SOCS3

Summary

SOCS3 (suppressor of cytokine signaling 3, HGNC:19391) is a protein-coding gene on chromosome 17q25.3, encoding Suppressor of cytokine signaling 3 (O14543). SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. It is a selective cancer dependency (DepMap: 12.0% of cell lines).

This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene is induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma. The protein encoded by this gene can bind to JAK2 kinase, and inhibit the activity of JAK2 kinase. Studies of the mouse counterpart of this gene suggested the roles of this gene in the negative regulation of fetal liver hematopoiesis, and placental development.

Source: NCBI Gene 9021 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 35 total
• Cancer dependency (DepMap): dependent in 12.0% of screened cell lines
• MANE Select transcript: NM_003955

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19391
Approved symbol	SOCS3
Name	suppressor of cytokine signaling 3
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	SSI-3, CIS3, SOCS-3, Cish3
Ensembl gene	ENSG00000184557
Ensembl biotype	protein_coding
OMIM	604176
Entrez	9021

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000330871, ENST00000587578, ENST00000907726, ENST00000912407

RefSeq mRNA: 3 — MANE Select: NM_003955 NM_001378932, NM_001378933, NM_003955

CCDS: CCDS11756

Canonical transcript exons

ENST00000330871 — 2 exons

Exon	Start	End
ENSE00001308158	78356778	78359183
ENSE00001364298	78359750	78360077

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 99.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 76.5837 / max 1949.4758, expressed in 1750 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168379	75.7893	1749
168375	0.4527	204
168377	0.1623	72
168378	0.1166	35
168376	0.0627	23

Top tissues by expression

280 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	99.53	gold quality
left uterine tube	UBERON:0001303	99.26	gold quality
vena cava	UBERON:0004087	99.03	gold quality
gall bladder	UBERON:0002110	98.97	gold quality
saphenous vein	UBERON:0007318	98.32	gold quality
pericardium	UBERON:0002407	97.79	gold quality
seminal vesicle	UBERON:0000998	97.72	gold quality
upper lobe of left lung	UBERON:0008952	97.20	gold quality
lower lobe of lung	UBERON:0008949	97.02	gold quality
upper lobe of lung	UBERON:0008948	97.00	gold quality
mammary duct	UBERON:0001765	96.51	gold quality
omental fat pad	UBERON:0010414	96.49	gold quality
peritoneum	UBERON:0002358	96.44	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.15	gold quality
cauda epididymis	UBERON:0004360	95.60	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.60	gold quality
nipple	UBERON:0002030	95.46	gold quality
upper leg skin	UBERON:0004262	95.30	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.10	gold quality
decidua	UBERON:0002450	94.89	gold quality
monocyte	CL:0000576	94.71	gold quality
mononuclear cell	CL:0000842	94.59	gold quality
cartilage tissue	UBERON:0002418	94.39	gold quality
smooth muscle tissue	UBERON:0001135	94.29	gold quality
leukocyte	CL:0000738	94.08	gold quality
cardia of stomach	UBERON:0001162	93.58	gold quality
tendon of biceps brachii	UBERON:0008188	93.36	gold quality
right lung	UBERON:0002167	93.25	gold quality
urethra	UBERON:0000057	93.12	gold quality
epithelium of mammary gland	UBERON:0003244	93.09	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-MTAB-8322	yes	2271.69
E-GEOD-134144	yes	1234.52
E-CURD-88	yes	1043.09
E-MTAB-8884	yes	710.38
E-MTAB-8911	yes	472.47
E-MTAB-6701	yes	120.72
E-MTAB-10287	yes	81.11
E-HCAD-8	yes	53.36
E-CURD-122	yes	49.55
E-MTAB-10553	yes	47.39
E-HCAD-1	yes	29.61
E-HCAD-4	yes	22.84
E-MTAB-8410	yes	21.63
E-GEOD-137537	yes	6.48
E-GEOD-130148	yes	4.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, APEX1, AR, ATF2, CEBPA, CEBPB, CEBPG, DNMT1, ESR1, FLT3, FOS, FOXO3, FOXP3, GFI1, HAND1, HNF1B, HSF1, IRF6, JUN, MFGE8, MTF1, NFKB1, NFKB, PAX1, PLAGL1, PPARG, RELA, RUNX1, SIN3A, SOX6, SP1, SP3, SPI1, SSRP1, STAT1, STAT3, STAT4, STAT5A, STAT5B, STAT6

