SOCS2

Summary

SOCS2 (suppressor of cytokine signaling 2, HGNC:19382) is a protein-coding gene on chromosome 12q22, encoding Suppressor of cytokine signaling 2 (O14508). Substrate-recognition component of a cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex, also named CRL5 complex), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as EPOR and GHR.

This gene encodes a member of the suppressor of cytokine signaling (SOCS) family. SOCS family members are cytokine-inducible negative regulators of cytokine receptor signaling via the Janus kinase/signal transducer and activation of transcription pathway (the JAK/STAT pathway). SOCS family proteins interact with major molecules of signaling complexes to block further signal transduction, in part, by proteasomal depletion of receptors or signal-transducing proteins via ubiquitination. The expression of this gene can be induced by a subset of cytokines, including erythropoietin, GM-CSF, IL10, interferon (IFN)-gamma and by cytokine receptors such as growth horomone receptor. The protein encoded by this gene interacts with the cytoplasmic domain of insulin-like growth factor-1 receptor (IGF1R) and is thought to be involved in the regulation of IGF1R mediated cell signaling. This gene has pseudogenes on chromosomes 20 and 22. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8835 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 26 total
• MANE Select transcript: NM_001270471

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19382
Approved symbol	SOCS2
Name	suppressor of cytokine signaling 2
Location	12q22
Locus type	gene with protein product
Status	Approved
Aliases	STATI2, SSI2, SOCS-2, SSI-2, CIS2, Cish2
Ensembl gene	ENSG00000120833
Ensembl biotype	protein_coding
OMIM	605117
Entrez	8835

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 24 protein_coding

ENST00000340600, ENST00000536696, ENST00000547229, ENST00000548091, ENST00000548537, ENST00000549122, ENST00000549206, ENST00000549510, ENST00000549887, ENST00000551556, ENST00000551883, ENST00000622746, ENST00000862890, ENST00000862891, ENST00000862892, ENST00000862893, ENST00000862894, ENST00000922434, ENST00000922435, ENST00000922436, ENST00000922437, ENST00000922438, ENST00000922439, ENST00000968843

RefSeq mRNA: 6 — MANE Select: NM_001270471 NM_001270467, NM_001270468, NM_001270469, NM_001270470, NM_001270471, NM_003877

CCDS: CCDS9047

Canonical transcript exons

ENST00000551556 — 2 exons

Exon	Start	End
ENSE00002366179	93572675	93573036
ENSE00002384980	93574722	93576745

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 98.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.3143 / max 419.4087, expressed in 1610 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127360	9.0302	1506
127362	3.1292	895
127367	2.0776	446
127361	1.9293	753
127363	1.3890	325
127359	1.0804	571
127368	0.5783	106
127355	0.4860	141
127358	0.4701	233
127357	0.1930	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.54	gold quality
oocyte	CL:0000023	98.12	gold quality
endocervix	UBERON:0000458	96.77	gold quality
vena cava	UBERON:0004087	96.72	gold quality
body of uterus	UBERON:0009853	96.33	gold quality
myometrium	UBERON:0001296	96.17	gold quality
seminal vesicle	UBERON:0000998	95.94	gold quality
choroid plexus epithelium	UBERON:0003911	95.31	gold quality
ectocervix	UBERON:0012249	95.06	gold quality
omental fat pad	UBERON:0010414	95.04	gold quality
peritoneum	UBERON:0002358	95.00	gold quality
prostate gland	UBERON:0002367	94.92	gold quality
pituitary gland	UBERON:0000007	94.83	gold quality
left uterine tube	UBERON:0001303	94.75	gold quality
adenohypophysis	UBERON:0002196	94.73	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.66	gold quality
mucosa of urinary bladder	UBERON:0001259	94.38	gold quality
cauda epididymis	UBERON:0004360	94.05	gold quality
uterus	UBERON:0000995	94.00	gold quality
upper lobe of left lung	UBERON:0008952	93.42	gold quality
lower lobe of lung	UBERON:0008949	93.34	gold quality
upper lobe of lung	UBERON:0008948	93.25	gold quality
cartilage tissue	UBERON:0002418	93.00	gold quality
decidua	UBERON:0002450	92.69	gold quality
endometrium	UBERON:0001295	92.62	gold quality
periodontal ligament	UBERON:0008266	92.48	gold quality
corpus epididymis	UBERON:0004359	92.15	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.93	gold quality
uterine cervix	UBERON:0000002	91.73	gold quality
vagina	UBERON:0000996	91.63	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	404.19
E-HCAD-4	yes	63.50
E-HCAD-6	yes	41.40
E-MTAB-9067	yes	10.80
E-CURD-122	yes	5.95
E-MTAB-5061	yes	5.68
E-GEOD-81547	no	9.85
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCL6, E2F1, FLT3, IRF1, IRF3, STAT1, STAT3, STAT5A, STAT5B

