SOCS3 (suppressor of cytokine signaling 3)

2012-02-01   Zoran Culig 

Experimental Urology, Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria

Identity

HGNC
LOCATION
17q25.3
LOCUSID
ALIAS
ATOD4,CIS3,Cish3,MGC71791,SOCS-3,SSI-3,SSI3
FUSION GENES

DNA/RNA

Description

Size: 3300 bases.

Transcription

2 introns. Transcription generates 3 different mRNAs, 2 spliced variants and 1 unspliced form.

Proteins

Atlas Image
KIR = kinase inhibitory region.

Description

225 amino acids, 24770 Da.

Expression

Widely expressed in normal and tumor tissues. Expression in tumors is variable due to its different functions.

Localisation

Cytoplasm.

Function

SOCS is a negative regulator of cytokines that signal through the JAK/STAT pathway. It binds to tyrosine kinase receptors such as gp130 subunit of receptors. It interacts with cytokine receptors or JAK kinases and interaction with growth factor receptors (insulin-like growth factor-I, insulin, fibroblast growth factor). It inhibits JAK2 kinase activity. Part of the ubiquitin-protein ligase complex which contains elongin, RNF7, and CUL5. Binding to leptin. Tumor promoting or tumor suppressive functions. Antagonizing cAMP-antiproliferative effects. SOCS3 suppresses erythropoietin in fetal liver and IL-6 signaling in vivo.

Mutations

Note

Mutations not detected.

Implicated in

Entity name
Lung cancer
Note
SOCS-3 acts as a tumor suppressor and is frequently lost in the disease. Its transient transfection in lung cancer cell lines leads to a decrease in proliferation.
Entity name
Liver cancer
Note
SOCS-3 is silenced by methylation. SOCS-3 is a tumor suppressor in this malignancy. It is implicated in regulation of migration of cancer cells. SOCS-3 deletion enhances JAK/STAT and FAK signaling.
Entity name
Barrets adenocarcinoma
Note
SOCS-3 is methylated. It is considered as a tumor suppressor.
Entity name
Glioblastoma multiforme
Note
SOCS-3 expression is lost through promoter methylation.
Entity name
Head and neck squamous cell cancer
Note
SOCS-3 is frequently down-regulated as a result of promoter methylation. It causes a growth inhibition.
Entity name
Hematological malignancies
Note
SOCS-3 inhibits megakaryocytic growth, overexpression of SOCS-3 is associated with a decreased survival of patients with follicular lymphoma.
Entity name
Melanoma
Note
SOCS-3 is a tumor promoter in melanoma and is constitutively expressed in several cell lines.
Entity name
Prostate cancer
Note
SOCS-3 stimulates proliferation and inhibits apoptosis in prostate cancer cells which do not express the androgen receptor. It may also antagonize the effects of fibroblasts growth factor and mitogen-activated protein kinases. In androgen-sensitive prostate cancer cells, SOCS-3 is induced by androgen and may inhibit androgen-stimulated proliferation and secretion.
Entity name
Diabetes
Note
SOCS-3 may antagonize function of insulin-like growth factors.
Entity name
Various cancers
Prognosis
Loss of protein expression and promoter hypermethylation occur in lung, liver cancer, head and neck squamous cell cancer. Overexpression occurs in melanoma and prostate cancer.

Bibliography

Pubmed IDLast YearTitleAuthors
171486812006Suppressor of cytokine signaling-3 antagonizes cAMP effects on proliferation and apoptosis and is expressed in human prostate cancer.Bellezza I et al
111595372001STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma.Brender C et al
183187602008Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia-negative chronic myeloproliferative disorders.Capello D et al
146177762003SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer.He B et al
173747322007Constitutive suppressor of cytokine signaling 3 expression confers a growth advantage to a human melanoma cell line.Komyod W et al
187708642008Prognostic relevance of SOCS3 hypermethylation in patients with glioblastoma multiforme.Martini M et al
160071952005Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma.Niwa Y et al
175137372007Type 2 diabetes impairs insulin receptor substrate-2-mediated phosphatidylinositol 3-kinase activity in primary macrophages to induce a state of cytokine resistance to IL-4 in association with overexpression of suppressor of cytokine signaling-3.O'Connor JC et al
197380592009Down-regulation of suppressor of cytokine signaling-3 causes prostate cancer cell death through activation of the extrinsic and intrinsic apoptosis pathways.Puhr M et al
160071692005SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition.Weber A et al

Other Information

Locus ID:

NCBI: 9021
MIM: 604176
HGNC: 19391
Ensembl: ENSG00000184557

Variants:

dbSNP: 9021
ClinVar: 9021
TCGA: ENSG00000184557
COSMIC: SOCS3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000184557ENST00000330871O14543
ENSG00000184557ENST00000330871Q6FI39
ENSG00000184557ENST00000587578K7EIF6

Expression (GTEx)

0
100
200
300
400
500
600

Pathways

PathwaySourceExternal ID
Ubiquitin mediated proteolysisKEGGko04120
Jak-STAT signaling pathwayKEGGko04630
Insulin signaling pathwayKEGGko04910
Adipocytokine signaling pathwayKEGGko04920
Type II diabetes mellitusKEGGko04930
Ubiquitin mediated proteolysisKEGGhsa04120
Jak-STAT signaling pathwayKEGGhsa04630
Insulin signaling pathwayKEGGhsa04910
Adipocytokine signaling pathwayKEGGhsa04920
Type II diabetes mellitusKEGGhsa04930
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
ECS complexKEGGhsa_M00388
ECS complexKEGGM00388
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
JAK-STAT signalingKEGGhsa_M00684
JAK-STAT signalingKEGGM00684
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Class I MHC mediated antigen processing & presentationREACTOMER-HSA-983169
Antigen processing: Ubiquitination & Proteasome degradationREACTOMER-HSA-983168
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Interferon SignalingREACTOMER-HSA-913531
Interferon alpha/beta signalingREACTOMER-HSA-909733
Regulation of IFNA signalingREACTOMER-HSA-912694
Interferon gamma signalingREACTOMER-HSA-877300
Regulation of IFNG signalingREACTOMER-HSA-877312
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-6 signalingREACTOMER-HSA-1059683
Growth hormone receptor signalingREACTOMER-HSA-982772
Signal TransductionREACTOMER-HSA-162582
Signaling by LeptinREACTOMER-HSA-2586552
Insulin resistanceKEGGhsa04931
Interleukin-6 family signalingREACTOMER-HSA-6783589
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Activates STAT3REACTOMER-HSA-8849474
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA36184STAT2GenePathwayassociated26111151

References

Pubmed IDYearTitleCitations
214817882011Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer.313
125603302003Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes.130
146177762003SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer.122
126265852003Activation of STAT3 by IL-6 and IL-10 in primary human macrophages is differentially modulated by suppressor of cytokine signaling 3.116
189894592008Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression.116
197378632009Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis.116
229259252012SOCS3 deficiency promotes M1 macrophage polarization and inflammation.115
160071952005Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma.112
223428412012Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity.102
177034122007Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes.100

Citation

Zoran Culig

SOCS3 (suppressor of cytokine signaling 3)

Atlas Genet Cytogenet Oncol Haematol. 2012-02-01

Online version: http://atlasgeneticsoncology.org/gene/44124/socs3-(suppressor-of-cytokine-signaling-3)