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• active MKK6 in HepG2 cells enhanced basal activity or IL-6-induced transcriptional activation of a SOCS3 promoter (PMID:11727828)
• evidence for pY429pY431 being a new high affinity binding site for SOCS-3 on the EpoR (PMID:12027890)
• SOCS-3 is a major regulator of growth hormone signaling in insulin-producing cells (PMID:12198248)
• chronic expression confers resistance to IFN-alpha in chronic myelogenous leukemia cells (PMID:12351404)
• These data suggest, that there are two, largely distinct modes of negative regulation of gp130 activity, despite the fact that both SOCS3 and SHP2 are recruited to the same site within gp130. (PMID:12403768)
• translational control plays an important role in stabilization and function of SOCS3 (PMID:12459551)
• SOCS-3 may have a role in IL-6-mediated insulin resistance in liver (PMID:12560330)
• Results describe the cloning and characterization of the promoter region of the human SOCS-3 gene. (PMID:12565872)
• Data showing that SOCS3 is not recruited to phosphotyrosine motifs of the IL-10 receptor complex suggest that IL-10 signaling is less sensitive than IL-6 signaling to inhibition by SOCS3. (PMID:12626585)
• induction of SOCS3 by Leishmania donovani provides a potent inhibitory mechanism by which intracellular microorganisms may suppress macrophage activation and interfere with the host immune response (PMID:12654831)
• SOCS-3 plays an important role in the suppression of cytokine signaling by GH in down-regulating the acute phase response after injury. (PMID:12688541)
• acceleration of degradation by tyrosine phosphorylation (PMID:12783885)
• These data indicate that SOCS-3 has an important role in regulating the onset and maintenance of T(H)2-mediated allergic immune disease. (PMID:12847520)
• hypermethylation in CpG islands of the functional SOCS-3 promoter that correlates with its transcription silencing in primary lung cancer tissue samples (PMID:14617776)
• rapidly induced in amnion FL cells in HSV-1 infection and appears to be mainly responsible for suppression of IFN signaling and IFN production during the HSV-1 infection. (PMID:15163721)
• Frequent hypermethylation of the functional SOCS-3 promoter correlates with its transcription silencing in NSCLC cell lines and primary lung cancer tissue samples; methylation silencing of SOCS-3 may be used as a marker for early detection of NSCLC (PMID:15217536)
• Our results demonstrate that SOCS-1 and SOCS-3 proteins inhibit IFN-alpha-induced activation of the Jak-STAT pathway and expression of the antiviral proteins 2’,5’-OAS and MxA. (PMID:15240148)
• Homozygosity for the A-allele of the C -920–>A promoter polymorphism of the SOCS3 gene may be associated with increased whole-body insulin sensitivity. (PMID:15249995)
• Leptin resembles immune molecules called cytokines, which another protein, Socs3, inhibits. Colleagues wondered whether Socs3 also suppresses leptin and promotes resistance to the hormone. (PMID:15300962)
• interleukin-1beta regulates interleukin-6-induced suppressor of cytokine signaling 3 expression (PMID:15308667)