miRNA regulators (miRDB)

98 targeting SOCS2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-1299	99.77	71.24	2389

Literature-anchored findings (GeneRIF, showing 40)

• SOCS-2 is overexpressed in advanced stages of chronic myeloid leukemia. It may be a component of a negative feedback mechanism that is functioning inadequately, induced by Bcr-Abl but unable to reverse its growth-promoting effects. (PMID:11861294)
• SOCS2 mediates the suppression of JAK2 phosphorylation by estrogen, which inhibits growth hormone signaling (PMID:12552091)
• SOCS1 and SOCS2 but not SOCS3 suppressed the growth of ovarian and breast cancer cells. (PMID:15361843)
• Association of single-nucleotide polymorphisms in the SOCS2 gene with type 2 diabetes in the Japanese was studied. (PMID:16406727)
• Results describe the 1.9-A crystal structure of the ternary complex of SOCS2 with elongin C and elongin B. (PMID:16675548)
• SOCS2 only interacts with the Y1077 motif, but with higher binding affinity and can interfere with CIS and STAT5a prey recruitment at this site. (PMID:16684815)
• SOCS2 expression is regulated by STAT5. (PMID:17008382)
• Using RT-PCR, we demonstrated for the first time that neutrophils express mRNA for SOCS-2. (PMID:17264307)
• A defect in expression of SOCS-2 and SOCS-3 genes may be crucial for the IGF-I hypersensitivity and progressive increase in erythroid cell population size characteristic of Polycythemia vera. (PMID:17325857)
• Favorable prognostic value of high SOCS2 expression in primary mammary carcinomas. (PMID:17651480)
• analysis of STAT5, CIS, and SOCS2 interactions with the growth hormone receptor (PMID:17666591)
• SOCS2 epigenetic downregulation might be an important second step in the genesis of cytokine-independent myeloproliferative disorder clones (PMID:18769447)
• difference in SOCS1, SOCS2 and SOCS3 transcript levels between normal individuals and SLE patients is not statistically significant (PMID:18820827)
• Acromegalic patients with active disease and hyperplastic polyps had higher levels of SOCS2 transcripts. (PMID:18844680)
• role of SOCS-2 in mediating HIV-1-induced immune evasion and dysregulation of IFNgamma signaling in primary human monocytes (PMID:19279332)
• SOCS2 is required for appropriate TLR4 signaling in maturating human DCs via both the MyD88-dependent and -independent signaling pathway (PMID:19779605)
• Probiotic administration increased expression of SOCS-2 and SOCS-3 in Helicobacter pylori infection to limit inflammatory signaling. (PMID:20136974)
• Data show that knockdown of SOCS2 resulted in the accumulation of p-Pyk2(Tyr402) and blocked NK cell effector functions. (PMID:20543098)
• We propose a model in which SOCS2 acts as a negative regulator of TLR-induced dendritic cell activation (PMID:21844389)
• LPS regulates SOCS2 transcription in a type I interferon dependent autocrine-paracrine loop. (PMID:22291912)
• Data demonstrated that suppressor of cytokine signaling 2 (SOCS2) protein level was distinctively increased by saponin, which in turn resulted in inhibition of HCV replication. (PMID:22745742)
• High SOCS2 is associated with idiopathic short stature. (PMID:22768656)
• Simultaneous stimulation of monocyte-derived DCs resulted in highly increased production of IL-1beta, IL-23 and SOCS2. (PMID:22795647)
• SOCS2 and SOCS6 expression are remarkably reduced in hepatocellular carcinoma and correlate with aggressive tumor progression and poor prognosis (PMID:23475171)
• SOCS2 associates with activated FLT3 through phosphotyrosine residues 589 and 919, and co-localizes with FLT3 in the cell membrane. (PMID:23548639)
• Estradiol can amplify GH intracellular signaling in human osteoblasts with an essential role played by the reduction of the SOCS2 mediated feedback loop. (PMID:23567159)
• crystal structure shows interaction between SOCS2-elongin BC and Cullin-5 (PMID:23897481)
• SOCS2 mediates the cross talk between androgen and growth hormone signaling in prostate cancer. (PMID:24031028)
• methylation of SOCS1, SOCS2, SOCS3 and CISH is infrequent in Ph-ve MPN. (PMID:24131863)
• SOCS2 correlates with malignancy and exerts growth-promoting effects in prostate cancer. (PMID:24280133)
• our study indicates that high SOCS2 expression is associated with poor survival in pediatric AML. (PMID:24559289)
• The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with Turner syndrome and growth hormone deficiency after long-term therapy. (PMID:24905066)
• Stage-independent downregulation of SOCS2 and SOCS6 correlate with disease-free survival in colorectal cancer. (PMID:25025962)
• This study shows that over-expression of SOCS2 reduces the psychostimulant effects of amphetamine, enhances PPI, and alters mesolimbic dopaminergic activity. (PMID:25283341)
• This study showed that there was significantly increased levels of SOCS-2 mRNA in elderly and Alzheimer’s disease brains. (PMID:25286386)
• miR-101 functions as a growth-suppressive miRNA in H. pylori related GC, and that its suppressive effects are mediated mainly by repressing SOCS2 expression. (PMID:25561270)
• crystals of SOCS2 in complex with its adaptor proteins, Elongin C and Elongin B, underwent a change in crystallographic parameters when treated with dimethyl sulfoxide during soaking experiments. (PMID:26121586)
• focus on SOCS2 and review its biological function as well as its implication in pathological processes (PMID:26709655)
• SOCS2 may improve outcome of TBI in mice by regulating aspects of the neuroinflammatory response (PMID:27071013)
• The induction of a tolerogenic phenotype in DCs by NPs was mediated by the AhR-dependent induction of Socs2, which resulted in inhibition of nuclear factor kappaB activation and proinflammatory cytokine production (properties of tolerogenic DCs). (PMID:27330188)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	socs2	ENSDARG00000045557
mus_musculus	Socs2	ENSMUSG00000020027
rattus_norvegicus	Socs2	ENSRNOG00000008965
drosophila_melanogaster	Socs44A	FBGN0033266
drosophila_melanogaster	Socs36E	FBGN0041184

