-transcriptional interactions (PTI) mediated by miRNAs. The size of a node is proportional to its node degree (i.e., the number of edges connected to the node). The colour of its border denotes a node’s expression perturbation. Node colour represents their ranking in the network (red is the highest ranking and yellow is the lowest). Edge colour indicates Pearson correlation coefficients between genes. The top three ranking miRNAs and genes are labelled.

Figure S6. Network prioritisation-derived ranks of protein-coding genes broken down according to their characteristic immune function. The box plots show the ranks of all protein-coding genes (points) appearing in the reconstructed regulatory networks from the signal transduction (top) and immune system (bottom) pathway categories, respectively. TFs are drawn in triangles and NF-κB family members (i.e., NFKB1, NFKB2, RELA, RELB, and REL) are labelled with their names. Genes with smaller values rank 11 higher in the networks. Genes are classified according to their characteristic function in the immune system, with the non-immune genes collected in a separate group that is overlaid by the highest number of genes. The boxes are ordered based on the average ranking of the involved genes, beginning with the highest average ranking on the left.

Figure S7. miRNA-gene interactions in immune signalling pathways. Identified miRNA-mediated gene regulation in pathways associated with the category immune system. This heat map shows all significantly enriched pathways in the category and all identified miRNA-gene interactions (Pearson correlation < 0). The annotation of the heat map is the same as in Figure 5 in the main text.

SUPPLEMENTARY TABLE CAPTIONS

Supplementary Table S1 Read counts of the annotated protein-coding genes. The mapped and annotated read counts of protein-coding genes in DCs. The DC samples were collected from 7 donors (S1-S7) and divided into two groups (caIKK-DC and Ctrl).

Supplementary Table S2 Read counts of the annotated miRNAs. The mapped and annotated read counts of miRNAs in DCs. The DC samples were collected from 7 donors (S1-S7) and divided into two groups (caIKK-DC and Ctrl).

Supplementary Table S3 Results of differential gene expression analysis of protein-coding genes. The table columns are Ensembl gene identifier, gene symbol, base mean of gene expression in all DC samples, log2 fold-change (caIKK-DC vs Ctrl), calculated statistics of Wald test, p-value, and adjusted p- value calculated using the Benjamini Hochberg method. Genes whose adjusted p-values are NA are those filtered out by independent filtering for multiple comparisons. The rows highlighted in yellow are the identified significantly differentially expressed protein-coding genes.

Supplementary Table S4 Results of differential gene expression analysis of miRNAs. The table columns are miRbase accession identifier, miRNA name, base mean of miRNA expression in all DC samples, log2 fold-change (caIKK-DC vs Ctrl), calculated statistics of Wald test, p-value, and adjusted p- value calculated using the Benjamini Hochberg method. miRNAs whose adjusted p-values are NA are those filtered out by independent filtering for multiple comparisons. The rows highlighted in yellow are the identified significantly differentially expressed miRNAs.

Supplementary Table S5 Results of gene set enrichment analysis. The table contains the results of a gene set enrichment analysis using Reactome pathways as gene sets. The table columns are the description of pathways, the Reactome identifiers, the category of a pathway, total number of molecules of a pathway, the number of identified genes from our RNA-seq data in a pathway, calculated enrichment score of a pathway, p-value and FDR of the enrichment analysis, and list of genes appearing in the pathway. A pathway may appear several times when it is associated with several categories. Category terms are highlighted in yellow and pathways associated with NF-κB signalling are highlighted in purple.

Supplementary Table S6 Curated miRNA-gene interactions. The table contains identified miRNA-gene interactions. The green columns are the general information about miRNA and their targeting genes including miRNA-gene interaction identifier, official gene symbol, transcript identifier of target genes, miRbase identifier of miRNAs, miRNA names, and miRNA family. The purple columns contain predictions about miRNA-gene interactions by TargetScan, including seed sequence of miRNA, mature sequences of miRNAs, total number of conserved/non-conserved miRNA binding sites as well as the number of different types of binding sites such as 8mer, 7mer_m8, 7mer_1a and 6mer, and cumulative weighted context scores for the putative miRNA binding sites. The cyan columns are experimental validation of miRNA- gene interactions from miRTarbase including the identifier of the database, types of experiments used to 14 validate the interactions (i.e., strong and weak evidence that denotes low and high throughput experimental validation, respectively), and the corresponding PubMed identifiers of the corresponding studies. The orange columns are information from starBase including the putative miRNA binding sites supported by the number of Ago CLIP-seq experiments that shows intersection of the miRNA binding sites with binding sites of Ago protein. The red column is the calculated Pearson correlation coefficients between miRNAs and their targeted genes using our RNA-seq data.

Supplementary Table S7 Ranking of IKBKB in pathways. The table contains the ranking of IKBKB in enriched pathways. The columns are gene names, ranking of genes, Reactome pathway name, Reactome identifier, category of pathways, and the results of gene set enrichment analysis.

Supplementary Table S8 Immune genes related with DC-mediated immune response. The table contains a list of immune genes that are related with immunological function of DCs. The columns are official gene symbols, characteristic immune function, and their expression profiles including base mean, log2 fold-change, p-value, and adjusted p-value. The genes mentioned in the main text are highlighted in yellow. NA: not available.

Supplementary Table S9 Identified miRNA-gene interactions for the pathway category immune system. The table contains a list of identified miRNA-gene interactions for the pathways under the category of immune system. The columns are miRNA names, official gene symbols of target genes, and Pearson correlation coefficients.

Supplementary Table S10 Association between gene and DC phenotypes. The table contains annotated gene-phenotype associations curated according to a literature review. The columns are categories of genes, official gene symbols, regulation of DC phenotypes by genes, DC phenotypes, and corresponding references.

Figure S2

Axonal growth inhibition (RHOA activation)

Axonal growth stimulation

Binding of TCF/LEF:CTNNB1 to target gene promoters

NRIF signals cell death from the nucleus

NRAGE signals death through JNK

PDE3B signalling

NADE modulates death signalling

p75NTR regulates axonogenesis

Formation of the beta-catenin:TCF transactivating complex

Cell death signalling via NRAGE, NRIF and NADE

Regulation of FZD by ubiquitination

Ceramide signalling

NFG and proNGF binds to p75NTR WNT mediated activation of DVL

PKB-mediated events

NF-kB is activated and signals survival

Deactivation of the beta-catenin transactivating complex

Disassembly of the destruction complex and recruitment of AXIN to the membrane

Negative regulation of TCF-dependent signaling by DVL-interacting proteins

Regulated proteolysis of p75NTR

Activation of AKT2 Downregulation of SMAD2/3:SMAD4 transcriptional activity

p75NTR signals via NF-kB

Degradation of AXIN SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription

Negative regulation of TCF-dependent signaling by WNT ligand antagonists

p75NTR recruits signalling complexes

p75 NTR receptor-mediated signalling

Regulation of TNFR1 signaling

TCF dependent signaling in response to WNT

ERKs are inactivated

TNFR1-mediated ceramide production

PKA activation

Degradation of DVL

p75NTR negatively regulates cell cycle via SC1

Asymmetric localization of PCP proteins

PI3K Cascade

TNFR1-induced NFkappaB signaling pathway

Formation of Incision Complex in GG-NER

Downregulation of TGF-beta receptor signaling Gap-filling DNA repair synthesis and ligation in GG-NER

Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer

TNFR1-induced proapoptotic signaling

Dual Incision in GG-NER

WNT5A-dependent internalization of FZD4

Beta-catenin phosphorylation cascade

Translesion synthesis by REV1

Repression of WNT target genes

TNF signaling ERK/MAPK targets

SOS-mediated signalling

Termination of translesion DNA synthesis DNA Damage Recognition in GG-NER PKA-mediated phosphorylation of CREB

Translesion synthesis by POLK PCP/CE pathway

CaMK IV-mediated phosphorylation of CREB S45 mutants of beta-catenin aren't phosphorylated

TGF-beta receptor signaling activates SMADs

CREB phosphorylation Initiation of Nuclear Envelope Reformation TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) Polymerase switching on the C-strand of the telomere T41 mutants of beta-catenin aren't phosphorylated

Global Genome Nucleotide Excision Repair (GG-NER) Removal of the Flap Intermediate from the C-strand

WNT5A-dependent internalization of FZD2, FZD5 and ROR2

S37 mutants of beta-catenin aren't phosphorylated

FasL/ CD95L signaling

TRKA activation by NGF

Degradation of beta-catenin by the destruction complex

Separation of Sister Chromatids

S33 mutants of beta-catenin aren't phosphorylated

Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)

WNT ligand biogenesis and trafficking

Formation of TC-NER Pre-Incision Complex Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template Telomere C-strand synthesis initiation

IRS-mediated signalling

TRAIL signaling Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) Processive synthesis on the C-strand of the telomere Nuclear Envelope Reassembly

Beta-catenin independent WNT signaling Translesion Synthesis by POLH

APC truncation mutants are not K63 polyubiquitinated

Cam-PDE 1 activation Signaling by TGF-beta Receptor Complex

IRS activation

NGF-independant TRKA activation

Nuclear Events (kinase and transcription factor activation)

Antagonism of Activin by Follistatin

Calmodulin induced events

Glycogen storage disease type 0 (liver GYS2) Telomere C-strand (Lagging Strand) Synthesis

APC truncation mutants have impaired AXIN binding Ca2+ pathway

Deletions in the AXIN genes in hepatocellular carcinoma result in elevated WNT signaling

phosphorylation site mutants of CTNNB1 are not targeted to the proteasome by the destruction complex

Death Receptor Signalling Dual incision in TC-NER Glycogen storage disease type IV (GBE1)

Transcription-Coupled Nucleotide Excision Repair (TC-NER)

Activation of TRKA receptors Signaling by WNT Mitotic Anaphase Translesion synthesis by POLI

Mismatch Repair Nucleotide Excision Repair

Signaling by BMP Downregulation of ERBB2:ERBB3 signaling

IRS-related events triggered by IGF1R Signal attenuation

AXIN missense mutants destabilize the destruction complex Myoclonic epilepsy of Lafora

DNA Damage Bypass

Mitotic Metaphase/Anaphase Transition PLC-gamma1 signalling

Glycogen storage disease type XV (GYG1) Retrograde neurotrophin signalling

Signaling by Activin

Glycogen storage disease type 0 (muscle GYS1)

Sensing of DNA Double Strand Breaks

truncated APC mutants destabilize the destruction complex

Gap-filling DNA repair synthesis and ligation in TC-NER Telomere Extension By Telomerase

Ligand-receptor interactions

Cohesin Loading onto Chromatin Recognition of DNA damage by PCNA-containing replication complex Insulin receptor signalling cascade Deletions in the AMER1 gene destabilize the destruction complex

PI3K/AKT activation VEGFR2 mediated vascular permeability

Resolution of Sister Chromatid Cohesion

AXIN mutants destabilize the destruction complex, activating WNT signaling Signalling to STAT3

WNT ligand secretion is abrogated by the PORCN inhibitor LGK974

Extension of Telomeres

GLI proteins bind promoters of Hh responsive genes to promote transcription Release of Hh-Np from the secreting cell

phospho-PLA2 pathway

Negative regulation of NOTCH4 signaling

VEGFR2 mediated cell proliferation

Toxicity of botulinum toxin type B (BoNT/B) Glycogen storage disease type II (GAA)

NOTCH4 Intracellular Domain Regulates Transcription

CaM pathway

Noncanonical activation of NOTCH3

MGMT-mediated DNA damage reversal Glycogen storage diseases Misspliced GSK3beta mutants stabilize beta-catenin SHC-related events triggered by IGF1R TCF7L2 mutants don't bind CTBP

Downregulation of ERBB2 signaling NOTCH3 Intracellular Domain Regulates Transcription Toxicity of botulinum toxin type E (BoNT/E) DNA Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks Signaling by TGF-beta family members DNA Double Strand Break Response Condensation of Prometaphase Chromosomes

Truncations of AMER1 destabilize the destruction complex Misspliced LRP5 mutants have enhanced beta-catenin-dependent signaling

Mitotic Metaphase and Anaphase Signaling by NTRK1 (TRKA)

NTRK3 as a dependence receptor Degradation of GLI1 by the proteasome

AMER1 mutants destabilize the destruction complex Toxicity of botulinum toxin type F (BoNT/F) Condensation of Prophase Chromosomes

Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes Nuclear Pore Complex (NPC) Disassembly

NTF3 activates NTRK3 signaling IGF1R signaling cascade Regulation of TP53 Expression Golgi Cisternae Pericentriolar Stack Reorganization

NOTCH3 Activation and Transmission of Signal to the Nucleus Toxicity of botulinum toxin type G (BoNT/G)

DNA Damage Reversal Hedgehog 'on' state

Toxicity of botulinum toxin type D (BoNT/D) XAV939 inhibits tankyrase, stabilizing AXIN Packaging Of Telomere Ends

NTF4 activates NTRK2 (TRKB) signaling Toxicity of botulinum toxin type A (BoNT/A) Mitotic Telophase/Cytokinesis BDNF activates NTRK2 (TRKB) signaling

ERBB2 Regulates Cell Motility GRB2 events in ERBB2 signaling DNA Double-Strand Break Repair Activated NTRK3 signals through PI3K Hedgehog ligand biogenesis

Mitotic Prometaphase Signaling by NOTCH4

VEGFA-VEGFR2 Pathway

Degradation of GLI2 by the proteasome

RNF mutants show enhanced WNT signaling and proliferation PI3K events in ERBB2 signaling

VEGF binds to VEGFR leading to receptor dimerization

Telomere Maintenance

Toxicity of tetanus toxin (TeNT) ALKBH3 mediated reversal of alkylation damage

Regulation of TP53 Degradation Fanconi Anemia Pathway

Signalling to ERK5

Depolymerisation of the Nuclear Lamina Signaling by NOTCH3 Signal Signaling by WNT in cancer Reversal of alkylation damage by DNA dioxygenases Activation of SMO

MASTL Facilitates Mitotic Progression Signaling by NTRK3 (TRKC) PLCG1 events in ERBB2 signaling Activated NTRK2 signals through PLCG1

Ca-dependent events Recruitment of NuMA to mitotic centrosomes

Insulin receptor recycling Hedgehog 'off' state DAG and IP3 signaling

NTRK2 activates RAC1 Activated NOTCH1 Transmits Signal to the Nucleus

HDR through MMEJ (alt-NHEJ)

Activated NTRK2 signals through FYN TP53 Regulates Transcription of Genes Involved in Cytochrome C Release