• SOCS-3 expression in human skeletal muscle in vivo is not related to insulin resistance in the presence of elevated IL-6 concentrations suggesting that cytokine action could differ in type 2 diabetic patients and nondiabetic obese subjects. (PMID:15331532)
• SOCS1 and SOCS2 but not SOCS3 suppressed the growth of ovarian and breast cancer cells. (PMID:15361843)
• overexpression of suppressor of cytokine signaling 3 is associated with anaplastic large cell lymphoma (PMID:15385932)
• The insertion of amino acid exchanges into the kinase inhibitory regions of SOCS-3 demonstrated a requirement of these domains for a proper inhibitory function. (PMID:15589317)
• The SOCS3 mRNA expression in bone marrow cells from CML patients who responded well to IFN-alpha therapy was significantly lower than that in cells from healthy volunteers and patients who were resistant to IFN-alpha therapy. (PMID:15607366)
• SOCS-3 is not a tumour suppressor but rather a protector of tumour cells. (PMID:15618960)
• SOCS3/CIS3 regulates hepatocyte growth factor-induced keratinocyte migration by inhibiting signal transducer and activator of transcription 3 phosphorylation (PMID:15629435)
• The induction of SOCS3 by HSV-1 occurs via STAT3 activation immediately after HSV-1 infection. (PMID:15939448)
• promoter methylation and subsequent transcript downregulation of SOCS-3 transcripts and, to a much lesser extent, SOCS-1 are involved in the multistep carcinogenesis of head and neck squamous cell carcinoma (PMID:16007169)
• loss of SOCS-3 by the associated DNA methylation confers cells advantage in growth and migration (PMID:16007195)
• estrogen receptor 1 directly regulates human SOCS-3 promoter activity in human breast cancer cells (PMID:16055089)
• Inhibition of function in dominant-negative SOCS3 transgenic mice clearly reduces the severity of allergic conjunctivitis (PMID:16210657)
• this study suggests a potential novel function of SOCS-3 in regulating keratinocyte proliferation and differentiation in vitro and during skin repair in vivo. (PMID:16374465)
• Results suggest a novel interaction between the SOCS1 and SOCS3 proteins and the FGFR3 signaling pathway. (PMID:16410555)
• SOCS-3 inhibits IL-1 signal transduction by inhibiting ubiquitination of TRAF6, thus preventing association and activation of TAK1. (PMID:16543409)
• Able to repress the activity of the Brk non-receptor tyrosine kinase. (PMID:16568091)
• role for IL-11 via pSTAT3 and SOCS3 in initiating and progressing decidualization (PMID:16709613)
• Our data also show that SOCS3 promoted maintenance of neural stem cells (PMID:16805839)
• Data demonstrate that SOCS3 inhibits leptin activation of AMPK and suggest this impairment of leptin signaling in skeletal muscle may contribute to the aberrant regulation of fatty acid metabolism observed in obesity. (PMID:16822822)
• Deletion of the SOCS3 gene in hepatocytes promotes the activation of STAT3, resistance to apoptosis, and an acceleration of proliferation, resulting in enhanced hepatitis-induced hepatocarcinogenesis. (PMID:16831601)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	socs3a	ENSDARG00000025428
danio_rerio	socs3b	ENSDARG00000026611
mus_musculus	Socs3	ENSMUSG00000053113
rattus_norvegicus	Socs3	ENSRNOG00000063373
drosophila_melanogaster	Socs44A	FBGN0033266
drosophila_melanogaster	Socs36E	FBGN0041184