Paralogs (7): CISH (ENSG00000114737), SOCS6 (ENSG00000170677), SOCS5 (ENSG00000171150), SOCS4 (ENSG00000180008), SOCS3 (ENSG00000184557), SOCS1 (ENSG00000185338), SOCS7 (ENSG00000274211)

Protein

Protein identifiers

Suppressor of cytokine signaling 2 — O14508 (reviewed: O14508)

Alternative names: Cytokine-inducible SH2 protein 2, STAT-induced STAT inhibitor 2

All UniProt accessions (6): O14508, F8VRV3, F8VS53, F8VU91, S4R3W1, S4R3Z4

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of a cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex, also named CRL5 complex), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as EPOR and GHR. Specifically recognizes and binds phosphorylated proteins via its SH2 domain, promoting their ubiquitination. The ECS(SOCS2) complex acts as a key regulator of growth hormone receptor (GHR) levels by mediating ubiquitination and degradation of GHR, following GHR phosphorylation by JAK2. The ECS(SOCS2) also catalyzes ubiquitination and degradation of JAK2-phosphorylated EPOR.

Subunit / interactions. Substrate-recognition component of the ECS(SOCS2) complex, composed of SOCS2, CUL5, ELOB, ELOC and RNF7/RBX2. Interacts with IGF1R. Interacts with DCUN1D1.