Activated NTRK3 signals through PLCG1 Estrogen-dependent gene expression Recruitment of mitotic centrosome proteins and complexes Cyclin A/B1/B2 associated events during G2/M transition Nuclear Envelope Breakdown Mitotic Prophase AURKA Activation by TPX2 Toxicity of botulinum toxin type C (BoNT/C)

TP53 Regulates Transcription of Death Receptors and Ligands

Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants

Signaling by Insulin receptor

Neurotoxicity of clostridium toxins Homology Directed Repair HHAT G278V abrogates palmitoylation of Hh-Np Deposition of new CENPA-containing nucleosomes at the centromere

Nonhomologous End-Joining (NHEJ) Regulation of TP53 Expression and Degradation

NOTCH4 Activation and Transmission of Signal to the Nucleus VEGF ligand-receptor interactions GLI3 is processed to GLI3R by the proteasome

TP53 Regulates Transcription of Caspase Activators and Caspases Signaling by Hedgehog TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain The role of GTSE1 in G2/M progression after G2 checkpoint Processing of DNA double-strand break ends

Signaling by NTRK2 (TRKB) Signaling by ERBB2 Repair

Regulation of TP53 Activity through Association with Co-factors

GRB7 events in ERBB2 signaling

TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest Base Excision Repair ALKBH2 mediated reversal of alkylation damage Activation of NIMA Kinases NEK9, NEK6, NEK7 M Phase Activated NTRK2 signals through RAS Hh mutants that don't undergo autocatalytic processing are degraded by ERAD Signaling by NTRKs Nucleosome assembly

TGFBR2 MSI Frameshift Mutants in Cancer Activated NTRK2 signals through FRS2 and FRS3 Activated NTRK3 signals through RAS Diseases of carbohydrate metabolism

TGFBR1 LBD Mutants in Cancer

Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)

Centrosome maturation

APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway Signaling by cytosolic FGFR1 fusion mutants

TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest Polo-like kinase mediated events TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain Signaling by VEGF

Regulation of TP53 Activity through Phosphorylation Signalling to ERKs

Chromosome Maintenance

HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA) Clearance of Nuclear Envelope Membranes from Chromatin

Signaling by FGFR1 amplification mutants SHC1 events in ERBB2 signaling PI5P Regulates TP53 Acetylation G2/M Transition

Signaling by Ligand-Responsive EGFR Variants in Cancer

TGFBR1 KD Mutants in Cancer Loss of Function of TGFBR1 in Cancer Neurophilin interactions with VEGF and VEGFR

ERBB2 Activates PTK6 Signaling TGFBR2 Kinase Domain Mutants in Cancer HDR through Single Strand Annealing (SSA)

Activated NTRK2 signals through PI3K Signaling by Hippo TP53 Regulates Transcription of Cell Death Genes Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex

PTK6 Expression Loss of Function of TGFBR2 in Cancer

Activated NTRK2 signals through CDK5 Transduction

Loss of proteins required for interphase microtubule organization from the centrosome

NTF3 activates NTRK2 (TRKB) signaling Regulation of TP53 Activity through Acetylation

ESR-mediated signaling Hh mutants abrogate ligand secretion FBXL7 down-regulates AURKA during mitotic entry and in early mitosis RA biosynthesis pathway Signaling by NOTCH1

GRB2 events in EGFR signaling Activation of ATR in response to replication stress

NOTCH1 Intracellular Domain Regulates Transcription

Base-Excision Repair, AP Site Formation

Displacement of DNA glycosylase by APEX1 TP53 Regulates Transcription of Cell Cycle Genes Expression and Processing of Neurotrophins SHC1 events in EGFR signaling Regulation of TP53 Activity

Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane Signaling by plasma membrane FGFR1 fusions NGF processing Signaling by Retinoic Acid

SMAD2/3 Phosphorylation Motif Mutants in Cancer Regulation of PLK1 Activity at G2/M Transition Signaling by Overexpressed Wild-Type EGFR in Cancer Signaling by Nuclear Receptors Formation of annular gap junctions

G2/M DNA damage checkpoint Resolution of Abasic Sites (AP sites) Recognition and association of DNA glycosylase with site containing an affected pyrimidine

Signaling by NOTCH

Signaling by TGF-beta Receptor Complex in Cancer Scavenging by Class H Receptors Loss of Nlp from mitotic centrosomes

Loss of Function of SMAD2/3 in Cancer Signalling to p38 via RIT and RIN Loss of Function of SMAD4 in Cancer

FGFR1 mutant receptor activation

Scavenging by Class B Receptors

PTK6 promotes HIF1A stabilization Inhibition of Signaling by Overexpressed EGFR Signaling by PDGF

Mitotic G2-G2/M phases HDR through Homologous Recombination (HRR) Signaling by EGFR in Cancer

Interaction between PHLDA1 and AURKA RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function NOTCH2 Activation and Transmission of Signal to the Nucleus Regulation of TP53 Activity through Methylation SMAD4 MH2 Domain Mutants in Cancer Transport of connexins along the secretory pathway

Downstream signal transduction Signaling by Receptor Tyrosine Kinases Signaling by PTK6 Signaling by activated point mutants of FGFR1 Prolonged ERK activation events Signaling by NOTCH2 SMAD2/3 MH2 Domain Mutants in Cancer Defective HEXA causes GM2G1 Scavenging of heme from plasma

TP53 Regulates Metabolic Genes Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1

Signalling to RAS

RUNX1 regulates transcription of genes involved in differentiation of HSCs EGFR downregulation

PTK6 Down-Regulation Signaling by EGFR

G2 Phase

Resolution of AP sites via the single-nucleotide replacement pathway

Cell G2/M Checkpoints Chylomicron assembly RUNX1 regulates expression of components of tight junctions Resolution of D-loop Structures through Holliday Junction Intermediates Intracellular signaling by second messengers Transport of connexons to the plasma membrane Depyrimidination

Depurination Signaling by EGFRvIII in Cancer

Resolution of D-Loop Structures G2/M DNA replication checkpoint VLDL assembly

RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known ARMS-mediated activation

Signaling by Non-Receptor Tyrosine Kinases Energy dependent regulation of mTOR by LKB1-AMPK RUNX1 regulates estrogen receptor mediated transcription TP53 Regulates Transcription of DNA Repair Genes

Signaling by SCF-KIT NOTCH2 intracellular domain regulates transcription

Scavenging by Class A Receptors

Recognition and association of DNA glycosylase with site containing an affected purine Gap junction degradation

t(4;14) translocations of FGFR3 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling Diseases of signal transduction

HDL assembly

PTK6 Regulates Cell Cycle Pre-NOTCH Expression and Processing Signaling by FGFR1 in disease Assembly of active LPL and LIPC lipase complexes

AKT phosphorylates targets in the nucleus RUNX1 regulates transcription of genes involved in BCR signaling Abasic sugar-phosphate removal via the single-nucleotide replacement pathway

HDL remodeling Resolution of AP sites via the multiple-nucleotide patch replacement pathway

RUNX1 regulates transcription of genes involved in differentiation of keratinocytes Intestinal infectious diseases Cell Cycle, Mitotic Binding and Uptake of Ligands by Scavenger Receptors Transcription of E2F targets under negative control by DREAM complex GAB1 signalosome

Scavenging by Class F Receptors G0 and Early G1 Signaling by MST1 Constitutive Signaling by EGFRvIII

Transcriptional Regulation by TP53

Homologous DNA Pairing and Strand Exchange EGFR interacts with phospholipase C-gamma mTOR signalling Activated point mutants of FGFR2 Regulation of KIT signaling

Cell Cycle Checkpoints Gap junction assembly

Frs2-mediated activation

PI-3K cascade:FGFR4 Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal

RUNX1 regulates transcription of genes involved in WNT signaling PTK6 Activates STAT3 Signaling by Leptin Defective pro-SFTPB causes pulmonary surfactant metabolism dysfunction 1 (SMDP1) and respiratory distress syndrome (RDS) Uptake and function of anthrax toxins p38MAPK events Defective SFTPA2 causes idiopathic pulmonary fibrosis (IPF) FGFR3 mutant receptor activation

Integrin signaling PTK6 Regulates Proteins Involved in RNA Processing LDL remodeling PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases Negative regulation of the PI3K/AKT network Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) Signaling by activated point mutants of FGFR3

SHC-mediated cascade:FGFR4 PIP3 activates AKT signaling Signaling by RAS mutants Cleavage of the damaged pyrimidine

Defective CSF2RB causes pulmonary surfactant metabolism dysfunction 5 (SMDP5) Pre-NOTCH Transcription and Translation

Cleavage of the damaged purine

Signaling by high-kinase activity BRAF mutants Oligomerization of connexins into connexons Amplification of signal from the kinetochores p53-Independent G1/S DNA damage checkpoint RUNX2 regulates chondrocyte maturation Transcriptional regulation by RUNX1 Plasma lipoprotein assembly Signaling by FGFR2 amplification mutants VLDL clearance Signaling by ERBB4 RUNX1 regulates transcription of genes involved in interleukin signaling Mitotic G1-G1/S phases Signaling by FGFR in disease

Pre-NOTCH Processing in Golgi

Activation of E2F1 target genes at G1/S HDL clearance

Regulation of PTEN localization Mitotic Spindle Checkpoint

POLB-Dependent Long Patch Base Excision Repair RUNX2 regulates osteoblast differentiation

mTORC1-mediated signalling Signaling by FGFR3 point mutants in cancer

Oncogenic MAPK signaling Diseases associated with visual transduction

Pre-NOTCH Processing in the Endoplasmic Reticulum Signaling by FGFR2 in disease

Regulation of RUNX1 Expression and Activity FGFR2 mutant receptor activation

PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 Gap junction trafficking PCNA-Dependent Long Patch Base Excision Repair

Plasma lipoprotein remodeling G1/S-Specific Transcription Cycle SHC1 events in ERBB4 signaling betaKlotho-mediated ligand binding Uptake and actions of bacterial toxins

p53-Independent DNA Damage Response PI3K events in ERBB4 signaling

Signaling by moderate kinase activity BRAF mutants

Uptake and function of diphtheria toxin Retinoid cycle disease events Presynaptic phase of homologous DNA pairing and strand exchange Phospholipase C-mediated cascade; FGFR4 Chylomicron remodeling Inhibition of TSC complex formation by PKB Defective pro-SFTPC causes pulmonary surfactant metabolism dysfunction 2 (SMDP2) and respiratory distress syndrome (RDS)

PI3K/AKT Signaling in Cancer

Signaling by FGFR3 in disease

Paradoxical activation of RAF signaling by kinase inactive BRAF

G1 Phase Chylomicron clearance

RUNX1 regulates transcription of genes involved in differentiation of myeloid cells Signaling by FGFR2 IIIa TM Downstream signaling of activated FGFR4

PTEN Regulation Diseases associated with surfactant metabolism

Ubiquitin Mediated Degradation of Phosphorylated Cdc25A AKT phosphorylates targets in the cytosol

MET activates STAT3

Establishment of Sister Chromatid Cohesion APC-Cdc20 mediated degradation of Nek2A Integrin alphaIIb beta3 signaling Regulation of mitotic cell cycle TFAP2 (AP-2) family regulates transcription of growth factors and their receptors Regulation of PTEN gene transcription

S Phase

Negative regulation of activity of TFAP2 (AP-2) family transcription factors G1/S DNA Damage Checkpoints RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)

RAS signaling downstream of NF1 loss-of-function variants Vesicle-mediated G1/S Transition

Plasma lipoprotein clearance Downregulation of ERBB4 signaling

Nuclear signaling by ERBB4 p130Cas linkage to MAPK signaling for integrins Defective CSF2RA causes pulmonary surfactant metabolism dysfunction 4 (SMDP4)

MAPK family signaling cascades Signaling by FGFR2 fusions RUNX2 regulates bone development

Retinoid metabolism disease events

Constitutive Signaling by AKT1 E17K in Cancer

Inactivation of APC/C via direct inhibition of the APC/C complex

Signaling by MET FGFR4 ligand binding and activation Adenylate cyclase activating pathway Signaling by BRAF and RAF fusions FRS-mediated FGFR4 signaling Signaling by FGFR4 in disease

Signaling by Rho GTPases LDL clearance Activation of the TFAP2 (AP-2) family of transcription factors Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components

2-LTR circle formation

Signaling by FGFR4 MET Receptor Activation

MET activates RAS signaling

Constitutive Signaling by Aberrant PI3K in Cancer

TFAP2 (AP-2) family regulates transcription of other transcription factors Plasma lipoprotein assembly, remodeling, and clearance Signaling by NOTCH1 in Cancer Gap junction trafficking and regulation Regulation of PTEN mRNA translation

Cyclin D associated events in G1 Regulation of gap junction activity

COPII-mediated vesicle transport

GRB2:SOS provides linkage to MAPK signaling for Integrins Signaling by FGFR3 fusions in cancer APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint

Cdc20:Phospho-APC/C mediated degradation of Cyclin A RUNX3 regulates RUNX1-mediated transcription Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate Erythrocytes take up oxygen and release carbon dioxide

Cyclin A:Cdk2-associated events at S phase entry Regulation of PTEN stability and activity c-src mediated regulation of Cx43 function and closure of gap junctions

Integration of viral DNA into host genomic DNA Diseases of metabolism FGFR4 mutant receptor activation

E2F-enabled inhibition of pre-replication complex formation E2F mediated regulation of DNA replication

Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors

FGFR3c ligand binding and activation

Endosomal Sorting Complex Required For Transport (ESCRT)

VLDLR internalisation and degradation Transcriptional Regulation by E2F6 MAPK6/MAPK4 signaling Rho GTPase cycle

TFAP2 (AP-2) family regulates transcription of cell cycle factors Erythrocytes take up carbon dioxide and release oxygen

APC/C-mediated degradation of cell cycle proteins Signaling by FGFR Negative regulation of MET activity Ubiquitin-dependent degradation of Cyclin D

Minus-strand DNA synthesis

RUNX3 regulates BCL2L11 (BIM) transcription

MET activates PTPN11 p53-Dependent G1/S DNA damage checkpoint FBXW7 Mutants and NOTCH1 in Cancer

Competing endogenous RNAs (ceRNAs) regulate PTEN translation

MET activates PI3K/AKT signaling Cyclin E associated events during G1/S transition

Signaling by NOTCH1 PEST Domain Mutants in Cancer

RUNX3 regulates NOTCH signaling Transport

Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins APC/C:Cdc20 mediated degradation of mitotic proteins Nuclear Receptor transcription pathway