Paralogs (7): CISH (ENSG00000114737), SOCS2 (ENSG00000120833), SOCS6 (ENSG00000170677), SOCS5 (ENSG00000171150), SOCS4 (ENSG00000180008), SOCS1 (ENSG00000185338), SOCS7 (ENSG00000274211)

Protein

Protein identifiers

Suppressor of cytokine signaling 3 — O14543 (reviewed: O14543)

Alternative names: Cytokine-inducible SH2 protein 3, STAT-induced STAT inhibitor 3

All UniProt accessions (3): O14543, K7EIF6, Q6FI39

UniProt curated annotations — full annotation on UniProt →

Function. SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS3 is involved in negative regulation of cytokines that signal through the JAK/STAT pathway. Inhibits cytokine signal transduction by binding to tyrosine kinase receptors including IL6ST/gp130, LIF, erythropoietin, insulin, IL12, GCSF and leptin receptors. Binding to JAK2 inhibits its kinase activity and regulates IL6 signaling. Suppresses fetal liver erythropoiesis. Regulates onset and maintenance of allergic responses mediated by T-helper type 2 cells. Probable substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

Subunit / interactions. Interacts with multiple activated proteins of the tyrosine kinase signaling pathway including IGF1 receptor, insulin receptor and JAK2. Binding to JAK2 is mediated through the KIR and SH2 domains to a phosphorylated tyrosine residue within the JAK2 JH1 domain. Binds specific activated tyrosine residues of the leptin, EPO, IL12, GSCF and gp130 receptors. Interaction with CSNK1E stabilizes SOCS3 protein. Component of the probable ECS(SOCS3) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and SOCS3. Interacts with CUL5, RNF7, ELOB and ELOC. Interacts with CUL2. Interacts with FGFR3. Interacts with INSR. Interacts with BCL10; this interaction may interfere with BCL10-binding with PELI2. Interacts with NOD2 (via CARD domain); the interaction promotes NOD2 degradation.

Tissue specificity. Widely expressed with high expression in heart, placenta, skeletal muscle, peripheral blood leukocytes, fetal and adult lung, and fetal liver and kidney. Lower levels in thymus.

Post-translational modifications. Phosphorylated on tyrosine residues after stimulation by the cytokines, IL-2, EPO or IGF1.

Disease relevance. There is some evidence that SOCS3 may be a susceptibility gene for atopic dermatitis linked to 17q25. SOCS3 messenger RNA is significantly more highly expressed in skin from patients with atopic dermatitis than in skin from healthy controls. Furthermore, a genetic association between atopic dermatitis and a haplotype in the SOCS3 gene has been found in two independent groups of patients.

Domain organisation. The ESS and SH2 domains are required for JAK phosphotyrosine binding. Further interaction with the KIR domain is necessary for signal and kinase inhibition. The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (3): NP_001365861, NP_001365862, NP_003946* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001496	SOCS_box	Domain
IPR028414	SOCS3_SOCS_box	Domain
IPR035863	SOCS3_SH2	Domain
IPR036036	SOCS_box-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00017

UniProt features (25 total): mutagenesis site 15, region of interest 3, domain 2, compositionally biased region 2, chain 1, sequence conflict 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14543-F1	72.50	0.11

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (15):

Position	Phenotype
22	complete loss of epo-induced stat5 signaling suppression. no suppression of jak2 phosphorylation.
25	complete loss of epo-induced stat5 signaling suppression. abolishes binding to jh1.
30	partial loss of epo-induced stat5 signaling suppression. no effect on lif-induced signaling suppression. abolishes bindi
31	complete loss of epo-induced stat5 signaling suppression. no effect on lif-induced stat3 signaling. abolishes binding to
31	little effect on epo-induced signaling suppression.
34	complete loss of epo/lif-induced signaling suppression.
41	complete loss of epo/lif-induced signaling inhibition. abolishes binding to jh1.
45	little effect on epo/lif signaling.
53	no effect on binding to y429/y431 phosphorylated epor.
58	impaired binding to y429/y431 phosphorylated epor.
71	complete loss of epo/lif-induced signaling suppression. no inhibition of jak2 phosphorylation.
71	no effect on epo/lif-induced signaling suppression. partial suppression of jak2 phosphorylation. no effect on binding to
93	impaired binding to y429/y431 phosphorylated epor.
94	greatly impaired binding to y429/y431 phosphorylated epor.
22	little effect on epo-induced stat5 signaling suppression.

