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O14543 (SOCS3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 125. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:SOCS3
Synonyms:CIS3, SSI3
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length225 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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 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. Ref.9

Pathway

Protein modification; protein ubiquitination.

Subunit structure

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, TCEB1 and TCEB2. Interacts with CUL2. Interacts with FGFR3. Interacts with INSR By similarity. Interacts with BCL10; this interaction may interfere with BCL10-binding with PELI2 By similarity. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.11

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.

Domain

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.

Post-translational modification

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

Involvement in disease

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.

Sequence similarities

Contains 1 SH2 domain.

Contains 1 SOCS box domain.

Ontologies

Keywords
   Biological processGrowth regulation
Ubl conjugation pathway
   Coding sequence diversityPolymorphism
   DomainSH2 domain
   Molecular functionSignal transduction inhibitor
   PTMPhosphoprotein
   Technical termComplete proteome
Pharmaceutical
Reference proteome
Gene Ontology (GO)
   Biological_processJAK-STAT cascade

Traceable author statement Ref.1. Source: ProtInc

JAK-STAT cascade involved in growth hormone signaling pathway

Traceable author statement. Source: Reactome

branching involved in labyrinthine layer morphogenesis

Inferred from electronic annotation. Source: Ensembl

cytokine-mediated signaling pathway

Traceable author statement. Source: Reactome

interferon-gamma-mediated signaling pathway

Traceable author statement. Source: Reactome

negative regulation of apoptotic process

Traceable author statement Ref.1. Source: ProtInc

negative regulation of insulin receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein kinase activity

Traceable author statement Ref.1. Source: GOC

placenta blood vessel development

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell differentiation

Inferred from electronic annotation. Source: Ensembl

protein ubiquitination

Inferred from electronic annotation. Source: UniProtKB-UniPathway

regulation of growth

Inferred from electronic annotation. Source: UniProtKB-KW

regulation of interferon-gamma-mediated signaling pathway

Traceable author statement. Source: Reactome

regulation of type I interferon-mediated signaling pathway

Traceable author statement. Source: Reactome

spongiotrophoblast differentiation

Inferred from electronic annotation. Source: Ensembl

trophoblast giant cell differentiation

Inferred from electronic annotation. Source: Ensembl

type I interferon signaling pathway

Traceable author statement. Source: Reactome

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

   Molecular_functionprotein kinase inhibitor activity

Traceable author statement Ref.1. Source: ProtInc

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

MAP1SQ66K746EBI-714146,EBI-2133734

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 225225Suppressor of cytokine signaling 3
PRO_0000181243

Regions

Domain46 – 14297SH2
Domain177 – 22448SOCS box
Region22 – 3312Kinase inhibitory region (KIR)
Region34 – 4512Extended SH2 subdomain (ESS)

Natural variations

Natural variant1251H → Y. Ref.1
Corresponds to variant rs1061489 [ dbSNP | Ensembl ].
VAR_030033

Experimental info

Mutagenesis221L → A or F: Little effect on EPO-induced STAT5 signaling suppression. Ref.5
Mutagenesis221L → D: Complete loss of EPO-induced STAT5 signaling suppression. No suppression of JAK2 phosphorylation. Ref.5
Mutagenesis251F → A: Complete loss of EPO-induced STAT5 signaling suppression. Abolishes binding to JH1. Ref.5
Mutagenesis301E → R: Partial loss of EPO-induced STAT5 signaling suppression. No effect on LIF-induced signaling suppression. Abolishes binding to JH1. Inhibits JAK2 phosphorylation. Ref.5
Mutagenesis311Y → A: Complete loss of EPO-induced STAT5 signaling suppression. No effect on LIF-induced STAT3 signaling. Abolishes binding to JH1. Ref.5
Mutagenesis311Y → F: Little effect on EPO-induced signaling suppression. Ref.5
Mutagenesis341V → E: Complete loss of EPO/LIF-induced signaling suppression. Ref.5
Mutagenesis411L → R: Complete loss of EPO/LIF-induced signaling inhibition. Abolishes binding to JH1. Ref.5
Mutagenesis451G → A: Little effect on EPO/LIF signaling. Ref.5
Mutagenesis531G → V: No effect on binding to Y429/Y431 phosphorylated EPOR. Ref.6
Mutagenesis581L → A: Impaired binding to Y429/Y431 phosphorylated EPOR. Ref.6
Mutagenesis711R → E: Complete loss of EPO/LIF-induced signaling suppression. No inhibition of JAK2 phosphorylation. Ref.5 Ref.7
Mutagenesis711R → 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. Ref.5 Ref.7
Mutagenesis931L → A: Impaired binding to Y429/Y431 phosphorylated EPOR. Ref.6
Mutagenesis941R → E: Greatly impaired binding to Y429/Y431 phosphorylated EPOR. Ref.6
Sequence conflict811T → A in BAA22430. Ref.1