Integration of provirus MET receptor recycling Autointegration results in viral DNA circles InlA-mediated entry of Listeria monocytogenes into host cells Negative regulation of FGFR4 signaling Transcriptional regulation by RUNX2 SCF(Skp2)-mediated degradation of p27/p21 MyD88 deficiency (TLR2/4) FGFR3 ligand binding and activation G-protein activation TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation transport RUNX2 regulates genes involved in cell migration ER to Golgi Anterograde Transport MyD88 deficiency (TLR5) Cargo concentration in the ER Mitochondrial ABC transporters FGFR3b ligand binding and activation IRAK4 deficiency (TLR2/4) Opioid Signalling Regulation of APC/C activators between G1/S and early anaphase

Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant

Autodegradation of Cdh1 by Cdh1:APC/C APC/C:Cdc20 mediated degradation of Cyclin B Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer

RUNX3 regulates CDKN1A transcription Membrane Trafficking Signaling by FGFR3 Inhibition of replication initiation of damaged DNA by RB1/E2F1

ATF6 (ATF6-alpha) activates chaperone genes

Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling O2/CO2 exchange in erythrocytes

Synthesis and processing of ENV and VPU

trans-Golgi Network Vesicle Budding Reverse Transcription of HIV RNA InlB-mediated entry of Listeria monocytogenes into host cell

Miscellaneous transport and binding events RUNX3 regulates YAP1-mediated transcription G beta:gamma signalling through PI3Kgamma Transcriptional regulation by RUNX3 DiseaseDisorders of transmembrane transporters IKBKB deficiency causes SCID RHO GTPases activate PAKs G-protein beta:gamma signalling

Signaling by NOTCH1 HD Domain Mutants in Cancer

Generic Transcription Pathway APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1

DARPP-32 events Membrane binding and targetting of GAG proteins Phosphorylation of the APC/C MET promotes cell motility Ubiquitin-dependent degradation of Cyclin D1

Negative regulation of FGFR3 signaling

RHO GTPase Effectors Clathrin derived vesicle budding

Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase YAP1- and WWTR1 (TAZ)-stimulated gene expression Intracellular oxygen transport Regulation of RUNX2 expression and activity MPS IIIC - Sanfilippo syndrome C Defective CYP11A1 causes Adrenal insufficiency, congenital, with 46,XY sex reversal (AICSR) ATF4 activates genes Translocation of SLC2A4 (GLUT4) to the plasma membrane RHO GTPases Activate ROCKs XBP1(S) activates chaperone genes MAPK1/MAPK3 signaling Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes Plus-strand DNA synthesis IRAK4 deficiency (TLR5) Constitutive Signaling by NOTCH1 PEST Domain Mutants ABC transporters in lipid homeostasis G alpha (12/13) signalling events RAF-independent MAPK1/3 activation RUNX3 Regulates Immune Response and Cell Migration GPCR downstream signalling APC/C:Cdc20 mediated degradation of Securin

MPS IIIA - Sanfilippo syndrome A ABC-family proteins mediated transport Neurodegenerative Diseases Diseases of Immune System Early Phase of HIV Life Cycle Synthesis And Processing Of GAG, GAGPOL Polyproteins

Phospholipase C-mediated cascade; FGFR3 Golgi Associated Vesicle Biogenesis MAPK1 (ERK2) activation p53-Dependent G1 DNA Damage Response RHO GTPases activate IQGAPs RUNX2 regulates genes involved in differentiation of myeloid cells

MPS IIID - Sanfilippo syndrome D Uncoating of the HIV Virion Listeria monocytogenes entry into host cells Spry regulation of FGF signaling MPS IV - Morquio syndrome A Negative regulation of FGFR2 signaling IkBA variant leads to EDA-ID G beta:gamma signalling through PLC beta

RHO GTPases Activate WASPs and WAVEs Regulation of RUNX3 expression and activity Diseases associated with the TLR signaling cascade Phosphorylation of Emi1

RHO GTPases Activate NADPH Oxidases SUMOylation of chromatin organization proteins SUMOylation of RNA binding proteins COPI-mediated anterograde transport G alpha (i) signalling events

Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants

Downstream signaling of activated FGFR3 Processing of SMDT1 Effects of PIP2 hydrolysis

Clathrin-mediated endocytosis

Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant

SCF-beta-TrCP mediated degradation of Emi1 G alpha (q) signalling events MPS VI - Maroteaux-Lamy syndrome

Signaling by FGFR2 Assembly Of The HIV Virion RHO GTPases activate CIT Notch-HLH transcription pathway Rab regulation of trafficking of Mitochondrial calcium ion transport RUNX3 regulates p14-ARF

RHO GTPases regulate CFTR trafficking MPS IV - Morquio syndrome B

UNC93B1 deficiency - HSE

ATF6 (ATF6-alpha) activates chaperones Defective ACTH causes Obesity and Pro-opiomelanocortinin deficiency (POMCD) Negative regulation of FGFR1 signaling PLC beta mediated events SUMOylation of DNA damage response and repair proteins SUMOylation of intracellular receptors

RHO GTPases Activate Formins RUNX3 regulates WNT signaling Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models PI-3K cascade:FGFR3 MPS II - Hunter syndrome MPS VII - Sly syndrome TICAM1 deficiency - HSE MET interacts with TNS proteins Lysosome Vesicle Biogenesis

Rev-mediated nuclear export of HIV RNA SUMOylation of ubiquitinylation proteins

Defects in vitamin and cofactor metabolism Arachidonate production from DAG Constitutive Signaling by NOTCH1 HD Domain Mutants G alpha (s) signalling events Stimuli-sensing channels Defective Mismatch Repair Associated With MSH2

TRP channels

Binding and entry of HIV virion Ion channel transport MAPK3 (ERK1) activation RHO GTPases activate KTN1 HIV Life Cycle Stabilization of p53 Severe congenital neutropenia type 4 (G6PC3) MET activates PTK2 signaling Diseases of Mismatch Repair (MMR) PERK regulates gene expression

RAF/MAP kinase cascade MPS I - Hurler syndrome RNA Pol II CTD phosphorylation and interaction with CE during HIV infection Tat-mediated HIV elongation arrest and recovery

MPS IX - Natowicz syndrome

G alpha (z) signalling events IRE1alpha activates chaperones

MET activates RAP1 and RAC1

Signaling by FGFR1 Intra-Golgi and retrograde Golgi-to-ER traffic

RHO GTPases Activate Rhotekin and Rhophilins SUMOylation of DNA methylation proteins TRAF3 deficiency - HSE

SHC-mediated cascade:FGFR2 RAB GEFs exchange GTP for GDP on RABs

IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR) Transcriptional activation of p53 responsive genes

Glycogen storage disease type Ib (SLC37A4) Defective LARGE causes MDDGA6 and MDDGB6

FRS-mediated FGFR3 signaling Late Phase of HIV Life Cycle Pausing and recovery of HIV elongation CREB3 factors activate genes TLR3 deficiency - HSE MAP2K and MAPK activation Infectious disease RHO GTPases activate PKNs Iron uptake and transport

Cargo recognition for clathrin-mediated endocytosis

FGFR2 alternative splicing SHC-mediated cascade:FGFR3 SUMOylation of DNA replication proteins SUMOylation of transcription cofactors

Budding and maturation of HIV virion Mitochondrial translation termination Mitochondrial translation initiation Defective Mismatch Repair Associated With PMS2 FGFR2 ligand binding and activation Ion transport by P-type ATPases Removal of the Flap Intermediate MPS IIIB - Sanfilippo syndrome B

HIV elongation arrest and recovery Nuclear import of Rev protein SUMO E3 ligases SUMOylate target proteins Aquaporin-mediated transport

Olfactory Signaling Pathway

Mucopolysaccharidoses TBC/RABGAPs Defective ABCA3 causes pulmonary surfactant metabolism dysfunction 3 (SMDP3) Autodegradation of the E3 ubiquitin ligase COP1

Transport of glycerol from adipocytes to the liver by Aquaporins Defective Mismatch Repair Associated With MSH6 Defective MTR causes methylmalonic aciduria and homocystinuria type cblG

Regulation of RAS by GAPs

Phenylketonuria Mitochondrial translation elongation FGFR1b ligand binding and activation FGFR1 ligand binding and activation FGFR2b ligand binding and activation

Defective Mismatch Repair Associated With MSH3 Transcription of the HIV genome

Defects in biotin (Btn) metabolism Defective MMACHC causes methylmalonic aciduria and homocystinuria type cblC

Defective Mismatch Repair Associated With MLH1

Downstream signaling of activated FGFR2 Defective MAOA causes Brunner syndrome (BRUNS) Peptide chain elongation SUMOylation of SUMOylation proteins Formation of HIV elongation complex in the absence of HIV Tat RAF activation Signaling by GPCR Transferrin endocytosis and recycling

FGFRL1 modulation of FGFR1 signaling Phospholipase C-mediated cascade; FGFR2 Defective CYP21A2 causes Adrenal hyperplasia 3 (AH3) small Intra-Golgi traffic Retrograde transport at the Trans-Golgi-Network

Unfolded Protein Response (UPR)

Glycogen storage disease type Ia (G6PC) Defective HLCS causes multiple carboxylase deficiency

Visual phototransduction HIV Infection Defective CYP17A1 causes Adrenal hyperplasia 5 (AH5) Transcriptional activation of cell cycle inhibitor p21 The retinoid cycle in cones (daylight vision) SUMOylation of transcription factors Vasopressin regulates renal water homeostasis via Aquaporins

Interactions of Rev with host cellular proteins Defective MTRR causes methylmalonic aciduria and homocystinuria type cblE

Golgi-to-ER retrograde transport

Processive synthesis on the lagging strand

Defective GGT1 causes Glutathionuria (GLUTH)

Defective TBXAS1 causes Ghosal hematodiaphyseal dysplasia (GHDD) Defective CUBN causes hereditary megaloblastic anemia 1 Negative regulation of MAPK pathway

Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 SUMOylation of immune response proteins

RNA Polymerase II HIV Promoter Escape FGFR1c and Klotho ligand binding and activation

GPCR ligand binding Na+/Cl- dependent neurotransmitter transporters

PTEN Loss of Function in Cancer Pausing and recovery of Tat-mediated HIV elongation Mitochondrial tRNA aminoacylation TYSND1 cleaves peroxisomal proteins Passive transport by Aquaporins Proton-coupled monocarboxylate transport

FGFR1c ligand binding and activation Defective HEXB causes GM2G2

FGFR2c ligand binding and activation Mitochondrial translation Defective GSS causes Glutathione synthetase deficiency (GSS deficiency)

The canonical retinoid cycle in rods (twilight vision) M/G1 Transition

Defective ABCB6 causes isolated colobomatous microphthalmia 7 (MCOPCB7)

G-protein mediated events Defective PAPSS2 causes SEMD-PA HIV Transcription Initiation Biosynthesis of A2E, implicated in retinal degradation Defects in cobalamin (B12) metabolism Zinc influx into cells by the SLC39 gene family

Defective AHCY causes Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) Defective GIF causes intrinsic factor deficiency Defective ABCB11 causes progressive familial intrahepatic cholestasis 2 and benign recurrent intrahepatic cholestasis 2

Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) Diseases of glycosylation

Defective CYP27B1 causes Rickets vitamin D-dependent 1A (VDDR1A)

RPIA deficiency: failed conversion of RU5P to R5P

Metabolic disorders of biological oxidation enzymes

Cytosolic tRNA aminoacylation Downstream signaling of activated FGFR1 TALDO1 deficiency: failed conversion of Fru(6)P, E4P to SH7P, GA3P Latent infection of Homo sapiens with Mycobacterium tuberculosis

Retinoid metabolism and transport Sodium-coupled sulphate, di- and tri-carboxylate transporters

Defective CYP1B1 causes Glaucoma Gastrin-CREB signalling pathway via PKC and MAPK FRS-mediated FGFR2 signaling TALDO1 deficiency: failed conversion of SH7P, GA3P to Fru(6)P, E4P

Defective CYP7B1 causes Spastic paraplegia 5A, autosomal recessive (SPG5A) and Congenital bile acid synthesis defect 3 (CBAS3) COPI-dependent Golgi-to-ER retrograde traffic SUMO is transferred from E1 to E2 (UBE2I, UBC9) PI-3K cascade:FGFR2 APOBEC3G mediated resistance to HIV-1 infection ABC transporter disorders Defective ABCC6 causes pseudoxanthoma elasticum (PXE) Unwinding of DNA

Eukaryotic Translation Elongation Lagging Strand Synthesis

SLC-mediated transmembrane transport

Defective CYP27A1 causes Cerebrotendinous xanthomatosis (CTX)

Diseases associated with glycosaminoglycan metabolism Defective MMAA causes methylmalonic aciduria type cblA

Zinc transporters HIV Transcription Elongation Defective B4GALT1 causes B4GALT1-CDG (CDG-2d) Defective CHSY1 causes TPBS RPIA deficiency: failed conversion of R5P to RU5P Defective ABCG5 causes sitosterolemia Defective MAT1A causes Methionine adenosyltransferase deficiency (MATD)

COPI-independent Golgi-to-ER retrograde traffic Defective CYP2R1 causes Rickets vitamin D-dependent 1B (VDDR1B) Defective ABCG8 causes gallbladder disease 4 and sitosterolemia Metal ion SLC transporters

Class C/3 (Metabotropic glutamate/pheromone receptors)

PI-3K cascade:FGFR1 Defective AMN causes hereditary megaloblastic anemia 1 Negative feedback regulation of MAPK pathway

Surfactant metabolism

Defective MMADHC causes methylmalonic aciduria and homocystinuria type cblD Transport of bile salts and organic acids, metal ions and amine compounds tRNA Aminoacylation Peroxisomal protein import Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) Eukaryotic Translation Termination molecules Defective TPMT causes Thiopurine S-methyltransferase deficiency (TPMT deficiency) The phototransduction cascade Polymerase switching

Class B/2 (Secretin family receptors)

SUMO is conjugated to E1 (UBA2:SAE1)

Defective ABCA1 causes Tangier disease Defective GCLC causes Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency (HAGGSD)

Defective GGT1 causes Glutathionuria (GLUTH) Interactions of Tat with host cellular proteins Incretin synthesis, secretion, and inactivation Vpu mediated degradation of CD4 Defective CD320 causes methylmalonic aciduria FRS-mediated FGFR1 signaling Processing and activation of SUMO Defective CHST6 causes MCDC1

Transport of organic anions Defective CYP2U1 causes Spastic paraplegia 56, autosomal recessive (SPG56) Host Interactions of HIV factors Defective B3GAT3 causes JDSSDHD Synthesis, secretion, and deacylation of Ghrelin Zinc efflux and compartmentalization by the SLC30 family