Function

Pathways and Gene Ontology

Reactome pathways

31 pathways

ID	Pathway
R-HSA-1059683	Interleukin-6 signaling
R-HSA-2586552	Signaling by Leptin
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-877300	Interferon gamma signaling
R-HSA-877312	Regulation of IFNG signaling
R-HSA-8849474	PTK6 Activates STAT3
R-HSA-8939242	RUNX1 regulates transcription of genes involved in differentiation of keratinocytes
R-HSA-8951664	Neddylation
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-912694	Regulation of IFNA/IFNB signaling
R-HSA-9674555	Signaling by CSF3 (G-CSF)
R-HSA-9705462	Inactivation of CSF3 (G-CSF) signaling
R-HSA-982772	Growth hormone receptor signaling
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-8854691	Interleukin-20 family signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-168256	Immune System
R-HSA-212436	Generic Transcription Pathway
R-HSA-392499	Metabolism of proteins
R-HSA-449147	Signaling by Interleukins
R-HSA-597592	Post-translational protein modification
R-HSA-6783589	Interleukin-6 family signaling
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8848021	Signaling by PTK6
R-HSA-8878171	Transcriptional regulation by RUNX1
R-HSA-9006927	Signaling by Non-Receptor Tyrosine Kinases
R-HSA-913531	Interferon Signaling

MSigDB gene sets: 604 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, REACTOME_INTERLEUKIN_6_SIGNALING, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, MCLACHLAN_DENTAL_CARIES_UP, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION

GO Biological Process (18): protein ubiquitination (GO:0016567), cytokine-mediated signaling pathway (GO:0019221), intracellular signal transduction (GO:0035556), negative regulation of apoptotic process (GO:0043066), positive regulation of cell differentiation (GO:0045597), negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426), negative regulation of insulin receptor signaling pathway (GO:0046627), negative regulation of inflammatory response (GO:0050728), branching involved in labyrinthine layer morphogenesis (GO:0060670), placenta blood vessel development (GO:0060674), T-helper 17 cell lineage commitment (GO:0072540), cellular response to interleukin-17 (GO:0097398), cellular response to leukemia inhibitory factor (GO:1990830), signal transduction (GO:0007165), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), negative regulation of signal transduction (GO:0009968), cell differentiation (GO:0030154), interleukin-6-mediated signaling pathway (GO:0070102)

GO Molecular Function (6): phosphotyrosine residue binding (GO:0001784), protein kinase inhibitor activity (GO:0004860), cytokine receptor binding (GO:0005126), miRNA binding (GO:0035198), protein binding (GO:0005515), protein tyrosine kinase inhibitor activity (GO:0030292)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasmic side of plasma membrane (GO:0009898)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Signaling by Interleukins	2
Interferon Signaling	2
Cytokine Signaling in Immune system	2
Immune System	2
Interleukin-6 family signaling	1
Signal Transduction	1
Interferon gamma signaling	1
Signaling by PTK6	1
Transcriptional regulation by RUNX1	1
Post-translational protein modification	1
Interferon alpha/beta signaling	1
Signaling by CSF3 (G-CSF)	1
Class I MHC mediated antigen processing & presentation	1
RNA Polymerase II Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to cytokine stimulus	3
signal transduction	2
protein modification by small protein conjugation	1
cell surface receptor signaling pathway	1
intracellular anatomical structure	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cell differentiation	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via JAK-STAT	1
negative regulation of receptor signaling pathway via STAT	1
insulin receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
embryonic morphogenesis	1
labyrinthine layer morphogenesis	1
morphogenesis of a branching epithelium	1
blood vessel development	1
placenta development	1
T-helper cell lineage commitment	1
T-helper 17 cell differentiation	1
response to interleukin-17	1
response to leukemia inhibitory factor	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway via STAT	1
regulation of signal transduction	1
negative regulation of cell communication	1

Protein interactions and networks

STRING

3570 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOCS3	JAK2	O60674	996
SOCS3	JAK1	P23458	994
SOCS3	TYK2	P29597	992
SOCS3	STAT3	P40763	961
SOCS3	IL6ST	P40189	960
SOCS3	ELOB	Q15370	914
SOCS3	LEPR	P48357	897
SOCS3	IL6	P05231	874
SOCS3	IL6R	P08887	869
SOCS3	STAT1	P42224	865
SOCS3	IL10	P22301	836
SOCS3	LEP	P41159	825
SOCS3	IRS1	P35568	815
SOCS3	EPOR	P19235	812
SOCS3	IRS2	Q9Y4H2	784