Subcellular location. Cytoplasm.

Tissue specificity. High expression in heart, placenta, lung, kidney and prostate. Predominantly expressed in pulmonary epithelia cells, specifically type II pneumocytes.

Post-translational modifications. Ubiquitinated; mediated by AREL1 and leading to its subsequent proteasomal degradation. Ubiquitination is dependent on its phosphorylation at Ser-52, by PKC. Ubiquitination is stimulated by LPS. Phosphorylation at Ser-52 by PKC facilitates its ubiquitination and proteasomal degradation.

Activity regulation. Substrate-binding is prevented by the covalent inhibitor MN551 that cross-links with Cys-111. Also inhibited by a MN551 derivative, MN714, which contains a pivaloyloxymethyl that allows cell permeability.

Domain organisation. The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes.

Induction. By a subset of cytokines, including EPO/erythropoietin and CSF2/GM-CSF.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (6): NP_001257396, NP_001257397, NP_001257398, NP_001257399, NP_001257400, NP_003868 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001496	SOCS_box	Domain
IPR028410	SOCS2_SOCS_box	Domain
IPR035862	SOCS2_SH2	Domain
IPR036036	SOCS_box-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00017, PF07525

UniProt features (39 total): strand 9, helix 7, mutagenesis site 6, sequence variant 5, sequence conflict 3, domain 2, region of interest 2, modified residue 2, chain 1, turn 1, cross-link 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
7ZLM	X-RAY DIFFRACTION	1.79
2C9W	X-RAY DIFFRACTION	1.9
7ZLS	X-RAY DIFFRACTION	1.92
7ZLP	X-RAY DIFFRACTION	1.94
6I5N	X-RAY DIFFRACTION	1.98
7ZLR	X-RAY DIFFRACTION	2.01
7ZLO	X-RAY DIFFRACTION	2.22
7ZLN	X-RAY DIFFRACTION	2.6
6I4X	X-RAY DIFFRACTION	2.69
6I5J	X-RAY DIFFRACTION	2.8
5BO4	X-RAY DIFFRACTION	2.9
4JGH	X-RAY DIFFRACTION	3
7M6T	X-RAY DIFFRACTION	3.19

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14508-F1	83.30	0.68

Functional residue map

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

Post-translational modifications (3): 30, 52, 173

Mutagenesis-validated functional residues (6):

Position	Phenotype
73	impaired ability to mediate ubiquitination of ghr.
87	no effect on protein half-life.
154	no effect on protein half-life.
163	abolished interaction with elob and eloc, preventing formation of the ecs(socs2) complex.
167	abolished interaction with elob and eloc, preventing formation of the ecs(socs2) complex.
173	increased protein half-life.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-1266695	Interleukin-7 signaling
R-HSA-8951664	Neddylation
R-HSA-9706369	Negative regulation of FLT3
R-HSA-982772	Growth hormone receptor signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-449147	Signaling by Interleukins
R-HSA-597592	Post-translational protein modification
R-HSA-9607240	FLT3 Signaling

MSigDB gene sets: 522 (showing top): VALK_AML_WITH_FLT3_ITD, ELVIDGE_HYPOXIA_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, WANG_CLIM2_TARGETS_UP, GOBP_RESPONSE_TO_ESTRADIOL, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, RORA1_01, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP

GO Biological Process (21): regulation of cell growth (GO:0001558), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), lactation (GO:0007595), regulation of signal transduction (GO:0009966), negative regulation of signal transduction (GO:0009968), protein ubiquitination (GO:0016567), cytokine-mediated signaling pathway (GO:0019221), response to estradiol (GO:0032355), cellular response to hormone stimulus (GO:0032870), intracellular signal transduction (GO:0035556), negative regulation of multicellular organism growth (GO:0040015), negative regulation of apoptotic process (GO:0043066), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of neuron differentiation (GO:0045666), negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426), growth hormone receptor signaling pathway (GO:0060396), negative regulation of growth hormone receptor signaling pathway (GO:0060400), mammary gland alveolus development (GO:0060749), erythropoietin-mediated signaling pathway (GO:0038162), regulation of multicellular organism growth (GO:0040014), growth hormone receptor signaling pathway via JAK-STAT (GO:0060397)