Sequences

Sequence LengthMass (Da)Tools
O14543 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: 08581DC411EFFF19

FASTA22524,770
        10         20         30         40         50         60 
MVTHSKFPAA GMSRPLDTSL RLKTFSSKSE YQLVVNAVRK LQESGFYWSA VTGGEANLLL 

        70         80         90        100        110        120 
SAEPAGTFLI RDSSDQRHFF TLSVKTQSGT KNLRIQCEGG SFSLQSDPRS TQPVPRFDCV 

       130        140        150        160        170        180 
LKLVHHYMPP PGAPSFPSPP TEPSSEVPEQ PSAQPLPGSP PRRAYYIYSG GEKIPLVLSR 

       190        200        210        220 
PLSSNVATLQ HLCRKTVNGH LDSYEKVTQL PGPIREFLDQ YDAPL 

« Hide

References

« Hide 'large scale' references
[1]"Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3."
Minamoto S., Ikegame K., Ueno K., Narazaki M., Naka T., Yamamoto H., Matsumoto T., Saito H., Hosoe S., Kishimoto T.
Biochem. Biophys. Res. Commun. 237:79-83(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT TYR-125.
Tissue: T-cell lymphoma.
[2]"Cloning and characterization of novel CIS family genes."
Masuhara M., Sakamoto H., Matsumoto A., Suzuki R., Yasukawa H., Mitsui K., Wakioka T., Tanimura S., Sasaki A., Misawa H., Yokouchi M., Ohtsubo M., Yoshimura A.
Biochem. Biophys. Res. Commun. 239:439-446(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor."
Dey B.R., Furlanetto R.W., Nissley P.
Biochem. Biophys. Res. Commun. 278:38-43(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Skeletal muscle.
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Placenta.
[5]"Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain."
Sasaki A., Yasukawa H., Suzuki A., Kamizono S., Syoda T., Kinjyo I., Sasaki M., Johnston J.A., Yoshimura A.
Genes Cells 4:339-351(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH JAK2, MUTAGENESIS OF LEU-22; PHE-25; GLU-30; TYR-31; VAL-34; LEU-41; GLY-45 AND ARG-71.
[6]"A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor."
Hoertner M., Nielsch U., Mayr L.M., Heinrich P.C., Haan S.
Eur. J. Biochem. 269:2516-2526(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH EPOR, MUTAGENESIS OF GLY-53; LEU-58; LEU-93 AND ARG-94.
[7]"SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 domain to the STAT4 docking site in the IL-12 receptor beta2 subunit."
Yamamoto K., Yamaguchi M., Miyasaka N., Miura O.
Biochem. Biophys. Res. Commun. 310:1188-1193(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH IL12RB2, MUTAGENESIS OF ARG-71.
[8]"Involvement of casein kinase Iepsilon in cytokine-induced granulocytic differentiation."
Okamura A., Iwata N., Nagata A., Tamekane A., Shimoyama M., Gomyo H., Yakushijin K., Urahama N., Hamaguchi M., Fukui C., Chihara K., Ito M., Matsui T.
Blood 103:2997-3004(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CSNK1E, PROTEIN STABILIZATION.
[9]"VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases."
Kamura T., Maenaka K., Kotoshiba S., Matsumoto M., Kohda D., Conaway R.C., Conaway J.W., Nakayama K.I.
Genes Dev. 18:3055-3065(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN AN E3 UBIQUITIN-PROTEIN LIGASE COMPLEX, INTERACTION WITH CUL5; RNF7; TCEB1 AND TCEB2.
[10]"Elevated expression and genetic association links the SOCS3 gene to atopic dermatitis."
Ekelund E., Saeaef A., Tengvall-Linder M., Melen E., Link J., Barker J., Reynolds N.J., Meggitt S.J., Kere J., Wahlgren C.-F., Pershagen G., Wickman M., Nordenskjoeld M., Kockum I., Bradley M.
Am. J. Hum. Genet. 78:1060-1065(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: POSSIBLE INVOLVEMENT IN ATOPIC DERMATITIS.
[11]"Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling."
Ben-Zvi T., Yayon A., Gertler A., Monsonego-Ornan E.
J. Cell Sci. 119:380-387(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH FGFR3.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB004904 mRNA. Translation: BAA22430.1.
AB006967 mRNA. Translation: BAA22537.1.
AF159854 mRNA. Translation: AAD42231.1.
BC060858 mRNA. Translation: AAH60858.1.
PIRJC5627.
JC5761.
RefSeqNP_003946.3. NM_003955.4.
UniGeneHs.527973.
Hs.703620.