IntAct

75 interactions, top by confidence:

A	B	Type	Score
YES1	SOCS3	psi-mi:“MI:0915”(physical association)	0.720
SOCS3	KIAA1958	psi-mi:“MI:0915”(physical association)	0.720
SOCS3	YES1	psi-mi:“MI:0915”(physical association)	0.720
PTK2	SOCS3	psi-mi:“MI:0915”(physical association)	0.560
SOCS3	PTK2	psi-mi:“MI:0915”(physical association)	0.560
TXK	SOCS3	psi-mi:“MI:0915”(physical association)	0.560
SOCS3	BLK	psi-mi:“MI:0915”(physical association)	0.560
SOCS3	TXK	psi-mi:“MI:0915”(physical association)	0.560
SOCS3	EGFR	psi-mi:“MI:0915”(physical association)	0.550
MAP1S	SOCS3	psi-mi:“MI:0915”(physical association)	0.540
SOCS3	MAP1S	psi-mi:“MI:0915”(physical association)	0.540
MAP1S	SOCS3	psi-mi:“MI:0403”(colocalization)	0.540
SOCS3	RGP1	psi-mi:“MI:0914”(association)	0.530
SOCS3	ELOC	psi-mi:“MI:0914”(association)	0.530
SOCS3	SH2D2A	psi-mi:“MI:0915”(physical association)	0.490
SOCS3	TRDN	psi-mi:“MI:0915”(physical association)	0.490
TRDN	SOCS3	psi-mi:“MI:0915”(physical association)	0.490
SH2D2A	SOCS3	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (200): SOCS3 (Two-hybrid), SOCS3 (Two-hybrid), KIAA1958 (Two-hybrid), SOCS3 (Affinity Capture-Western), PTK6 (Affinity Capture-Western), SOCS3 (Two-hybrid), SOCS3 (Two-hybrid), TBK1 (Reconstituted Complex), SOCS3 (Reconstituted Complex), SOCS3 (Affinity Capture-Western), SH2D2A (Two-hybrid), TRDN (Two-hybrid), YWHAQ (Two-hybrid), SOCS3 (PCA), SOCS3 (Affinity Capture-Luminescence)

ESM2 similar proteins: B2RZ59, O12990, O14543, O14796, O35324, O35718, O60880, O88583, O88890, O88900, P05433, P08487, P0CE43, P10686, P19174, P43403, P43404, P43405, P46108, P46109, P47941, P81718, P87378, P97504, Q00655, Q04929, Q06AA1, Q09178, Q14449, Q22070, Q2I6J0, Q3ZBB1, Q45HK4, Q5ICW4, Q5U2U2, Q60760, Q62077, Q62120, Q62689, Q63768

Diamond homologs: O00459, O08908, O14508, O14512, O14543, O14544, O15524, O35716, O35717, O35718, O46404, O54928, O55033, O70512, O75159, O88582, O88583, P23726, P23727, P26450, P27986, Q0VC91, Q29RN6, Q2HJ53, Q54RB7, Q5R685, Q5RCM6, Q5RDX2, Q62225, Q63787, Q63788, Q63789, Q64143, Q68AM8, Q7YRV6, Q861R0, Q8UUU2, Q8VHQ2, Q8WXH5, Q90X67

SIGNOR signaling

18 interactions.

