Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Suppressor of cytokine signaling 3

Gene

SOCS3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 gp130, LIF, erythropoietin, insulin, IL12, GCSF and leptin receptors. Binding to JAK2 inhibits its kinase activity. Suppresses fetal liver erythropoiesis. Regulates onset and maintenance of allergic responses mediated by T-helper type 2 cells. Regulates IL-6 signaling in vivo (By similarity). 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. Seems to recognize IL6ST (By similarity).By similarity1 Publication

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

GO - Molecular functioni

  • phosphotyrosine residue binding Source: Ensembl
  • protein kinase inhibitor activity Source: ProtInc

GO - Biological processi

Keywordsi

Molecular functionSignal transduction inhibitor
Biological processGrowth regulation, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-1059683 Interleukin-6 signaling
R-HSA-2586552 Signaling by Leptin
R-HSA-6785807 Interleukin-4 and 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 signaling
R-HSA-982772 Growth hormone receptor signaling
R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation
SignaLinkiO14543
SIGNORiO14543
UniPathwayiUPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
Suppressor of cytokine signaling 3
Short name:
SOCS-3
Alternative name(s):
Cytokine-inducible SH2 protein 3
Short name:
CIS-3
STAT-induced STAT inhibitor 3
Short name:
SSI-3
Gene namesi
Name:SOCS3
Synonyms:CIS3, SSI3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000184557.4
HGNCiHGNC:19391 SOCS3
MIMi604176 gene
neXtProtiNX_O14543

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Pathology & Biotechi

Involvement in diseasei

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.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi22L → A or F: Little effect on EPO-induced STAT5 signaling suppression. 1 Publication1
Mutagenesisi22L → D: Complete loss of EPO-induced STAT5 signaling suppression. No suppression of JAK2 phosphorylation. 1 Publication1
Mutagenesisi25F → A: Complete loss of EPO-induced STAT5 signaling suppression. Abolishes binding to JH1. 1 Publication1
Mutagenesisi30E → R: Partial loss of EPO-induced STAT5 signaling suppression. No effect on LIF-induced signaling suppression. Abolishes binding to JH1. Inhibits JAK2 phosphorylation. 1 Publication1
Mutagenesisi31Y → A: Complete loss of EPO-induced STAT5 signaling suppression. No effect on LIF-induced STAT3 signaling. Abolishes binding to JH1. 1 Publication1
Mutagenesisi31Y → F: Little effect on EPO-induced signaling suppression. 1 Publication1
Mutagenesisi34V → E: Complete loss of EPO/LIF-induced signaling suppression. 1 Publication1
Mutagenesisi41L → R: Complete loss of EPO/LIF-induced signaling inhibition. Abolishes binding to JH1. 1 Publication1
Mutagenesisi45G → A: Little effect on EPO/LIF signaling. 1 Publication1
Mutagenesisi53G → V: No effect on binding to Y429/Y431 phosphorylated EPOR. 1 Publication1
Mutagenesisi58L → A: Impaired binding to Y429/Y431 phosphorylated EPOR. 1 Publication1
Mutagenesisi71R → E: Complete loss of EPO/LIF-induced signaling suppression. No inhibition of JAK2 phosphorylation. 2 Publications1
Mutagenesisi71R → K: No effect on EPO/LIF-induced signaling suppression. Partial suppression of JAK2 phosphorylation. No effect on binding to JH1. Loss of binding to IL12RB2. 2 Publications1
Mutagenesisi93L → A: Impaired binding to Y429/Y431 phosphorylated EPOR. 1 Publication1
Mutagenesisi94R → E: Greatly impaired binding to Y429/Y431 phosphorylated EPOR. 1 Publication1

Organism-specific databases

DisGeNETi9021
MalaCardsiSOCS3
OpenTargetsiENSG00000184557
PharmGKBiPA134885765

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001812431 – 225Suppressor of cytokine signaling 3Add BLAST225

Post-translational modificationi

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

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiO14543
PaxDbiO14543
PeptideAtlasiO14543
PRIDEiO14543
ProteomicsDBi48078

PTM databases

iPTMnetiO14543
PhosphoSitePlusiO14543

Expressioni

Tissue specificityi

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.