GO Molecular Function (7): cytokine receptor binding (GO:0005126), growth hormone receptor binding (GO:0005131), insulin-like growth factor receptor binding (GO:0005159), JAK pathway signal transduction adaptor activity (GO:0008269), phosphorylation-dependent protein binding (GO:0140031), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), Cul5-RING ubiquitin ligase complex (GO:0031466)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Cytokine Signaling in Immune system	3
Signaling by Interleukins	1
Post-translational protein modification	1
FLT3 Signaling	1
Immune System	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	3
intracellular anatomical structure	2
multicellular organism growth	2
regulation of receptor signaling pathway via JAK-STAT	2
signaling receptor binding	2
cellular anatomical structure	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
cell surface receptor signaling pathway via STAT	1
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
regulation of signal transduction	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
protein modification by small protein conjugation	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
response to lipid	1
response to oxygen-containing compound	1
response to hormone	1
cellular response to chemical stimulus	1
cellular response to endogenous stimulus	1
regulation of multicellular organism growth	1
negative regulation of developmental growth	1
negative regulation of multicellular organismal process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
cell surface receptor signaling pathway via JAK-STAT	1

Protein interactions and networks

STRING

1851 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOCS2	GHR	P10912	953
SOCS2	ELOB	Q15370	879
SOCS2	ELOC	Q15369	872
SOCS2	EPOR	P19235	854
SOCS2	JAK2	O60674	746
SOCS2	YTHDF2	Q9Y5A9	716
SOCS2	STAT3	P40763	714
SOCS2	CUL5	Q93034	708
SOCS2	FLT3	P36888	669
SOCS2	RNF7	Q9UBF6	667
SOCS2	STAT5B	P51692	667
SOCS2	IGF1	P01343	660
SOCS2	STAT5A	P42229	644
SOCS2	IRS1	P35568	620
SOCS2	PRLR	P16471	613

IntAct

47 interactions, top by confidence:

A	B	Type	Score
SOCS2	CUL5	psi-mi:“MI:2364”(proximity)	0.880
SOCS2	CUL5	psi-mi:“MI:0915”(physical association)	0.880
CUL5	SOCS2	psi-mi:“MI:0914”(association)	0.880
SOCS2	ELOC	psi-mi:“MI:0915”(physical association)	0.570
ELOC	SOCS2	psi-mi:“MI:0915”(physical association)	0.570
YES1	SOCS2	psi-mi:“MI:0915”(physical association)	0.560
STK16	SOCS2	psi-mi:“MI:0915”(physical association)	0.560
SOCS2	YES1	psi-mi:“MI:0915”(physical association)	0.560
SOCS2	STK16	psi-mi:“MI:0915”(physical association)	0.560
VHL	SOCS2	psi-mi:“MI:0915”(physical association)	0.560
ELOC	SOCS2	psi-mi:“MI:0915”(physical association)	0.540
ELOC	SOCS2	psi-mi:“MI:0407”(direct interaction)	0.540
SOCS2		psi-mi:“MI:0407”(direct interaction)	0.440
	SOCS2	psi-mi:“MI:0407”(direct interaction)	0.440
SOCS2	KIT	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (206): TCEB2 (Co-purification), TCEB1 (Co-purification), SOCS2 (Two-hybrid), GHR (Protein-peptide), SOCS2 (Affinity Capture-Western), STK38 (Affinity Capture-Western), CUL5 (Affinity Capture-MS), GHR (Protein-peptide), EPOR (Protein-peptide), SOCS2 (Affinity Capture-Western), GHR (Affinity Capture-Western), SOCS2 (PCA), BUB1B (Affinity Capture-MS), CACUL1 (Affinity Capture-MS), CALM3 (Affinity Capture-MS)

ESM2 similar proteins: A6QLK6, O14508, O35717, O70277, O75382, O88582, O95057, P09851, P20936, P49138, P50904, P57790, P62993, P62994, P87379, Q05B84, Q07883, Q08012, Q13588, Q14145, Q16644, Q2T9Z7, Q3SYZ2, Q5PR73, Q5R4J7, Q5R6S2, Q5R774, Q5RKN4, Q5ZLD3, Q60631, Q66H84, Q66II3, Q684M4, Q6GPJ9, Q6TDP3, Q6YKA8, Q6ZPT1, Q7YRV6, Q861R0, Q8TC17