Amyloid fiber formation Defective OPLAH causes 5-oxoprolinase deficiency (OPLAHD)

Defective ABCB4 causes progressive familial intrahepatic cholestasis 3, intrahepatic cholestasis of pregnancy 3 and gallbladder disease 1 Formation of the HIV-1 Early Elongation Complex Inositol transporters Defective FMO3 causes Trimethylaminuria (TMAU) Defective TCN2 causes hereditary megaloblastic anemia SUMOylation Defective CYP11B1 causes Adrenal hyperplasia 4 (AH4)

Amino acid transport across the plasma membrane Defective ABCC9 causes dilated cardiomyopathy 10, familial atrial fibrillation 12 and hypertrichotic osteochondrodysplasia

SHC-mediated cascade:FGFR1 Cellular hexose transport

RNA polymerase II transcribes snRNA genes

Vpr-mediated nuclear import of PICs

Defective ABCD1 causes adrenoleukodystrophy (ALD) Defective UGT1A1 causes hyperbilirubinemia SRP-dependent cotranslational protein targeting to membrane DNA strand elongation

Phospholipase C-mediated cascade: FGFR1 Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) Defective ACY1 causes encephalopathy Defective CHST3 causes SEDCJD

RNA Pol II CTD phosphorylation and interaction with CE Bicarbonate transporters

EGFR Transactivation by Gastrin Defective ST3GAL3 causes MCT12 and EIEE15 Defective ABCA12 causes autosomal recessive congenital ichthyosis type 4B

Defective CYP11B2 causes Corticosterone methyloxidase 1 deficiency (CMO-1 deficiency) Interleukin-2 signaling Defective EXT1 causes exostoses 1, TRPS2 and CHDS

SUMO is proteolytically processed Abortive elongation of HIV-1 transcript in the absence of Tat CDK-mediated phosphorylation and removal of Cdc6

Activation of the phototransduction cascade Defective CYP4F22 causes Ichthyosis, congenital, autosomal recessive 5 (ARCI5) Interleukin-15 signaling Pentose phosphate pathway disease

Glucagon-type ligand receptors Interleukin-9 signaling Defective SLC35D1 causes Schneckenbecken dysplasia (SCHBCKD)

Insulin processing Defective ABCD4 causes methylmalonic aciduria and homocystinuria, cblj type (MAHCJ) Defective ABCA3 causes pulmonary surfactant metabolism dysfunction type 3 (SMDP3) Defective ABCC2 causes Dubin-Johnson syndrome Mitochondrial protein import

Peptide hormone metabolism

Translation Leading Strand Synthesis Transport of vitamins, nucleosides, and related molecules Rhesus glycoproteins mediate ammonium transport. Defective CYP26C1 causes Focal facial dermal dysplasia 4 (FFDD4) Interactions of Vpr with host cellular proteins

RNA Polymerase II Transcription Pre-Initiation And Promoter Opening

Tat-mediated elongation of the HIV-1 transcript Defective DPAGT1 causes DPAGT1-CDG (CDG-1j) and CMSTA2

Calcitonin-like ligand receptors

Inactivation, recovery and regulation of the phototransduction cascade

Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation Defective B3GALT6 causes EDSP2 and SEMDJL1 Defective CYP19A1 causes Aromatase excess syndrome (AEXS) Defective EXT2 causes exostoses 2 Cation-coupled Chloride cotransporters

Organic cation/anion/zwitterion transport Meiotic recombination

Defective LMBRD1 causes methylmalonic aciduria and homocystinuria type cblF

Defective UGT1A4 causes hyperbilirubinemia Vif-mediated degradation of APOBEC3G Attachment of GPI anchor to uPAR Defective CHST14 causes EDS, musculocontractural type

Hydroxycarboxylic acid-binding receptors

Defective CYP26B1 causes Radiohumeral fusions with other skeletal and craniofacial anomalies (RHFCA)

Diseases associated with N-glycosylation of proteins

Interleukin-21 signaling

Regulation of signaling by CBL Regulation of IFNA signaling Defective ALG1 causes ALG1-CDG (CDG-1k) Defective LFNG causes SCDO3 Defective B4GALT7 causes EDS, progeroid type Response of Mtb to phagocytosis Transport of inorganic cations/anions and amino acids/oligopeptides Metabolism Sodium/Proton exchangers

Defective CYP24A1 causes Hypercalcemia, infantile (HCAI) Interleukin receptor SHC signaling Switching of origins to a post-replicative state

Metabolism of Angiotensinogen to Angiotensins Synthesis of DNA

RNA Polymerase II Transcription Relaxin receptors Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane

Meiosis

Influenza Infection

Synthesis of glycosylphosphatidylinositol (GPI) Protein repair Proton/oligopeptide cotransporters

Organic cation transport Cell redox homeostasis

Defective MOGS causes MOGS-CDG (CDG-2b) RNA Polymerase II Transcription Elongation

Defective MGAT2 causes MGAT2-CDG (CDG-2a) RAB geranylgeranylation Regulation of IFNG signaling

Vasopressin-like receptors RNA Polymerase II Transcription Termination

Meiotic synapsis Interleukin-23 signaling Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2

Interleukin-2 family signaling Free fatty acid receptors Defective ALG12 causes ALG12-CDG (CDG-1g) Post-translational protein phosphorylation Peptide hormone biosynthesis Orc1 removal from chromatin Diseases associated with O-glycosylation of proteins Transport of nucleotide sugars Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization DNA replication initiation Reactions specific to the complex N-glycan synthesis pathway

Defective B4GALT1 causes B4GALT1-CDG (CDG-2d) Synthesis of Dolichyl-phosphate Transport of fatty acids Class A/1 (Rhodopsin-like receptors)

Translocation of ZAP-70 to Immunological synapse

Interleukin-6 signaling Formation of HIV-1 elongation complex containing HIV-1 Tat Formation of the Early Elongation Complex Organic anion transporters

Multifunctional anion exchangers Generation of second messenger molecules

Opsins RNA Polymerase II Pre-transcription Events Defective MMAB causes methylmalonic aciduria type cblB Protein methylation Post-translational modification: synthesis of GPI-anchored proteins

Defective ALG11 causes ALG11-CDG (CDG-1p) Organic anion transport

Defective RFT1 causes RFT1-CDG (CDG-1n) Defective MAN1B1 causes MRT15 Synthesis of dolichyl-phosphate-glucose Tolerance of reactive oxygen produced by macrophages

Neddylation

Orexin and neuropeptides FF and QRFP bind to their respective receptors Gene Sodium-coupled phosphate cotransporters

Interferon alpha/beta signaling N-Glycan antennae elongation Glycoprotein hormones Interleukin-3, Interleukin-5 and GM-CSF signaling Defective GALNT3 causes familial hyperphosphatemic tumoral calcinosis (HFTC)

Peptide ligand-binding receptors Defective ALG9 causes ALG9-CDG (CDG-1l) The role of Nef in HIV-1 replication and disease pathogenesis Essential pentosuria Synthesis of dolichyl-phosphate mannose DNA Proton-coupled neutral amino acid transporters Mtb iron assimilation by chelation Hereditary fructose intolerance

Cleavage of Growing Transcript in the Termination Region Host Interactions with Influenza Factors Defective POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3 Influenza Virus Induced Apoptosis

Defective ALG14 causes congenital myasthenic syndrome (ALG14-CMS) Essential fructosuria Defective ALG3 causes ALG3-CDG (CDG-1d) Tolerance by Mtb to nitric oxide produced by macrophages Downstream TCR signaling Sodium/Calcium exchangers Interferon gamma signaling

Defective MUT causes methylmalonic aciduria mut type Hormone ligand-binding receptors Defective ALG8 causes ALG8-CDG (CDG-1h)

RNA Polymerase II Transcription Initiation And Promoter Clearance Defective C1GALT1C1 causes Tn polyagglutination syndrome (TNPS) Post-translational protein modification

Serotonin receptors Formation of RNA Pol II elongation complex IL-6-type cytokine receptor ligand interactions Defective CFTR causes cystic fibrosis

Intestinal saccharidase deficiencies

Defective MPDU1 causes MPDU1-CDG (CDG-1f) Synthesis of UDP-N-acetyl-glucosamine Interleukin-12 family signaling Lysosphingolipid and LPA receptors

Defective B3GALTL causes Peters-plus syndrome (PpS) of ISG15 antiviral mechanism

Sialic acid metabolism Carboxyterminal post-translational modifications of tubulin Tachykinin receptors bind tachykinins

Synthesis of substrates in N-glycan biosythesis Interleukin-4 and Interleukin-13 signaling Defective ALG6 causes ALG6-CDG (CDG-1c) N-glycan antennae elongation in the medial/trans-Golgi Interleukin-6 family signaling Defective ABCC8 can cause hypoglycemias and hyperglycemias

TCR signaling Defective ALG2 causes ALG2-CDG (CDG-1i)

Defective GALNT12 causes colorectal cancer 1 (CRCS1) Type II Na+/Pi cotransporters Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1

Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein

Rap1 signalling Asparagine N-linked glycosylation Protein folding Defective SLC22A12 causes renal hypouricemia 1 (RHUC1) Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages)

Amine ligand-binding receptors

Antiviral mechanism by IFN-stimulated genes Inhibition of Host mRNA Processing and RNA Silencing

Phosphorylation of CD3 and TCR zeta chains

Josephin domain DUBs

Post-chaperonin tubulin folding pathway Defective SLC34A3 causes Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) Histamine receptors

Nucleotide-like (purinergic) receptors

Chemokine receptors bind chemokines RNA Polymerase II Promoter Escape

NS1 Mediated Effects on Host Pathways Formyl peptide receptors bind formyl peptides and many other ligands Transport to the Golgi and subsequent modification Reproduction Interleukin-20 family signaling Progressive trimming of alpha-1,2-linked mannose residues from Man9/8/7GlcNAc2 to produce Man5GlcNAc2 Activation of RAS in B cells Defective SLC7A7 causes lysinuric protein intolerance (LPI) Defective SLC39A4 causes acrodermatitis enteropathica, zinc-deficiency type (AEZ) GDP-fucose biosynthesis Nef and signal transduction Interleukin-12 signaling Eicosanoid ligand-binding receptors

Defective CP causes aceruloplasminemia (ACERULOP)

Interleukin-10 signaling Interferon Signaling

RNA Polymerase II Transcription Initiation

N-glycan trimming in the ER and Calnexin/Calreticulin cycle

Reduction of cytosolic Ca++ levels

Synthesis of GDP-mannose Defective SLC6A5 causes hyperekplexia 3 (HKPX3) expression Eukaryotic Translation Initiation Defective SLC35A2 causes congenital disorder of glycosylation 2M (CDG2M) Protein ubiquitination Butyrophilin (BTN) family interactions Deubiquitination

Ub-specific processing proteases Signaling by Interleukins Defective SLC26A3 causes congenital secretory chloride diarrhea 1 (DIAR1) Dopamine receptors Defective SLCO2A1 causes primary, autosomal recessive hypertrophic osteoarthropathy 2 (PHOAR2) N-glycan trimming and elongation in the cis-Golgi Replication

The activation of arylsulfatases

Defective SLC12A6 causes agenesis of the corpus callosum, with peripheral neuropathy (ACCPN) Reactions specific to the hybrid N-glycan synthesis pathway

Interleukin-7 signaling Defective SLC27A4 causes ichthyosis prematurity syndrome (IPS) Elevation of cytosolic Ca2+ levels

Inhibition of Interferon Synthesis

Gamma carboxylation, hypusine formation and arylsulfatase activation

Adaptive Immune System Defective SLC9A6 causes X-linked, syndromic mental retardation,, Christianson type (MRXSCH)

Growth hormone receptor signaling Variant SLC6A20 contributes towards hyperglycinuria (HG) and iminoglycinuria (IG) P2Y receptors Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters

Downstream signaling events of B Cell Receptor (BCR) Calcineurin activates NFAT

Muscarinic acetylcholine receptors NIK-->noncanonical NF-kB signaling Defective SLC17A5 causes Salla disease (SD) and ISSD Adrenoceptors

Defective SLC2A10 causes arterial tortuosity syndrome (ATS) proteins Signaling by the B Cell Receptor (BCR) Defective SLC34A1 causes hypophosphatemic nephrolithiasis/osteoporosis 1 (NPHLOP1) Defective SLC24A5 causes oculocutaneous albinism 6 (OCA6) Metalloprotease DUBs

Defective SLC2A9 causes hypouricemia renal 2 (RHUC2) O-linked glycosylation

Variant SLC6A14 may confer susceptibility towards obesity Inhibition of PKR

Defective SLC22A18 causes lung cancer (LNCR) and embryonal rhabdomyosarcoma 1 (RMSE1) Adenosine P1 receptors Activation of the pre-replicative complex

Interleukin-38 signaling Prostanoid ligand receptors Defective SLC5A2 causes renal glucosuria (GLYS1) DNA Replication Pre-Initiation CD22 mediated BCR regulation Inhibition of IFN-beta L13a-mediated translational silencing of Ceruloplasmin expression Basigin interactions Synthesis of active ubiquitin: roles of E1 and E2 enzymes

Other interleukin signaling Leukotriene receptors

POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation

Interleukin-27 signaling Calnexin/calreticulin cycle MHC class II antigen presentation

Beta oxidation of octanoyl-CoA to hexanoyl-CoA Nef Mediated CD8 Down-regulation Hypusine synthesis from eIF5A-lysine

Defective SLC6A2 causes orthostatic intolerance (OI) Defective SLC24A4 causes hypomineralized amelogenesis imperfecta (AI)

Interleukin-36 pathway

Defective SLC6A19 causes Hartnup disorder (HND) Defective SLC24A1 causes congenital stationary night blindness 1D (CSNB1D) Defective SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A)

Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS)

Nectin/Necl trans heterodimerization POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA Beta oxidation of myristoyl-CoA to lauroyl-CoA Tie2 Signaling

Ovarian tumor domain proteases TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway Defective SLC1A1 is implicated in schizophrenia 18 (SCZD18) and dicarboxylic aminoaciduria (DCBXA) UCH proteinases Common Pathway of Fibrin Clot Formation

Interleukin-33 signaling Defective HK1 causes hexokinase deficiency (HK deficiency) TNFR2 non-canonical NF-kB pathway Activation of NF-kappaB in B cells Nef mediated downregulation of MHC class I complex cell surface expression Extrinsic Pathway of Fibrin Clot Formation Platelet calcium homeostasis Influenza Life Cycle Defective SLC36A2 causes iminoglycinuria (IG) and hyperglycinuria (HG) E3 ubiquitin ligases ubiquitinate target proteins Gamma-carboxylation of protein precursors