A	Effect	B	Mechanism
SOCS3	down-regulates	IRS1	binding
SOCS3	“down-regulates activity”	IL6ST	binding
SOCS3	“down-regulates activity”	JAK3	binding
STAT1	“up-regulates quantity by expression”	SOCS3	“transcriptional regulation”
NfKb-p65/p50	“up-regulates quantity by expression”	SOCS3	“transcriptional regulation”
SOCS3	down-regulates	STAT3
STAT3	“up-regulates quantity by expression”	SOCS3	“transcriptional regulation”
SOCS3	“down-regulates activity”	JAK1	binding
SOCS3	down-regulates	NfKb-p65/p50
SOCS3	“down-regulates activity”	JAK2	binding
SOCS3	“down-regulates activity”	STAT3
MFGE8	“up-regulates quantity by expression”	SOCS3	“transcriptional regulation”
FLT3	“up-regulates quantity by expression”	SOCS3	“transcriptional regulation”
STAT5A	“up-regulates quantity by expression”	SOCS3	“transcriptional regulation”
SOCS3	“down-regulates quantity by destabilization”	SIGLEC7	binding
SOCS3	“up-regulates quantity”	“Elongin E3-Cul-5”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 41 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Constitutive Signaling by Aberrant PI3K in Cancer	5	18.7×	5e-04
MAPK family signaling cascades	5	15.1×	1e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	14.2×	1e-03
PIP3 activates AKT signaling	7	13.8×	2e-04
RAF/MAP kinase cascade	7	12.6×	2e-04
Signaling by Receptor Tyrosine Kinases	7	10.6×	5e-04
Diseases of signal transduction by growth factor receptors and second messengers	5	8.4×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	5	33.5×	1e-04
protein autophosphorylation	5	19.6×	7e-04
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	12.7×	7e-04
positive regulation of cell migration	5	8.3×	9e-03
intracellular signal transduction	8	8.2×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

35 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

141 predictions. Top by Δscore:

Variant	Effect	Δscore
17:78359179:GGGGG:G	acceptor_gain	0.9900
17:78359180:GGGG:G	acceptor_gain	0.9900
17:78359181:GGG:G	acceptor_gain	0.9900
17:78359181:GGGC:G	acceptor_loss	0.9900
17:78359182:GG:G	acceptor_gain	0.9900
17:78359183:GCTG:G	acceptor_loss	0.9900
17:78359184:C:CC	acceptor_gain	0.9900
17:78359184:CT:C	acceptor_loss	0.9900
17:78359744:TCCTA:T	donor_loss	0.9900
17:78359745:CCTA:C	donor_loss	0.9900
17:78359746:CTACC:C	donor_loss	0.9900
17:78359747:TA:T	donor_loss	0.9900
17:78359748:A:T	donor_loss	0.9900
17:78359749:CCT:C	donor_loss	0.9900
17:78359187:C:CT	acceptor_gain	0.9700
17:78359773:T:TA	donor_gain	0.9700
17:78359748:A:AC	donor_gain	0.9600
17:78359749:C:CC	donor_gain	0.9600
17:78359188:G:T	acceptor_gain	0.9500
17:78359740:T:TA	donor_gain	0.9500
17:78359273:TGGGG:T	donor_gain	0.9100
17:78359301:T:A	donor_gain	0.9000
17:78358435:A:AC	donor_gain	0.8800
17:78358436:C:CC	donor_gain	0.8800
17:78359283:A:AC	donor_gain	0.8500
17:78359284:C:CC	donor_gain	0.8500
17:78359398:A:AC	donor_gain	0.8200
17:78359399:C:CC	donor_gain	0.8200
17:78359186:G:C	acceptor_loss	0.7700
17:78358292:C:A	acceptor_gain	0.7500

AlphaMissense

1459 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:78358445:G:C	F217L	1.000
17:78358445:G:T	F217L	1.000
17:78358446:A:G	F217S	1.000
17:78358447:A:G	F217L	1.000
17:78358506:A:T	V197D	1.000
17:78358515:C:G	R194P	1.000
17:78358517:A:C	C193W	1.000
17:78358563:A:G	L178S	1.000
17:78358728:A:G	L123P	1.000
17:78358745:G:C	F117L	1.000
17:78358745:G:T	F117L	1.000
17:78358747:A:G	F117L	1.000
17:78358790:G:C	F102L	1.000
17:78358790:G:T	F102L	1.000
17:78358791:A:G	F102S	1.000
17:78358792:A:G	F102L	1.000
17:78358812:A:G	I95T	1.000
17:78358812:A:T	I95N	1.000
17:78358816:G:C	R94G	1.000
17:78358816:G:T	R94S	1.000
17:78358818:A:G	L93P	1.000
17:78358820:G:C	N92K	1.000
17:78358820:G:T	N92K	1.000
17:78358823:C:A	K91N	1.000
17:78358823:C:G	K91N	1.000
17:78358845:A:T	V84D	1.000
17:78358847:G:C	S83R	1.000
17:78358847:G:T	S83R	1.000
17:78358849:T:G	S83R	1.000
17:78358851:A:G	L82P	1.000