3D structure databases

ProteinModelPortalO14543.
SMRO14543. Positions 30-185.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114488. 68 interactions.
IntActO14543. 23 interactions.
MINTMINT-149732.
STRING9606.ENSP00000330341.

PTM databases

PhosphoSiteO14543.

Proteomic databases

PaxDbO14543.
PRIDEO14543.

Protocols and materials databases

DNASU9021.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000330871; ENSP00000330341; ENSG00000184557.
GeneID9021.
KEGGhsa:9021.
UCSCuc002jvl.2. human.

Organism-specific databases

CTD9021.
GeneCardsGC17M076352.
HGNCHGNC:19391. SOCS3.
HPACAB012220.
MIM604176. gene.
neXtProtNX_O14543.
PharmGKBPA134885765.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG281730.
HOGENOMHOG000236320.
HOVERGENHBG105645.
InParanoidO14543.
KOK04696.
OMAKRTYYIY.
PhylomeDBO14543.
TreeFamTF321368.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_6900. Immune System.
SignaLinkO14543.
UniPathwayUPA00143.

Gene expression databases

ArrayExpressO14543.
BgeeO14543.
CleanExHS_SOCS3.
GenevestigatorO14543.

Family and domain databases

Gene3D3.30.505.10. 2 hits.
InterProIPR000980. SH2.
IPR028413. SOCS.
IPR028414. SOCS3.
IPR001496. SOCS_C.
[Graphical view]
PANTHERPTHR10385. PTHR10385. 1 hit.
PTHR10385:SF4. PTHR10385:SF4. 1 hit.
PfamPF00017. SH2. 1 hit.
PF07525. SOCS_box. 1 hit.
[Graphical view]
SMARTSM00252. SH2. 1 hit.
SM00253. SOCS. 1 hit.
SM00969. SOCS_box. 1 hit.
[Graphical view]
SUPFAMSSF55550. SSF55550. 1 hit.
PROSITEPS50001. SH2. 1 hit.
PS50225. SOCS. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiSOCS3.
GenomeRNAi9021.
NextBio33797.
PROO14543.
SOURCESearch...

Entry information

Entry nameSOCS3_HUMAN
AccessionPrimary (citable) accession number: O14543
Secondary accession number(s): O14509
Entry history
Integrated into UniProtKB/Swiss-Prot: April 16, 2002
Last sequence update: January 1, 1998
Last modified: April 16, 2014
This is version 125 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 17

Human chromosome 17: entries, gene names and cross-references to MIM