Synthesis of diphthamide-EEF2

B-WICH complex positively regulates rRNA expression Ficolins bind to repetitive carbohydrate structures on the target cell surface Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell Entry of Influenza Virion into Host Cell via Endocytosis CDO in myogenesis Gamma-carboxylation, transport, and amino-terminal cleavage of proteins

Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA)

Antigen activates B Cell Receptor (BCR) leading to generation of second messengers Cytokine Signaling in Immune system Defective SLC2A2 causes Fanconi-Bickel syndrome (FBS) Defective SLC22A5 causes systemic primary carnitine deficiency (CDSP) Chaperonin-mediated protein folding Defective SLC5A1 causes congenital glucose/galactose malabsorption (GGM)

Nef Mediated CD4 Down-regulation

Fusion of the Influenza Virion to the Host Cell Endosome Defective SLC6A18 may confer susceptibility to iminoglycinuria and/or hyperglycinuria Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA (Transcription) PECAM1 interactions

Fertilization Nef mediated downregulation of CD28 cell surface expression

Fusion and Uncoating of the Influenza Virion

Beta oxidation of palmitoyl-CoA to myristoyl-CoA SLC transporter disorders Prolactin receptor signaling Defective SLC5A5 causes thyroid dyshormonogenesis 1 (TDH1) Intrinsic Pathway of Fibrin Clot Formation Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum) Defective SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A) Assembly of the ORC complex at the origin of replication

O-glycosylation of TSR domain-containing proteins

IRF3 mediated activation of type 1 IFN Assembly of the pre-replicative complex Sperm:Oocyte Membrane Binding

Interleukin-1 family signaling Defective RHAG causes regulator type Rh-null hemolytic anemia (RHN) RIP-mediated NFkB activation via ZBP1 O-linked glycosylation of mucins TNFs bind their physiological receptors Adherens junctions interactions Signal regulatory protein family interactions Interleukin-1 processing Regulation of signaling by NODAL

Defective SLC34A2 causes pulmonary alveolar microlithiasis (PALM) Defective SLC17A8 causes autosomal dominant deafness 25 (DFNA25)

Defective SLC11A2 causes hypochromic microcytic anemia, with iron overload 1 (AHMIO1) ER Quality Control Compartment (ERQC)

Transcriptional regulation of pluripotent stem cells Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus

Defective SLC7A9 causes cystinuria (CSNU) Type I hemidesmosome assembly Class I MHC mediated antigen processing & presentation ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression Interaction With Cumulus Cells Kinesins

Cell surface interactions at the vascular wall

mitochondrial fatty acid beta-oxidation of saturated fatty acids The proton buffering model Export of Viral Ribonucleoproteins from Nucleus Prostacyclin signalling through prostacyclin receptor

Beta oxidation of butanoyl-CoA to acetyl-CoA

Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT) Variant SLC6A20 contributes towards hyperglycinuria (HG) and iminoglycinuria (IG) Positive epigenetic regulation of rRNA expression Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding

STAT6-mediated induction of chemokines Costimulation by the CD28 family Transport of Ribonucleoproteins into the Host Nucleus

Interleukin-35 Signalling Defective SLC35A1 causes congenital disorder of glycosylation 2F (CDG2F) Uncoating of the Influenza Virion Myogenesis Viral RNP Complexes in the Host Cell Nucleus Formation of Fibrin Clot (Clotting Cascade)

Defective SLC20A2 causes idiopathic basal ganglia calcification 1 (IBGC1) Lectin pathway of complement activation Antigen processing: Ubiquitination & Proteasome degradation CDT1 association with the CDC6:ORC:origin complex Regulation by TREX1 Complex I biogenesis Defective SLC35A3 causes arthrogryposis, mental retardation, and seizures (AMRS) Defective SLC1A3 causes episodic ataxia 6 (EA6)

Removal of aminoterminal propeptides from gamma-carboxylated proteins Defective SLC12A1 causes Bartter syndrome 1 (BS1) DNA methylation

EPHA-mediated growth cone collapse Interleukin-37 signaling DCC mediated attractive signaling The fatty acid cycling model Regulation of gene expression in early pancreatic precursor cells

Interleukin-17 signaling Acrosome Reaction

Defective SLC35A1 causes congenital disorder of glycosylation 2F (CDG2F)

Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) Association of TriC/CCT with target proteins during biosynthesis

Synthesis of Hepoxilins (HX) and Trioxilins (TrX) Netrin mediated repulsion signals Interaction With The Zona Pellucida Defective SLC33A1 causes spastic paraplegia 42 (SPG42) Adenylate cyclase inhibitory pathway Defective SLC34A2 causes pulmonary alveolar microlithiasis (PALM)

LGI-ADAM interactions Termination of O-glycan biosynthesis IRF3-mediated induction of type I IFN

EPHB-mediated forward signaling

Interleukin-18 signaling CDC6 association with the ORC:origin complex

Beta oxidation of hexanoyl-CoA to butanoyl-CoA Signaling by NODAL

Sperm Motility And Taxes Cell-cell junction organization Defective SLC6A19 causes Hartnup disorder (HND) Propionyl-CoA catabolism Cap-dependent Translation Initiation Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS)

Platelet homeostasis

AKT-mediated inactivation of FOXO1A Tight junction interactions Defective SLC26A4 causes Pendred syndrome (PDS) Platelet sensitization by LDL

ZBP1(DAI) mediated induction of type I IFNs EPH-ephrin mediated repulsion of cells

Synthesis of 12-eicosatetraenoic acid derivatives Defective SLC3A1 causes cystinuria (CSNU)

Regulation of gene expression in beta cells Antigen Presentation: Folding, assembly and peptide loading of class I MHC cRNA Synthesis NEP/NS2 Interacts with the Cellular Export Machinery Nephrin family interactions Influenza Viral RNA Transcription and Replication Factors involved in megakaryocyte development and platelet production SIRT1 negatively regulates rRNA expression Cell junction organization PD-1 signaling Role of second messengers in netrin-1 signaling

Epigenetic regulation of gene expression Defective SLC2A1 causes GLUT1 deficiency syndrome 1 (GLUT1DS1) Synthesis of 5-eicosatetraenoic acids Defective SLC9A9 causes autism 16 (AUTS16) Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding Platelet Adhesion to exposed collagen Synthesis of Prostaglandins (PG) and Thromboxanes (TX) PRC2 methylates histones and DNA Transcriptional regulation of white adipocyte differentiation Defective SLCO1B1 causes hyperbilirubinemia, Rotor type (HBLRR) Cell-Cell Virus Assembly and Release Classical antibody-mediated complement activation Immune CTLA4 inhibitory signaling

Formation of the ternary complex, and subsequently, the 43S complex Defective SLCO1B1 causes hyperbilirubinemia, Rotor type (HBLRR) Activation of the AP-1 family of transcription factors

Defective SLC35C1 causes congenital disorder of glycosylation 2C (CDG2C)

Regulation of pyruvate dehydrogenase (PDH) complex Mitochondrial Uncoupling Proteins Negative epigenetic regulation of rRNA expression

STING mediated induction of host immune responses

The IPAF inflammasome Defective SLC29A3 causes histiocytosis-lymphadenopathy plus syndrome (HLAS)

Regulation of innate immune responses to cytosolic DNA Regulation of beta-cell development

The AIM2 inflammasome

Creation of C4 and C2 activators Defective SLC6A18 may confer susceptibility to iminoglycinuria and/or hyperglycinuria Antigen processing-Cross presentation Cross-presentation of particulate exogenous antigens (phagosomes) Respiratory electron transport

Defective SLC4A4 causes renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA) GTP hydrolysis and joining of the 60S ribosomal subunit mitochondrial fatty acid beta-oxidation of unsaturated fatty acids

Formation of tubulin folding intermediates by CCT/TriC Defective SLC12A3 causes Gitelman syndrome (GS)

EPH-Ephrin signaling Netrin-1 signaling DSCAM interactions Viral Messenger RNA Synthesis Linoleic acid (LA) metabolism

Synthesis of Leukotrienes (LT) and Eoxins (EX) SDK interactions Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells TET1,2,3 and TDG demethylate DNA Nitric oxide stimulates guanylate cyclase

CD28 co-stimulation alpha-linolenic acid (ALA) metabolism Ribosomal scanning and start codon recognition NoRC negatively regulates rRNA expression

DEx/H-box helicases activate type I IFN and inflammatory cytokines production

Formation of a pool of free 40S subunits

Mitochondrial Fatty Acid Beta-Oxidation

The NLRP1 inflammasome Arachidonic acid metabolism

vRNA Synthesis

Budding Recycling of eIF2:GDP

Formation of ATP by chemiosmotic coupling Dissolution of Fibrin Clot LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production Viral mRNA Translation Packaging of Eight RNA Segments Transcription from mitochondrial promoters Keratinization Ephrin signaling

Folding of actin by CCT/TriC Cell-extracellular matrix interactions Assembly of Viral Components at the Budding Site

Formation of apoptosome

Prefoldin mediated transfer of substrate to CCT/TriC

Cross-presentation of soluble exogenous antigens (endosomes) Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells

cGMP effects vRNP Assembly

Synthesis of 15-eicosatetraenoic acid derivatives Sema4D induced cell migration and growth-cone collapse

Pyruvate metabolism NCAM1 interactions Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S

Inflammasomes Endosomal/Vacuolar pathway Developmental Release

Activation of HOX genes during differentiation

Cytosolic sensors of pathogen-associated DNA Interconversion of 2-oxoglutarate and 2-hydroxyglutarate Alpha-oxidation of phytanate

Initial triggering of complement RNA Polymerase III Chain Elongation Alternative complement activation Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)

RNA Polymerase III Transcription Activation of C3 and C5 ER-Phagosome pathway

Mitochondrial transcription termination

Citric acid cycle (TCA cycle) NCAM signaling for neurite out-growth alpha-linolenic (omega3) and linoleic (omega6) acid metabolism communication SystemCD28 dependent PI3K/Akt signaling

Terminal pathway of complement

Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins. CD28 dependent Vav1 pathway Formation of the cornified envelope

Regulation of cytoskeletal remodeling and cell spreading by IPP complex components

Sema4D in semaphorin signaling The NLRP3 inflammasome Mitochondrial transcription initiation

Axon guidance

Activation of caspases through apoptosome-mediated cleavage

Synthesis of very long-chain fatty acyl-CoAs Localization of the PINCH-ILK-PARVIN complex to focal adhesions

NOD1/2 Signaling Pathway RNA Polymerase III Transcription Termination

CRMPs in Sema3A signaling SMAC binds to IAPs Cytochrome c-mediated apoptotic response Transport of HA trimer, NA tetramer and M2 tetramer from the endoplasmic reticulum to the Golgi Apparatus Activation of anterior HOX genes in hindbrain development during early embryogenesis Signal transduction by L1

RNA Polymerase I Transcription RNA Polymerase III Transcription Initiation From Type 1 Promoter

Beta-oxidation of very long chain fatty acids

Regulation of Complement cascade

Peroxisomal lipid metabolism Semaphorin interactions

Sema4D mediated inhibition of cell attachment and migration

RNA Polymerase III Transcription Initiation

RNA Polymerase III Abortive And Retractive Initiation Synthesis of pyrophosphates in the cytosol Translation initiation complex formation

Defective SLCO1B3 causes hyperbilirubinemia, Rotor type (HBLRR) Defective AVP causes neurohypophyseal diabetes insipidus (NDI)

Complement cascade Pyruvate metabolism and Citric Acid (TCA) cycle Beta-oxidation of pristanoyl-CoA

Platelet Aggregation (Plug Formation)

Activation, myristolyation of BID and translocation to mitochondria

Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways

Reelin signalling pathway

RNA Polymerase I Chain Elongation

Fatty acyl-CoA biosynthesis Defective SLC26A2 causes chondrodysplasias

Synthesis of bile acids and bile salts via 24-hydroxycholesterol RNA Polymerase III Transcription Initiation From Type 3 Promoter Synthesis of bile acids and bile salts via 27-hydroxycholesterol Synthesis of IP3 and IP4 in the cytosol RET signaling Interleukin-1 signaling GP1b-IX-V activation signalling SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion

NrCAM interactions GPVI-mediated activation cascade Biology TRAF6 mediated IRF7 activation Fatty acid metabolism Activation and oligomerization of BAK protein Apoptotic factor-mediated response

MAPK targets/ Nuclear events mediated by MAP kinases SMAC-mediated apoptotic response

Import of palmitoyl-CoA into the mitochondrial matrix Neutrophil degranulation Synthesis of IP2, IP, and Ins in the cytosol

L1CAM interactions

Negative regulators of DDX58/IFIH1 signaling

RNA Polymerase I Transcription Termination Other semaphorin interactions

Advanced glycosylation endproduct receptor signaling

Sema3A PAK dependent Axon repulsion Activation of BIM and translocation to mitochondria RNA Polymerase III Transcription Initiation From Type 2 Promoter

Transport of the SLBP independent Mature mRNA Inhibition of adenylate cyclase pathway Synthesis of IPs in the nucleus Metabolism of vitamin K

Transport of Mature mRNA Derived from an Intronless Transcript Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol

Platelet activation, signaling and aggregation

activated TAK1 mediates p38 MAPK activation Recycling pathway of L1 Gene Silencing by RNA

SMAC-mediated dissociation of IAP:caspase complexes

Adrenaline signalling through Alpha-2 adrenergic receptor

Defective AVP causes neurohypophyseal diabetes insipidus (NDI)

TRAF3-dependent IRF activation pathway

RNA Polymerase I Promoter Clearance Biosynthesis of maresin-like SPMs Intrinsic Pathway for Apoptosis JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1

DDX58/IFIH1-mediated induction of interferon-alpha/beta

eNOS activation

MAP3K8 (TPL2)-dependent MAPK1/3 activation

Synthesis of bile acids and bile salts

Inositol phosphate metabolism NOSTRIN mediated eNOS trafficking Vitamin E Activation of BAD and translocation to mitochondria

DAP12 interactions

PIWI-interacting RNA (piRNA) biogenesis BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members Inactivation of CDC42 and RAC1 TRAF6 mediated NF-kB activation Neurofascin interactions

Innate Immune System RNA Polymerase I Promoter Opening Interaction between L1 and Ankyrins

Transfer of LPS from LBP carrier to CD14

Thrombin signalling through proteinase activated receptors (PARs) Activation of RAC1 Signaling by ROBO receptors Synthesis of IPs in the ER lumen