dbSNP variants (sampled 300 via entrez): RS1000211656 (17:78356749 G>A,T), RS1000464799 (17:78362149 C>T), RS1000470773 (17:78357861 C>G), RS1000542531 (17:78357664 G>A), RS1000668995 (17:78357625 C>T), RS1001062401 (17:78362617 T>C), RS1001357088 (17:78357213 G>A,T), RS1001678143 (17:78357163 A>C,G), RS1002192866 (17:78357335 G>A), RS1002710202 (17:78362533 T>C), RS1002788028 (17:78356283 G>A), RS1003314845 (17:78356468 G>C), RS1003377748 (17:78359881 C>A,T), RS1003623925 (17:78360774 G>A,T), RS1004047028 (17:78360088 C>A)

Disease associations

OMIM: gene MIM:604176 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002039_1	Blood trace element (Se levels)	5.000000e-06
GCST006014_27	Creatine kinase levels	1.000000e-11
GCST010042_30	Asthma	6.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004534	creatine kinase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4969170	SOCS3		0.00	0

CTD chemical–gene interactions

133 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, increases methylation, affects localization, increases phosphorylation, increases abundance (+4 more)	7
Valproic Acid	affects cotreatment, decreases expression, increases methylation	6
Resveratrol	affects cotreatment, decreases reaction, increases expression, decreases response to substance	5
Arsenic	increases reaction, affects reaction, increases abundance, increases phosphorylation, affects expression (+5 more)	5
Benzo(a)pyrene	decreases reaction, decreases expression, increases methylation, increases secretion, increases abundance (+5 more)	5
Lipopolysaccharides	increases expression, affects cotreatment, decreases reaction	4
Particulate Matter	increases abundance, increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
(+)-JQ1 compound	decreases reaction, increases expression, increases reaction, decreases expression, affects cotreatment	3
Estradiol	decreases expression, increases expression, decreases reaction, affects binding, increases reaction	3
entinostat	decreases expression, affects cotreatment	2
dorsomorphin	affects cotreatment, decreases reaction, increases abundance, increases expression, decreases expression	2
Fulvestrant	decreases reaction, increases expression, decreases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	decreases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases expression	2
Formaldehyde	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	2
Asbestos, Crocidolite	decreases expression, increases expression	2
Palmitic Acid	affects cotreatment, increases expression, affects expression	2
GSK-J4	increases expression	1
Glupearl 19S	increases expression	1
6-hydroxy-3-O-methylkaempferol 6-O-glucopyranoside	decreases expression, decreases reaction, increases expression, increases reaction	1
TL8-506	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
naringenin	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1

Cellosaurus cell lines

12 cell lines: 10 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7ZJ	Abcam Raji SOCS3 KO	Cancer cell line	Male
CVCL_C0AC	Abcam THP-1 SOCS3 KO	Cancer cell line	Male
CVCL_C7C0	Abcam PC-3 SOCS3 KO	Cancer cell line	Male
CVCL_D8B4	Ubigene A-549 SOCS3 KO	Cancer cell line	Male
CVCL_D8EN	Ubigene BEAS-2B SOCS3 KO	Transformed cell line	Male
CVCL_D8VV	Ubigene HCT 116 SOCS3 KO	Cancer cell line	Male
CVCL_D9SI	Ubigene HEK293 SOCS3 KO	Transformed cell line	Female
CVCL_E0PJ	Ubigene HeLa SOCS3 KO	Cancer cell line	Female
CVCL_RN36	AS-M.5 SOCS3-Luc clone E	Cancer cell line	Male
CVCL_TP97	HAP1 SOCS3 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.