Diamond homologs: G5ECJ6, O00459, O08908, O14508, O14544, O35717, O46404, O88582, P00519, P00520, P00521, P10447, P14234, P15498, P23726, P23727, P26450, P27986, P41242, P41243, P42679, P42684, P54100, P62993, P62994, Q08012, Q08DN7, Q45FX5, Q4JIM5, Q54RB7, Q5R4J7, Q5R685, Q5RCM6, Q60631, Q62662, Q63787, Q63788, Q63789, Q64143, Q6P6U0

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
IRF1	“up-regulates quantity by expression”	SOCS2	“transcriptional regulation”
IRF3	“up-regulates quantity by expression”	SOCS2	“transcriptional regulation”
FLT3	“up-regulates quantity by expression”	SOCS2	“transcriptional regulation”
STAT5A	“up-regulates quantity by expression”	SOCS2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 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
Neddylation	5	13.9×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein ubiquitination	5	11.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

842 predictions. Top by Δscore:

Variant	Effect	Δscore
12:93574706:T:TA	acceptor_gain	1.0000
12:93574711:A:AG	acceptor_gain	1.0000
12:93574712:A:G	acceptor_gain	1.0000
12:93571422:G:GT	donor_gain	0.9900
12:93572117:G:GT	donor_gain	0.9900
12:93572828:G:GT	donor_gain	0.9900
12:93574708:A:AG	acceptor_gain	0.9900
12:93574709:A:AG	acceptor_gain	0.9900
12:93574710:C:G	acceptor_gain	0.9900
12:93574713:A:AG	acceptor_gain	0.9900
12:93574714:A:AG	acceptor_gain	0.9900
12:93574715:A:G	acceptor_gain	0.9900
12:93574717:CCCAG:C	acceptor_loss	0.9900
12:93574718:CCAGG:C	acceptor_loss	0.9900
12:93574719:CAGGA:C	acceptor_loss	0.9900
12:93574720:A:AT	acceptor_loss	0.9900
12:93574720:AG:A	acceptor_gain	0.9900
12:93574720:AGGAT:A	acceptor_gain	0.9900
12:93574721:G:A	acceptor_loss	0.9900
12:93574721:GG:G	acceptor_gain	0.9900
12:93574721:GGA:G	acceptor_gain	0.9900
12:93574721:GGATG:G	acceptor_gain	0.9900
12:93571418:TCTGG:T	donor_gain	0.9800
12:93573032:GACAG:G	donor_gain	0.9800
12:93573033:ACAG:A	donor_loss	0.9800
12:93573034:CAG:C	donor_loss	0.9800
12:93573035:AG:A	donor_loss	0.9800
12:93573036:GG:G	donor_loss	0.9800
12:93573037:G:A	donor_loss	0.9800
12:93573038:T:G	donor_loss	0.9800

AlphaMissense

1259 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:93574790:T:C	F70L	1.000
12:93574791:T:C	F70S	1.000
12:93574792:C:A	F70L	1.000
12:93574792:C:G	F70L	1.000
12:93574794:T:C	L71S	1.000
12:93574800:G:C	R73T	1.000
12:93574800:G:T	R73I	1.000
12:93574801:A:C	R73S	1.000
12:93574801:A:T	R73S	1.000
12:93574836:C:T	S85F	1.000
12:93574892:T:C	F104L	1.000
12:93574894:C:A	F104L	1.000
12:93574894:C:G	F104L	1.000
12:93574937:T:C	F119L	1.000
12:93574939:T:A	F119L	1.000
12:93574939:T:G	F119L	1.000
12:93574724:T:A	W48R	0.999
12:93574724:T:C	W48R	0.999
12:93574754:G:C	A58P	0.999
12:93574767:T:C	L62S	0.999
12:93574784:G:A	G68R	0.999
12:93574784:G:C	G68R	0.999
12:93574785:G:A	G68E	0.999
12:93574785:G:T	G68V	0.999
12:93574794:T:G	L71W	0.999
12:93574797:T:A	I72N	0.999
12:93574805:A:C	S75R	0.999
12:93574806:G:T	S75I	0.999
12:93574807:C:A	S75R	0.999
12:93574807:C:G	S75R	0.999