Trafficking and processing of endosomal TLR Nicotinamide salvaging

Transport of the SLBP Dependant Mature mRNA The citric acid (TCA) cycle and respiratory electron transport Activation of BH3-only proteins

MAP kinase activation CHL1 interactions

Response to elevated platelet cytosolic Ca2+ Metabolism of fat-soluble vitamins Hemostasis NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 Transport of Mature mRNAs Derived from Intronless Transcripts

Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon Cholesterol biosynthesis via desmosterol Biosynthesis of D-series resolvins MicroRNA (miRNA) biogenesis

Biosynthesis of aspirin-triggered D-series resolvins

ROS, RNS production in phagocytes Cholesterol biosynthesis via lathosterol Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation Biosynthesis of maresins Transport of Mature mRNA derived from an Intron-Containing Transcript RNA Polymerase I Transcription Initiation CASP8 activity is inhibited NOSIP mediated eNOS trafficking Role of ABL in ROBO-SLIT signaling

Release of apoptotic factors from the mitochondria

DAP12 signaling

Activation of PUMA and translocation to mitochondria Glycosphingolipid metabolism

Activation, translocation and oligomerization of BAX Recycling of bile acids and salts TAK1 activates NFkB by phosphorylation and activation of IKKs complex Disinhibition of SNARE formation Toll Like Receptor 10 (TLR10) Cascade

IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation Intestinal hexose absorption

Synthesis of Ketone Bodies Vitamin B1 (thiamin) metabolism Highly calcium permeable postsynaptic nicotinic acetylcholine receptors Vitamins B6 activation to pyridoxal phosphate RNA Polymerase I Promoter Escape

Nicotinate metabolism IPs transport between cytosol and ER lumen Post-transcriptional silencing by small RNAs Regulation of commissural axon pathfinding by SLIT and ROBO eNOS activation and regulation NADPH regeneration Defective DOLK causes DOLK-CDG (CDG-1m)

Toll Like Receptor 4 (TLR4) Cascade Defective GNE causes sialuria, Nonaka myopathy and inclusion body myopathy 2

Ubiquinol biosynthesis FCERI mediated MAPK activation Utilization of Ketone Bodies

Toll-Like Receptors Cascades Fc epsilon receptor (FCERI) signaling Sphingolipid de novo biosynthesis

Biosynthesis of maresin conjugates in tissue regeneration (MCTR) mRNA Splicing - Minor Pathway

Regulation of cortical dendrite branching

CD209 (DC-SIGN) signaling MyD88-independent TLR4 cascade Defective MPI causes MPI-CDG (CDG-1b) ROBO receptors bind AKAP5

SLIT2:ROBO1 increases RHOA activity

Transcriptional regulation by small RNAs Digestion Activation of NOXA and translocation to mitochondria MyD88 cascade initiated on plasma membrane TRIF-mediated programmed cell death TRIF(TICAM1)-mediated TLR4 signaling

Biotin transport and metabolism Small interfering RNA (siRNA) biogenesis Platelet degranulation Activation of BMF and translocation to mitochondria Bile acid and bile salt metabolism

Fcgamma receptor (FCGR) dependent phagocytosis

Defective DPM2 causes DPM2-CDG (CDG-1u) Signal amplification

Metabolism of cofactors Abacavir transmembrane transport Highly sodium permeable acetylcholine nicotinic receptors Defective NEU1 causes sialidosis Toll Like Receptor 9 (TLR9) Cascade

Biosynthesis of protectins Dimerization of procaspase-8 Defective DPM3 causes DPM3-CDG (CDG-1o)

Abacavir metabolism

IPs transport between ER lumen and nucleus Digestion of dietary lipid

Cholesterol biosynthesis Biosynthesis of DHA-derived SPMs Regulation of expression of SLITs and ROBOs Regulation of actin dynamics for phagocytic cup formation Transport of Mature Transcript to Cytoplasm

Regulation by c-FLIP

FCERI mediated NF-kB activation TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation Role of LAT2/NTAL/LAB on calcium mobilization Biosynthesis of DHA-derived sulfido conjugates

MyD88:Mal cascade initiated on plasma membrane Intestinal lipid absorption

Regulation of TLR by endogenous ligand

Regulation of necroptotic cell death mRNA Splicing - Major Pathway Intestinal absorption Sphingolipid metabolism Biosynthesis of electrophilic Ï‰-3 PUFA oxo-derivatives

Toll Like Receptor 5 (TLR5) Cascade

Ketone body metabolism Formation of Senescence-Associated Heterochromatin Foci (SAHF)

Postsynaptic nicotinic acetylcholine receptors

ADP signalling through P2Y purinoceptor 1 IKK complex recruitment mediated by RIP1 Defective GALT can cause Galactosemia Molybdenum cofactor biosynthesis PPARA activates gene expression

C-type lectin receptors (CLRs)

Highly calcium permeable nicotinic acetylcholine receptors Defective GALE can cause Epimerase-deficiency galactosemia (EDG) IPs transport between nucleus and cytosol Heme degradation

Metabolism of vitamins and cofactors Wax biosynthesis Biosynthesis of protectin and resolvin conjugates in tissue regeneration (PCTR and RCTR)

IPs transport between ER lumen and cytosol Metabolism of folate and pterines

Antimicrobial peptides IRAK1 recruits IKK complex Synthesis of wybutosine at G37 of tRNA(Phe)

Defective GALK1 can cause Galactosemia II (GALCT2) Oxidative Stress Induced Senescence mRNA Splicing Digestion Toll Like Receptor 2 (TLR2) Cascade Electron transport from NADPH to Ferredoxin FCERI mediated Ca+2 mobilization IP3 and IP4 transport between cytosol and nucleus FCGR activation Toll Like Receptor 3 (TLR3) Cascade

Metabolism of nitric oxide

Diseases associated with glycosylation precursor biosynthesis Toll Like Receptor TLR1:TLR2 Cascade Metabolism of water-soluble vitamins and cofactors Synthesis of Lipoxins (LX) Presynaptic nicotinic acetylcholine receptors

IPs transport between nucleus and ER lumen

TRAF6-mediated induction of TAK1 complex within TLR4 complex MyD88 dependent cascade initiated on endosome via Death Receptors in the presence of ligand

Senescence-Associated Secretory Phenotype (SASP) Thromboxane signalling through TP receptor

Abacavir transport and metabolism

Role of phospholipids in phagocytosis mRNA 3'-end processing

Biosynthesis of E-series 18(R)-resolvins IRAK2 mediated activation of TAK1 complex RSK activation Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)

DNA Damage/Telomere Stress Induced Senescence RIPK1-mediated regulated necrosis

Regulation of Glucokinase by Glucokinase Regulatory Protein

Defective BTD causes biotidinase deficiency Vitamin B2 (riboflavin) metabolism Toll Like Receptor 7/8 (TLR7/8) Cascade Biosynthesis of specialized proresolving mediators (SPMs) IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation Glycogen synthesis

Defective GFPT1 causes CMSTA1 ADP signalling through P2Y purinoceptor 12

IP6 and IP7 transport between cytosol and nucleus Metabolism of steroids

Toll Like Receptor TLR6:TLR2 Cascade and Cellular Activation of GABAB receptors Defective DHDDS causes retinitis pigmentosa 59 Major pathway of rRNA processing in the nucleolus and cytosol Digestion of dietary carbohydrate Biosynthesis of EPA-derived SPMs Heme biosynthesis Metal sequestration by antimicrobial proteins Lipid particle organization

Mitochondrial iron-sulfur cluster biogenesis

Metabolism of porphyrins Dectin-2 family Metabolism of lipids Defective DPM1 causes DPM1-CDG (CDG-1e)

Gluconeogenesis Triglyceride catabolism

Cobalamin (Cbl, vitamin B12) transport and metabolism Formation of the active cofactor, UDP-glucuronate

Ion influx/efflux at host-pathogen interface tRNA modification in the nucleus and cytosol TICAM1,TRAF6-dependent induction of TAK1 complex Processing of Capped Intron-Containing Pre-mRNA Aromatic amines can be N-hydroxylated or N-dealkylated by CYP1A2 Vitamin C (ascorbate) metabolism Regulation of cholesterol biosynthesis by SREBP (SREBF) Defective PGM1 causes PGM1-CDG (CDG1t)

Biosynthesis of E-series 18(S)-resolvins Activation of Nicotinic Acetylcholine Receptors Cellular Senescence Glycogen breakdown (glycogenolysis) via Dependence Receptors in the absence of ligand Ras activation upon Ca2+ influx through NMDA receptor Oncogene Induced Senescence

Defective SRD5A3 causes SRD5A3-CDG (CDG-1q) and KHRZ Glycolysis Regulated Necrosis

tRNA processing in the mitochondrion rRNA processing in the mitochondrion TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling

Activation of Ca-permeable Kainate Receptor

TLR3-mediated TICAM1-dependent programmed cell death

Activation of gene expression by SREBF (SREBP)

CREB phosphorylation through the activation of Ras Vitamin B5 (pantothenate) metabolism

Triglyceride metabolism TICAM1-dependent activation of IRF3/IRF7 Caspase activation via extrinsic apoptotic signalling pathway

rRNA modification in the nucleus and cytosol Defective PMM2 causes PMM2-CDG (CDG-1a)

CLEC7A (Dectin-1) signaling HSP90 chaperone cycle for steroid hormone receptors (SHR)

rRNA processing in the nucleus and cytosol Vitamin D (calciferol) metabolism Programmed Defensins

Plasmalogen biosynthesis GABA A receptor activation Glycogen metabolism rRNA modification in the mitochondrion Pyrophosphate hydrolysis tRNA modification in the mitochondrion Biosynthesis of DPA-derived SPMs

Glucuronidation Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits

TICAM1, RIP1-mediated IKK complex recruitment Glutathione synthesis and recycling

Aflatoxin activation and detoxification

GABA B receptor activation

Conjugation of phenylacetate with glutamine

Glucose metabolism

Reversible hydration of carbon dioxide

CYP2E1 reactions Biosynthesis of DPAn-6 SPMs

Galactose catabolism

tRNA processing Detoxification of Reactive Oxygen Species

CLEC7A (Dectin-1) induces NFAT activation

Metabolism of steroid hormones absorption responses

CREB phosphorylation through the activation of Adenylate Cyclase

Glucocorticoid biosynthesis rRNA processing

Coenzyme A biosynthesis tRNA processing in the nucleus Triglyceride biosynthesis Formation of xylulose-5-phosphate Collagen chain trimerization 5-Phosphoribose 1-diphosphate biosynthesis

Cytosolic iron-sulfur cluster assembly Glutathione conjugation Activation of Na-permeable kainate receptors

Regulation of HSF1-mediated heat shock response

Post NMDA receptor activation events Cellular responses to stress Acetylcholine binding and downstream events Ionotropic activity of kainate receptors Metabolism

Regulation of PAK-2p34 activity by PS-GAP/RHG10 Alpha-defensins PP2A-mediated dephosphorylation of key metabolic factors Metabolism Biosynthesis of DPAn-3-derived protectins and resolvins

CLEC7A/inflammasome pathway Amino Acid conjugation Conjugation of carboxylic acids Apoptosis Macroautophagy Pentose phosphate pathway Biological oxidations GABA receptor activation

Dectin-1 mediated noncanonical NF-kB signaling snRNP Assembly Biosynthesis of DPAn-3 SPMs Phase II - Conjugation of compounds

Beta defensins Miscellaneous substrates

Estrogen biosynthesis Regulation of Apoptosis

Androgen biosynthesis Cellular response to heat stress Conjugation of salicylate with glycine

Metabolism of carbohydrates

CREB phosphorylation through the activation of CaMKK

Metabolism of non-coding RNA

Lactose synthesis Activation of NMDA receptor and postsynaptic events

SLBP independent Processing of Histone Pre-mRNAs FMO oxidises nucleophiles

Unblocking of NMDA receptor, glutamate binding and activation Cell Acetylation

Vitamins GABA A (rho) receptor activation

Glucagon signaling in metabolic regulation Anchoring fibril formation Transcriptional activation of mitochondrial biogenesis Conjugation of benzoate with glycine Mineralocorticoid biosynthesis Organelle HSF1 activation Integration of energy metabolism

CREB phosphorylation through the activation of CaMKII Molecules associated with elastic fibres AUF1 (hnRNP D0) binds and destabilizes mRNA Pregnenolone biosynthesis

Biosynthesis of DPAn-3-derived maresins Collagen biosynthesis and modifying enzymes Apoptosis induced DNA fragmentation Activation of kainate receptors upon glutamate binding Xenobiotics Glycosaminoglycan metabolism

PKA activation in glucagon signalling

Caspase-mediated cleavage of cytoskeletal proteins

Presynaptic function of Kainate receptors Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) Regulation of activated PAK-2p34 by proteasome mediated degradation Cytosolic sulfonation of small molecules Cellular response to hypoxia

Nonsense-Mediated Decay (NMD)

Methylation Processing of Capped Intronless Pre-mRNA Activation of PPARGC1A (PGC-1alpha) by phosphorylation

Tandem of pore domain in a weak inwardly rectifying K+ channels (TWIK)

Lysosomal oligosaccharide catabolism Fructose metabolism Biosynthesis of DPAn-3-derived 13-series resolvins to Metabolism of nucleotides

Cytochrome P450 - arranged by substrate type Response to metal ions

TWIK-releated acid-sensitive K+ channel (TASK) HSF1-dependent transactivation Insulin-like Growth Factor-2 mRNA Binding Proteins (IGF2BPs/IMPs/VICKZs) bind RNA Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA

AMPK inhibits chREBP transcriptional activation activity Neurotransmitter receptors and postsynaptic signal transmission Metallothioneins bind metals Extracellular Apoptotic execution phase

Fatty acids Phase I - Functionalization of compounds Breakdown of the nuclear lamina Insulin effects increased synthesis of Xylulose-5-Phosphate of Regulation of mRNA stability by proteins that bind AU-rich elements

Apoptotic cleavage of cell adhesion proteins Fructose biosynthesis

Activation of CaMK IV TWIK-related alkaline pH activated K+ channel (TALK) Assembly of collagen fibrils and other multimeric structures Pyrimidine catabolism

PAOs oxidise polyamines to amines

Cristae formation Glucagon-like Peptide-1 (GLP1) regulates insulin secretion

Glutamate binding, activation of AMPA receptors and synaptic plasticity Elastic fibre formation mRNA Capping

Stimulation of the cell death response by PAK-2p34 Mitochondrial biogenesis

Crosslinking of collagen fibrils

Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)

PKA-mediated phosphorylation of key metabolic factors Activation of DNA fragmentation factor