Gene expression databases

BgeeiENSG00000184557
CleanExiHS_SOCS3
ExpressionAtlasiO14543 baseline and differential
GenevisibleiO14543 HS

Organism-specific databases

HPAiCAB012220
HPA068569

Interactioni

Subunit structurei

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 (PubMed:10421843). Binds specific activated tyrosine residues of the leptin, EPO, IL12, GSCF and gp130 receptors (PubMed:12027890, PubMed:14559241). Interaction with CSNK1E stabilizes SOCS3 protein (PubMed:15070676). Component of the probable ECS(SOCS3) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and SOCS3 (PubMed:15601820). Interacts with CUL5, RNF7, ELOB and ELOC (PubMed:15601820). Interacts with CUL2 (PubMed:15601820). Interacts with FGFR3 (PubMed:16410555). Interacts with INSR (By similarity). Interacts with BCL10; this interaction may interfere with BCL10-binding with PELI2 (By similarity). Interacts with NOD2 (via CARD domain); the interaction promotes NOD2 degradation (PubMed:23019338).By similarity7 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi114488, 78 interactors
CORUMiO14543
IntActiO14543, 37 interactors
MINTiO14543
STRINGi9606.ENSP00000330341

Structurei

3D structure databases

ProteinModelPortaliO14543
SMRiO14543
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini46 – 142SH2PROSITE-ProRule annotationAdd BLAST97
Domaini177 – 224SOCS boxPROSITE-ProRule annotationAdd BLAST48

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni22 – 33Kinase inhibitory region (KIR)Add BLAST12
Regioni34 – 45Extended SH2 subdomain (ESS)Add BLAST12

Domaini

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.By similarity

Keywords - Domaini

SH2 domain

Phylogenomic databases

eggNOGiKOG4566 Eukaryota
ENOG4111V4J LUCA
GeneTreeiENSGT00760000119136
HOGENOMiHOG000236320
HOVERGENiHBG105645
InParanoidiO14543
KOiK04696
OMAiKRTYYIY
OrthoDBiEOG091G0NEU
PhylomeDBiO14543
TreeFamiTF321368

Family and domain databases

CDDicd10384 SH2_SOCS3, 1 hit
Gene3Di3.30.505.10, 1 hit
InterProiView protein in InterPro
IPR000980 SH2
IPR036860 SH2_dom_sf
IPR028414 SOCS3
IPR035863 SOCS3_SH2
IPR001496 SOCS_box
IPR036036 SOCS_box-like_dom_sf
PANTHERiPTHR44534 PTHR44534, 1 hit
PfamiView protein in Pfam
PF00017 SH2, 1 hit
PF07525 SOCS_box, 1 hit
SMARTiView protein in SMART
SM00252 SH2, 1 hit
SM00253 SOCS, 1 hit
SM00969 SOCS_box, 1 hit
SUPFAMiSSF158235 SSF158235, 1 hit
SSF55550 SSF55550, 1 hit
PROSITEiView protein in PROSITE
PS50001 SH2, 1 hit
PS50225 SOCS, 1 hit

Sequencei

Sequence statusi: Complete.

O14543-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MVTHSKFPAA GMSRPLDTSL RLKTFSSKSE YQLVVNAVRK LQESGFYWSA
60 70 80 90 100
VTGGEANLLL SAEPAGTFLI RDSSDQRHFF TLSVKTQSGT KNLRIQCEGG
110 120 130 140 150
SFSLQSDPRS TQPVPRFDCV LKLVHHYMPP PGAPSFPSPP TEPSSEVPEQ
160 170 180 190 200
PSAQPLPGSP PRRAYYIYSG GEKIPLVLSR PLSSNVATLQ HLCRKTVNGH
210 220
LDSYEKVTQL PGPIREFLDQ YDAPL
Length:225
Mass (Da):24,770
Last modified:January 1, 1998 - v1
Checksum:i08581DC411EFFF19
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti81T → A in BAA22430 (PubMed:9266833).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_030033125H → Y1 PublicationCorresponds to variant dbSNP:rs1061489Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB004904 mRNA Translation: BAA22430.1
AB006967 mRNA Translation: BAA22537.1
AF159854 mRNA Translation: AAD42231.1
BC060858 mRNA Translation: AAH60858.1
CCDSiCCDS11756.1
PIRiJC5627
JC5761
RefSeqiNP_003946.3, NM_003955.4
UniGeneiHs.527973
Hs.703620

Genome annotation databases

EnsembliENST00000330871; ENSP00000330341; ENSG00000184557
GeneIDi9021
KEGGihsa:9021

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiSOCS3_HUMAN
AccessioniPrimary (citable) accession number: O14543
Secondary accession number(s): O14509
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 16, 2002
Last sequence update: January 1, 1998
Last modified: July 18, 2018
This is version 167 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Pharmaceutical, Reference proteome

Documents

  1. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways

We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.

Do not show this banner again
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health