dbSNP variants (sampled 300 via entrez): RS1000046512 (12:93597469 C>T), RS1000063919 (12:93573798 G>A), RS1000098416 (12:93597662 C>G), RS1000181770 (12:93583850 A>T), RS1000229676 (12:93617471 G>C), RS1000251086 (12:93590522 C>T), RS1000340052 (12:93603505 T>G), RS1000354359 (12:93576903 A>G), RS1000365080 (12:93620030 A>T), RS1000401852 (12:93625876 A>G), RS1000417442 (12:93619730 C>T), RS1000434707 (12:93590190 G>A), RS1000435642 (12:93579906 G>A), RS1000462857 (12:93570984 G>A,C), RS1000472328 (12:93593002 T>C)

Disease associations

OMIM: gene MIM:605117 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000174_17	Height	6.000000e-10
GCST000175_22	Height	2.000000e-07
GCST000817_116	Height	1.000000e-34
GCST000817_30	Height	3.000000e-12
GCST001876_8	Pubertal anthropometrics	4.000000e-06
GCST001956_28	Height	7.000000e-11
GCST002632_3	Hepatic lipid content in extreme obesity	4.000000e-07
GCST002647_50	Height	4.000000e-49
GCST002702_125	Height	6.000000e-12
GCST006867_118	Type 2 diabetes	4.000000e-08
GCST008163_315	Height	9.000000e-12
GCST008839_154	Height	1.000000e-52
GCST008839_65	Height	3.000000e-34
GCST008993_1	Joint damage in rheumatoid arthritis	4.000000e-06
GCST012227_539	Hip circumference adjusted for BMI	2.000000e-12
GCST012227_540	Hip circumference adjusted for BMI	3.000000e-08
GCST90020028_1664	Hip circumference adjusted for BMI	3.000000e-23
GCST90020028_1665	Hip circumference adjusted for BMI	2.000000e-10
GCST90020028_1666	Hip circumference adjusted for BMI	3.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0001382	puberty
EFO:0006506	hepatic lipid content measurement
EFO:0005413	joint damage measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, affects cotreatment, increases abundance, increases expression	8
Benzo(a)pyrene	decreases methylation, increases expression, affects methylation	4
Estradiol	affects cotreatment, increases expression, decreases expression	4
Tetrachlorodibenzodioxin	affects expression, increases expression	4
(+)-JQ1 compound	decreases reaction, increases expression, decreases expression	3
Cisplatin	affects response to substance, affects expression, decreases expression	3
Zinc	affects cotreatment, increases expression, affects expression, decreases expression	3
Cyclosporine	decreases expression, increases expression	3
Particulate Matter	decreases expression, decreases reaction, increases abundance, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
entinostat	affects cotreatment, increases expression	2
Resveratrol	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	increases expression, increases abundance	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Calcitriol	decreases expression, increases expression, affects cotreatment	2
Formaldehyde	decreases expression, increases expression	2
Lipopolysaccharides	decreases reaction, increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	affects cotreatment, increases expression, decreases expression	2
Tretinoin	increases expression	2
Valproic Acid	affects expression, decreases expression	2
Aflatoxin B1	increases expression, affects expression	2
Cadmium Chloride	decreases expression, increases expression	2
GSK-J4	decreases expression	1
sotorasib	decreases expression, affects cotreatment	1
TL8-506	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
4-oxoretinoic acid	increases expression	1

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8B3	Ubigene A-549 SOCS2 KO	Cancer cell line	Male
CVCL_D8VU	Ubigene HCT 116 SOCS2 KO	Cancer cell line	Male
CVCL_D9SH	Ubigene HEK293 SOCS2 KO	Transformed cell line	Female
CVCL_E0PI	Ubigene HeLa SOCS2 KO	Cancer cell line	Female
CVCL_XT64	HAP1 SOCS2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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