ChREBP activates metabolic gene expression Interconversion of nucleotide di- and triphosphates

Regulation of insulin secretion Trafficking of AMPA receptors

Processing of Intronless Pre-mRNAs

Collagen formation HuR (ELAVL1) binds and stabilizes mRNA

Aryl hydrocarbon receptor signalling Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha

Fibronectin matrix formation Apoptotic cleavage of cellular proteins Regulation of Hypoxia-inducible Factor (HIF) by oxygen

Trafficking of GluR2-containing AMPA receptors

Astrocytic Glutamate-Glutamine Uptake And Metabolism

SLBP Dependent Processing of Replication-Dependent Histone Pre-mRNAs Eicosanoids

Transport and synthesis of PAPS Death Endogenous sterols Fructose catabolism

Tandem pore domain halothane-inhibited K+ channel (THIK)

Acetylcholine regulates insulin secretion Attenuation phase

biogenesis MTF1 activates gene expression Tandem pore domain potassium channels

Deadenylation-dependent mRNA decay Synaptic adhesion-like molecules Ca2+ activated K+ channels

Ethanol oxidation TWIK related potassium channel (TREK) Nucleobase biosynthesis

Nucleobase catabolism

Amine Oxidase reactions KSRP (KHSRP) binds and destabilizes mRNA

COX reactions

mRNA Editing

Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA

Invadopodia formation

Activation of AMPA receptors Nucleotide salvage

Phospholipid metabolism

Neurotransmitter uptake and metabolism In glial cells external

Sterols are 12-hydroxylated by CYP8B1 Free fatty acids regulate insulin secretion

Voltage gated Potassium channels Neurexins and neuroligins

Regulation of gene expression by Hypoxia-inducible Factor

Adrenaline,noradrenaline inhibits insulin secretion matrix

Phosphate bond hydrolysis by NTPDase proteins TWIK-related spinal cord K+ channel (TRESK) RNA Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha

mRNA decay by 3' to 5' exoribonuclease

Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion Activation of Matrix Metalloproteinases

Degradation of the extracellular matrix

Sulfide oxidation to sulfate

Integrin cell surface interactions

Biogenic amines are oxidatively deaminated to aldehydes by MAOA and MAOB

Pyrimidine biosynthesis

Protein-protein interactions at synapses Deadenylation of mRNA

Purine salvage HS-GAG biosynthesis

Potassium Channels

Purine ribonucleoside monophosphate biosynthesis

Glutamate Neurotransmitter Release Cycle Cysteine formation from homocysteine mRNA Editing: C to U Conversion mRNA decay by 5' to 3' exoribonuclease Pink/Parkin Mediated Mitophagy Transmission across Chemical Synapses

HCN channels

ECM proteoglycans CS/DS degradation

Purine catabolism Synthesis of PI

Chondroitin sulfate/dermatan sulfate metabolism

Anchoring of the basal body to the plasma membrane Serine biosynthesis and Pyrimidine salvage

Degradation of cysteine and homocysteine Non-integrin membrane-ECM interactions mRNA Editing: A to I Conversion Phase 3 - rapid repolarisation Laminin interactions

Synthesis of PG Acyl chain remodelling of PE

Dopamine Neurotransmitter Release Cycle

Formation of editosomes by ADAR proteins

Cilium Assembly

Heparan sulfate/heparin (HS-GAG) metabolism

ARL13B-mediated ciliary trafficking of INPP5E

Collagen degradation

Phase 2 - plateau phase

Physiological factors Amino acid synthesis and interconversion (transamination) Mitophagy

Chondroitin sulfate biosynthesis ATP sensitive Potassium channels

Synthesis of PC stimuli Presynaptic depolarization and calcium channel opening Hyaluronan metabolism

Receptor-type tyrosine-protein phosphatases BMAL1:CLOCK,NPAS2 activates circadian gene expression Synthesis of PIPs at the late endosome membrane Sulfur amino acid metabolism

Formation of selenosugars for excretion Synthesis of PA Neurotransmitter release cycle organization

Synthesis of PE

Degradation of GABA

Inwardly rectifying K+ channels

Keratan sulfate/keratin metabolism A tetrasaccharide linker sequence is required for GAG synthesis

Syndecan interactions

Phosphate bond hydrolysis by NUDT proteins Metabolism of amino acids and derivatives Dermatan sulfate biosynthesis Synthesis of PIPs at the early endosome membrane Intraflagellar transport

Glycerophospholipid biosynthesis

Transmission across Electrical Synapses Cargo trafficking to the periciliary membrane Ion homeostasis HS-GAG degradation Acyl chain remodeling of CL

Phase 1 - inactivation of fast Na+ channels Choline catabolism

GABA synthesis, release, reuptake and degradation SeMet incorporation into proteins Cardiac conduction C6 deamination of adenosine

VxPx cargo-targeting to cilium

Potassium transport channels

Methionine salvage pathway Receptor Mediated Mitophagy Neurotransmitter clearance PI and PC transport between ER and Golgi membranes

Hyaluronan uptake and degradation Threonine catabolism Norepinephrine Neurotransmitter Release Cycle

Acetylcholine Neurotransmitter Release Cycle

Activation of G protein gated Potassium channels Formation of the Editosome

Synthesis of PS Acyl chain remodeling of DAG and TAG maintenance Acyl chain remodelling of PC Reuptake of GABA

PI Metabolism Methylation of MeSeH for excretion

RORA activates gene expression

Hyaluronan biosynthesis and export

Serotonin Neurotransmitter Release Cycle

Branched-chain amino acid catabolism Classical Kir channels

Phase 4 - resting membrane potential Phase 0 - rapid depolarisation

Melanin biosynthesis Selenoamino acid metabolism

Hydrolysis of LPE BBSome-mediated cargo-targeting to cilium

Keratan sulfate degradation

Keratan sulfate biosynthesis

Agmatine biosynthesis Trafficking of myristoylated proteins to the cilium Acyl chain remodelling of PG Circadian Electric Transmission Across Gap Junctions Acyl chain remodelling of PS

Glyoxylate metabolism and glycine degradation Synthesis of CL Synthesis of PIPs in the nucleus

Metabolism of ingested SeMet, Sec, MeSec into H2Se GABA synthesis

Serotonin clearance from the synaptic cleft

Metabolism of polyamines

Acyl chain remodelling of PI

Carnitine synthesis

Synthesis of PIPs at the plasma membrane Hydrolysis of LPC

Dopamine clearance from the synaptic cleft

Regulation of ornithine decarboxylase (ODC)

Metabolism of ingested H2SeO4 and H2SeO3 into H2Se

Glycerophospholipid catabolism

Amine-derived hormones

Metabolism of ingested MeSeO2H into MeSeH

Selenocysteine synthesis

Glycine degradation Synthesis of PIPs at the Golgi membrane NeuronalMetabolism of serotonin Synthesis of PIPs at the ER membrane

G protein gated Potassium channels

Interconversion of polyamines Urea cycle Muscle HDACs deacetylate histones Creatine metabolism Chromatin

Enzymatic degradation of dopamine by COMT Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism Clock

Enzymatic degradation of Dopamine by monoamine oxidase

Synthesis of BMP PIPs transport between early and late endosome membranes HATs acetylate histones

Catecholamine biosynthesis

NR1D1 (REV-ERBA) represses gene expression

Serotonin and melatonin biosynthesis

Histidine catabolism PIPs transport between early endosome and Golgi membranes PIPs transport between Golgi and plasma membranes

PIPs transport between late endosome and Golgi membranes

Chromatin modifying enzymes

Phenylalanine and tyrosine catabolism

Thyroxine biosynthesis

PIPs transport between plasma and early endosome membranes Lysine catabolism System

Tryptophan catabolism

PKMTs methylate histone lysines

Proline catabolism contraction organization

Striated Muscle Contraction

HDMs demethylate histones

Smooth Muscle Contraction

RMTs methylate histone arginines

Regulation of thyroid hormone activity Figure S4 miRNA (n = 36)

hsa−miR−16−5phsa−miR−15a−5phsa−miR−20a−5phsa−miR−424−5phsa−miR−144−3phsa−miR−101−3phsa−let−7e−5phsa−miR−34a−5phsa−miR−21−5phsa−miR−503−5phsa−miR−155−5phsa−miR−125a−5phsa−miR−142−3phsa−miR−18a−5phsa−miR−193a−3phsa−miR−146a−5phsa−miR−146b−5phsa−miR−9−5phsa−miR−451ahsa−miR−378a−3phsa−miR−9−3phsa−miR−142−5phsa−miR−126−3phsa−miR−101−5phsa−miR−21−3phsa−miR−16−1−3phsa−miR−15a−3phsa−miR−126−5phsa−miR−193a−5phsa−miR−20a−3phsa−miR−155−3phsa−miR−503−3phsa−miR−144−5phsa−miR−378a−5phsa−miR−146b−3phsa−miR−221−5p mir_fdr mir_log2fc 9 9 8 9 4 5 1 1 92 84 86 65 60 52 53 27 46 45 43 34 24 29 21 11 16 10 201198175170149130139125102120 Signal Transduction 10310383 86 64 62 48 45 39 31 36 27 30 16 12 12 9 11 5 7 6 4 4 1 1 1 1 2 3 2 1 1 2 1 1930/2727 Death Receptor Signalling 7794314341 15 1 1 132/144 Signaling by TGF−beta family members 16 18 10 2 9 9 4 9 6 3 1 1 2 2 1 1 2 1 93/102 MAPK6/MAPK4 signaling 66222331312 211 1 1 87/94 PCP/CE pathway 7 6 4 3 1 1 1 1 1 85/92 Hedgehog 'on' state 4 3 2 4 2 2 1 1 1 1 1 2 1 1 80/86 Degradation of beta−catenin by the destruction complex 5 6 2 4 3 2 4 1 3 82/84 Signaling by NOTCH4 7 6 2 2 1 3 5 2 1 1 2 1 81/82 Signaling by TGF−beta Receptor Complex 14 15 8 2 8 8 2 7 5 1 1 1 2 2 1 1 2 1 73/73 Regulation of PTEN stability and activity 33421311 1 211 1 1 67/69 Regulation of RAS by GAPs 4 2 3 3 1 2 1 1 1 1 1 64/68 Asymmetric localization of PCP proteins 4 3 3 1 1 1 60/64 Degradation of GLI1 by the proteasome 2 1 2 3 1 1 1 1 1 58/60 Degradation of GLI2 by the proteasome 2 1 1 2 1 1 1 1 1 58/60 GLI3 is processed to GLI3R by the proteasome 2 1 1 2 1 1 1 2 1 58/60 Degradation of DVL 3 2 1 1 1 1 55/57 Degradation of AXIN 3 3 2 2 1 1 53/55 Signaling by Non−Receptor Tyrosine Kinases 4261 2 13 111 122 1 2 1 1 49/55 Signaling by PTK6 4261 2 13 111 122 1 2 1 1 49/55 Negative regulation of NOTCH4 signaling 3 2 1 1 1 1 1 1 53/54 Signaling by NOTCH3 22231223321 1 1111 45/49 TNF signaling 3 3 1 2 1 2 1 2 1 40/46 Signaling by SCF−KIT 4322241122111 1 1 1 1 37/43 Regulation of TNFR1 signaling 1 1 1 2 1 2 1 1 1 30/36 Signaling by NOTCH2 3312221322 1 1 1 31/33 TGF−beta receptor signaling activates SMADs 775232131 11 2 21 1 2 1 32/32 Downstream signal transduction 5 3 3 1 2 1 2 1 1 1 1 28/29 Downregulation of TGF−beta receptor signaling 663131131 1 1 1 2 1 26/26 TNFR1−induced NFkappaB signaling pathway 2 2 2 1 2 1 2 1 25/26 NOTCH2 Activation and Transmission of Signal to the Nucleus 2 2 1 2 1 1 3 1 2 1 21/22 TGF−beta receptor signaling in EMT (epithelial to mesenchymal transition) 2 2 2 4 1 1 16/16 p75NTR signals via NF−kB 1 1 1 1 1 15/16 NF−kB is activated and signals survival 1 1 1 1 12/13 p75NTR recruits signalling complexes 1 1 1 1 1 12/13 NOTCH4 Activation and Transmission of Signal to the Nucleus 1 1 2 1 1 2 11/11 PTK6 Regulates Cell Cycle 4/6 Antagonism of Activin by Follistatin 4/4 Metabolism 45 58 42 42 31 29 36 20 6 14 15 18 14 9 6 4 3 3 1 2 1 1 1 1734/2095 Selenoamino acid metabolism 1 1 2 1 1 1 110/118 Selenocysteine synthesis 1 89/94 Metabolism of polyamines 3 1 1 1 72/85 Regulation of ornithine decarboxylase (ODC) 2 1 1 49/51 Creatine metabolism 1 6/10 Immune System 86 83 66 65 49 45 29 40 20 22 24 19 15 9 7 7 7 5 5 2 1 3 3 2 1 2 1 2 1 1 1 1630/2074 Cytokine Signaling in Immune system 32 29 25 21 17 22 12 12 14 9 9 9 5 5 2 3 1 3 2 2 1 2 2 1 1 2 1 1 578/686 Signaling by Interleukins 25 24 22 15 15 17 10 10 12 7 7 8 4 3 1 3 1 3 2 1 1 2 2 1 1 2 1 1 394/453 Fc epsilon receptor (FCERI) signaling 875665412221311 1 1 1 1 1 125/210 Signaling by the B Cell Receptor (BCR) 88254 1 211 1 1 106/175 FCERI mediated NF−kB activation 4313321 111 1 76/157 Toll−like Receptor Cascades 6812576533313211 1 111 1 142/153 C−type lectin receptors (CLRs) 66185222122 2 1 135/144 Interleukin−1 family signaling 8775321123 12 1 1 1 1 1 125/138 Toll Like Receptor 4 (TLR4) Cascade 6811576433313211 1 111 1 121/126 TCR signaling 64364231124 1 1 1 1 1 108/125 Interleukin−4 and Interleukin−13 signaling 75746937722321 1 11 1 1121 94/112 Downstream TCR signaling 4324321 12 1 1 1 1 1 90/104 Antigen processing−Cross presentation 5 4 1 2 1 1 1 2 92/102 Interleukin−1 signaling 76643211 3 12 1 1 98/102 TNFR2 non−canonical NF−kB pathway 4 2 2 2 1 1 1 1 1 1 88/101 CLEC7A (Dectin−1) signaling 55155212111 2 1 97/100 MyD88−independent TLR4 cascade 5795763333122 1 1 11 1 94/97 TRIF(TICAM1)−mediated TLR4 signaling 5795763333122 1 1 11 1 94/97 MyD88:MAL(TIRAP) cascade initiated on plasma membrane 589555432313211 1 1 1 1 92/96 Toll Like Receptor 2 (TLR2) Cascade 589555432313211 1 1 1 1 92/96 Toll Like Receptor TLR1:TLR2 Cascade 589555432313211 1 1 1 1 92/96 Toll Like Receptor TLR6:TLR2 Cascade 589555432313211 1 1 1 1 92/96 Toll Like Receptor 9 (TLR9) Cascade 5 8 10 5 5 5 5 3 2 3 1 3 2 1 1 1 1 1 1 90/95 Toll Like Receptor 3 (TLR3) Cascade 5795763333122 1 1 1 1 91/93 Role of LAT2/NTAL/LAB on calcium mobilization 2 2 1 1 1 13/92 MyD88 dependent cascade initiated on endosome 589555432313211 1 1 1 1 87/91 Toll Like Receptor 7/8 (TLR7/8) Cascade 589555432313211 1 1 1 1 87/91 TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation 589555432313211 1 1 1 1 86/90 ER−Phagosome pathway 5 4 1 1 1 1 1 80/86 MyD88 cascade initiated on plasma membrane 589555432313211 1 1 1 82/85 Toll Like Receptor 10 (TLR10) Cascade 589555432313211 1 1 1 82/85 Toll Like Receptor 5 (TLR5) Cascade 589555432313211 1 1 1 82/85 Downstream signaling events of B Cell Receptor (BCR) 6 5 1 3 3 1 2 1 1 1 79/81 DDX58/IFIH1−mediated induction of interferon−alpha/beta 3382322311 1 11 1 11 1 62/77 Interleukin−17 signaling 4755443323122 1 1 68/71 Activation of NF−kappaB in B cells 3 2 1 2 1 1 1 1 65/67 Cytosolic sensors of pathogen−associated DNA 2 3 2 1 1 1 1 58/63 MAP kinase activation 4755443323122 1 1 63/63 Dectin−1 mediated noncanonical NF−kB signaling 2 1 1 2 1 1 1 1 59/62 NIK−−>noncanonical NF−kB signaling 2 1 1 2 1 1 1 56/59 Nucleotide−binding domain, leucine rich repeat containing receptor (NLR) signaling pathways 33431222 1 12 1 1 1 49/54 Cross−presentation of soluble exogenous antigens (endosomes) 2 1 1 44/50 Interleukin−10 signaling 1 2 2 1 1 3 2 1 42/47 Interleukin−2 family signaling 4 4 1 1 1 2 1 1 1 37/44 Interleukin−3, Interleukin−5 and GM−CSF signaling 4 3 2 1 1 2 1 1 1 1 1 40/44 CD28 co−stimulation 2 2 2 1 2 2 2 2 2 2 1 1 28/33 NOD1/2 Signaling Pathway 2 2 2 3 1 2 1 1 1 2 1 31/31 TAK1 activates NFkB by phosphorylation and activation of IKKs complex 2 2 3 2 1 2 1 1 2 1 26/28 Interleukin receptor SHC signaling 2 2 1 1 1 1 1 1 24/27 Interleukin−6 family signaling 2 3 1 2 1 1 1 1 1 19/24 TRAF6 mediated NF−kB activation 1 1 4 1 1 2 1 1 1 1 1 22/24 IKK complex recruitment mediated by RIP1 1 1 2 1 2 2 1 1 1 22/23 # of miRNA targets CD28 dependent PI3K/Akt signaling 2 2 1 1 1 1 1 1 1 1 1 19/22 103 CTLA4 inhibitory signaling 3 3 1 2 1 4 19/21 78 52 ZBP1(DAI) mediated induction of type I IFNs 1 1 1 1 19/21 26 TICAM1, RIP1−mediated IKK complex recruitment 1 1 2 1 2 2 1 1 19/19 0 RIP−mediated NFkB activation via ZBP1 1 1 1 1 17/17 miRNA log2FC 4 MAP3K8 (TPL2)−dependent MAPK1/3 activation 2 3 1 1 2 1 1 2 16/16 2 Interleukin−15 signaling 3 3 1 1 1 1 14/14 0 Interleukin−2 signaling 10/12 −2 NF−kB activation through FADD/RIP−1 pathway mediated by caspase−8 and −10 1 1 1 1 12/12 −4 IRAK1 recruits IKK complex 2 2 1 1 1 1 10/10 miRNA FDR 2e−21 IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation 2 2 1 1 1 1 10/10 2e−16 DEx/H−box helicases activate type I IFN and inflammatory cytokines production 7/7 1e−11 Metabolism of proteins 74 84 57 62 44 40 33 26 20 27 20 19 10 13 8 11 7 4 1 2 1 3 1 1 1 1 2 1 1755/2011 7e−07 Cap−dependent Translation Initiation 2 2 1 3 2 114/120 5e−02 Pathway ES Eukaryotic Translation Initiation 2 2 1 3 2 114/120 5 SRP−dependent cotranslational protein targeting to membrane 1 1 1 1 1 1 106/115 2.5 GTP hydrolysis and joining of the 60S ribosomal subunit 1 1 1 3 2 108/113 0 L13a−mediated translational silencing of Ceruloplasmin expression 1 1 1 1 2 107/112 −2.5 Formation of a pool of free 40S subunits 1 1 1 97/102 −5 Pathway FDR Eukaryotic Translation Elongation 1 88/95 9e−24 Eukaryotic Translation Termination 1 89/94 2e−18 Peptide chain elongation 1 85/90 7e−13 2e−07 SUMOylation of immune response proteins 1 11/11 5e−02 Gene expression (Transcription) 74 69 50 49 41 51 34 39 25 15 26 21 14 10 7 9 6 6 3 4 2 2 1 1 1 1 1 1 1 1 1304/1477 Transcriptional regulation by RUNX3 975435352 12 4 111 1 94/96 Regulation of RUNX2 expression and activity 542113 11 11 11 1 70/73 Regulation of RUNX3 expression and activity 4 3 1 1 1 2 54/55 Regulation of RUNX1 Expression and Activity 4 3 2 1 2 1 3 2 1 1 1 17/27 RUNX3 regulates NOTCH signaling 1 1 1 2 2 2 1 14/14 RUNX3 regulates p14−ARF 1 1 2 1 1 1 1 10/10 RUNX3 regulates WNT signaling 1 1 1 1 8/8 Regulation of TP53 Expression 1 2 1 2/2 Developmental Biology 36 39 33 32 22 22 16 18 13 12 10 8 9 6 6 6 4 4 1 1 2 2 1 1 1 1 2 800/1036 Regulation of expression of SLITs and ROBOs 3 2 1 2 1 1 162/173 Interaction between L1 and Ankyrins 2 1 1 1 29/29 Disease 48 44 23 38 28 29 15 24 11 15 13 13 11 6 3 5 5 5 1 2 1 3 4 1 1 1 1 790/942 Influenza Infection 642345211 12 111 148/163 Influenza Life Cycle 4 3 1 2 1 4 1 1 1 2 1 1 139/152 Influenza Viral RNA Transcription and Replication 3 1 1 2 1 2 1 1 1 2 1 1 130/143 Host Interactions of HIV factors 6637152112111 1 125/139 Viral mRNA Translation 1 1 1 1 1 85/97 Diseases of glycosylation 11 21132 2 211 1 77/86 Disorders of transmembrane transporters 3 1 2 3 2 1 63/70 ABC transporter disorders 3 1 2 3 2 1 60/63 Defective CFTR causes cystic fibrosis 3 1 2 3 2 1 58/61 Diseases associated with O−glycosylation of proteins 1 1 2 1 3 2 1 1 53/60 Hh mutants that don't undergo autocatalytic processing are degraded by ERAD 2 1 2 2 2 1 1 54/56 Vif−mediated degradation of APOBEC3G 2 1 1 1 50/55 Vpu mediated degradation of CD4 2 1 1 2 1 50/53 Diseases associated with the TLR signaling cascade 2 1 1 1 1 24/27 Diseases of Immune System 2 1 1 1 1 24/27 Signaling by cytosolic FGFR1 fusion mutants 1 1 1 1 1 1 18/18 Constitutive Signaling by NOTCH1 HD Domain Mutants 1 1 2 1 1 1 2 1 2 1 14/15 Signaling by NOTCH1 HD Domain Mutants in Cancer 1 1 2 1 1 1 2 1 2 1 14/15 Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant 1 1 1 2 1 1 1 7/7 IkBA variant leads to EDA−ID 1 1 1 7/7 Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant 1 1 1 2 1 1 1 7/7 IKBKB deficiency causes SCID 1 1 1 3/3 IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA−ID) (via TLR) 1 1 1 3/3 Vesicle−mediated transport 42 47 33 30 23 25 11 12 1 9 4 5 16 3 1 4 3 6 1 2 1 593/730 Transport of small molecules 14 18 19 26 13 10 14 4 2 6 5 5 5 3 3 3 3 1 1 608/718 Metabolism of RNA 18 16 11 8 4 4 10 5 4 3 3 3 2 2 1 1 1 1 1 1 650/717 Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) 3 4 1 1 1 1 1 1 111/116 Nonsense−Mediated Decay (NMD) 3 4 1 1 1 1 1 1 111/116 Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) 1 1 91/96 Regulation of mRNA stability by proteins that bind AU−rich elements 4 3 2 1 1 2 3 1 2 1 1 85/89 AUF1 (hnRNP D0) binds and destabilizes mRNA 2 1 2 1 1 53/55 tRNA processing in the mitochondrion 18/42 Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA 1 1 1 2 2 1 16/17 Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA 2 2 1 1 1 2 1 16/17 Hemostasis 20 21 19 20 20 19 7 13 8 11 7 6 4 1 3 2 1 2 1 2 3 2 2 483/688 Cell Cycle 23 21 18 17 15 16 13 13 8 7 8 6 2 2 1 2 1 1 2 2 551/599 Mitotic G1−G1/S phases 11 8 7 2 4 4 6 9 3 2 3 2 1 1 2 1 141/149 G1/S Transition 75422236122 1 1 1 124/131 Cyclin A:Cdk2−associated events at S phase entry 65331214121 1 1 82/85 Cyclin E associated events during G1/S transition 64321214121 1 1 80/83 Regulation of APC/C activators between G1/S and early anaphase 3 2 1 2 1 1 1 77/80 APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint 3 2 1 1 1 1 71/73 APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 3 2 1 1 1 1 70/72 CDK−mediated phosphorylation and removal of Cdc6 3 2 1 1 1 1 1 1 69/72 Cdc20:Phospho−APC/C mediated degradation of Cyclin A 3 2 1 1 1 1 70/72 Orc1 removal from chromatin 2 1 1 1 1 1 68/71 G1/S DNA Damage Checkpoints 5323 11212 1 1 1 64/68 APC/C:Cdc20 mediated degradation of Securin 3 2 1 1 1 65/67 p53−Dependent G1 DNA Damage Response 4222 111 1 1 1 1 62/66 p53−Dependent G1/S DNA damage checkpoint 4222 111 1 1 1 1 62/66 Autodegradation of Cdh1 by Cdh1:APC/C 3 2 1 1 1 62/63 SCF(Skp2)−mediated degradation of p27/p21 3 1 1 1 1 1 1 57/60 The role of GTSE1 in G2/M progression after G2 checkpoint 4 2 2 1 1 1 56/60 CDT1 association with the CDC6:ORC:origin complex 2 1 1 1 1 56/59 Stabilization of p53 3 2 1 2 1 1 1 1 55/57 FBXL7 down−regulates AURKA during mitotic entry and in early mitosis 2 1 1 1 1 53/55 SCF−beta−TrCP mediated degradation of Emi1 2 1 1 2 1 53/55 Ubiquitin Mediated Degradation of Phosphorylated Cdc25A 3 2 1 2 1 1 1 1 1 51/53 p53−Independent DNA Damage Response 3 2 1 2 1 1 1 1 1 51/53 p53−Independent G1/S DNA damage checkpoint 3 2 1 2 1 1 1 1 1 51/53 Autodegradation of the E3 ubiquitin ligase COP1 2 1 1 1 1 1 1 1 50/52 Ubiquitin−dependent degradation of Cyclin D 2 1 1 1 1 50/52 Ubiquitin−dependent degradation of Cyclin D1 2 1 1 1 1 50/52 Cyclin D associated events in G1 6 4 4 2 2 4 5 2 1 2 1 1 43/44 G1 Phase 6 4 4 2 2 4 5 2 1 2 1 1 43/44 Cellular responses to external stimuli 24 24 23 24 10 18 13 10 11 5 7 8 2 2 2 1 1 4 1 2 1 1 1 421/471 Cellular response to hypoxia 5 3 5 4 2 1 2 1 2 1 67/75 Regulation of Hypoxia−inducible Factor (HIF) by oxygen 5 3 5 4 2 1 2 1 2 1 67/75 Neuronal System 799117774112442233 131 339/391 Extracellular matrix organization 334873114251212323311111 1 253/296 DNA Repair 77632741 24312232 1 276/295 Organelle biogenesis and maintenance 15 14 13 9 7 10 5 3 2 1 4 3 1 1 2 1 1 247/282 Chromatin organization 10 12 9 8 13 18 4 7 4 1 8 2 5 3 1 2 1 1 223/241 Muscle contraction 2326 43 23 112 1 171/204 Programmed Cell Death 964454433131211 1 1 2 1 1 1 1 167/182 Regulation of Apoptosis 2 1 1 2 1 1 51/53 Regulation of activated PAK−2p34 by proteasome mediated degradation 2 1 1 2 1 1 48/50 Regulation of necroptotic cell death 1 1 1 1 12/16 Activation of BAD and translocation to mitochondria 4 3 1 1 2 1 2 1 1 1 1 14/15 BH3−only proteins associate with and inactivate anti−apoptotic BCL−2 members 2 1 1 2 1 1 1 1 1 1 9/9 DNA Replication 4 3 3 1 3 2 2 1 2 1 1 1 121/127 CDK−mediated phosphorylation and removal of Cdc6 3 2 1 1 1 1 1 1 69/72 Orc1 removal from chromatin 2 1 1 1 1 1 68/71 CDT1 association with the CDC6:ORC:origin complex 2 1 1 1 1 56/59 Cell−Cell communication 4 3 2 1 2 3 1 1 1 1 1 2 2 1 1 102/122 Reproduction 122 15111 21 1 11 92/114 Circadian Clock 346433424232212 1 1 1 1 67/70 Mitophagy 1 3 2 1 26/29 Digestion and absorption 14/27 path_es path_fdr