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Protein

Suppressor of cytokine signaling 3

Gene

SOCS3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 similarity

Pathway: 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

  • protein kinase inhibitor activity Source: ProtInc

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Signal transduction inhibitor

Keywords - Biological processi

Growth regulation, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiREACT_111133. Growth hormone receptor signaling.
REACT_169118. Signaling by Leptin.
REACT_24980. Regulation of IFNG signaling.
REACT_25078. Interferon gamma signaling.
REACT_25162. Interferon alpha/beta signaling.
REACT_25216. Regulation of IFNA signaling.
REACT_27307. Interleukin-6 signaling.
REACT_75842. Antigen processing: Ubiquitination & Proteasome degradation.
SignaLinkiO14543.
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
ProteomesiUP000005640 Componenti: Chromosome 17

Organism-specific databases

HGNCiHGNC:19391. SOCS3.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

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.

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi22 – 221L → A or F: Little effect on EPO-induced STAT5 signaling suppression. 1 Publication
Mutagenesisi22 – 221L → D: Complete loss of EPO-induced STAT5 signaling suppression. No suppression of JAK2 phosphorylation. 1 Publication
Mutagenesisi25 – 251F → A: Complete loss of EPO-induced STAT5 signaling suppression. Abolishes binding to JH1. 1 Publication
Mutagenesisi30 – 301E → R: Partial loss of EPO-induced STAT5 signaling suppression. No effect on LIF-induced signaling suppression. Abolishes binding to JH1. Inhibits JAK2 phosphorylation. 1 Publication
Mutagenesisi31 – 311Y → A: Complete loss of EPO-induced STAT5 signaling suppression. No effect on LIF-induced STAT3 signaling. Abolishes binding to JH1. 1 Publication
Mutagenesisi31 – 311Y → F: Little effect on EPO-induced signaling suppression. 1 Publication
Mutagenesisi34 – 341V → E: Complete loss of EPO/LIF-induced signaling suppression. 1 Publication
Mutagenesisi41 – 411L → R: Complete loss of EPO/LIF-induced signaling inhibition. Abolishes binding to JH1. 1 Publication
Mutagenesisi45 – 451G → A: Little effect on EPO/LIF signaling. 1 Publication
Mutagenesisi53 – 531G → V: No effect on binding to Y429/Y431 phosphorylated EPOR. 1 Publication
Mutagenesisi58 – 581L → A: Impaired binding to Y429/Y431 phosphorylated EPOR. 1 Publication
Mutagenesisi71 – 711R → E: Complete loss of EPO/LIF-induced signaling suppression. No inhibition of JAK2 phosphorylation. 2 Publications
Mutagenesisi71 – 711R → 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 Publications
Mutagenesisi93 – 931L → A: Impaired binding to Y429/Y431 phosphorylated EPOR. 1 Publication
Mutagenesisi94 – 941R → E: Greatly impaired binding to Y429/Y431 phosphorylated EPOR. 1 Publication

Organism-specific databases

PharmGKBiPA134885765.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 225225Suppressor of cytokine signaling 3PRO_0000181243Add
BLAST

Post-translational modificationi

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

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiO14543.
PRIDEiO14543.

PTM databases

PhosphoSiteiO14543.

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

BgeeiO14543.
CleanExiHS_SOCS3.
ExpressionAtlasiO14543. baseline and differential.
GenevisibleiO14543. HS.

Organism-specific databases

HPAiCAB012220.

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, TCEB1 and TCEB2 (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

WithEntry#Exp.IntActNotes
GAB1Q134804EBI-714146,EBI-517684
KIAA1958Q8N8K93EBI-714146,EBI-10181113
KITP107213EBI-714146,EBI-1379503
MAP1SQ66K746EBI-714146,EBI-2133734
PTK2I6L9963EBI-714146,EBI-10181089
YES1P079473EBI-714146,EBI-515331

Protein-protein interaction databases

BioGridi114488. 72 interactions.
IntActiO14543. 35 interactions.
MINTiMINT-149732.
STRINGi9606.ENSP00000330341.

Structurei

3D structure databases

ProteinModelPortaliO14543.
SMRiO14543. Positions 30-185.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini46 – 14297SH2PROSITE-ProRule annotationAdd
BLAST
Domaini177 – 22448SOCS boxPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni22 – 3312Kinase inhibitory region (KIR)Add
BLAST
Regioni34 – 4512Extended SH2 subdomain (ESS)Add
BLAST

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

Sequence similaritiesi

Contains 1 SH2 domain.PROSITE-ProRule annotation
Contains 1 SOCS box domain.PROSITE-ProRule annotation

Keywords - Domaini

SH2 domain

Phylogenomic databases

eggNOGiNOG281730.
HOGENOMiHOG000236320.
HOVERGENiHBG105645.
InParanoidiO14543.
KOiK04696.
OMAiKRTYYIY.
PhylomeDBiO14543.
TreeFamiTF321368.

Family and domain databases

Gene3Di3.30.505.10. 2 hits.
InterProiIPR000980. SH2.
IPR028413. SOCS.
IPR028414. SOCS3.
IPR001496. SOCS_C.
[Graphical view]
PANTHERiPTHR10385. PTHR10385. 1 hit.
PTHR10385:SF4. PTHR10385:SF4. 1 hit.
PfamiPF00017. SH2. 1 hit.
PF07525. SOCS_box. 1 hit.
[Graphical view]
SMARTiSM00252. SH2. 1 hit.
SM00253. SOCS. 1 hit.
SM00969. SOCS_box. 1 hit.
[Graphical view]
SUPFAMiSSF55550. SSF55550. 1 hit.
PROSITEiPS50001. SH2. 1 hit.
PS50225. SOCS. 1 hit.
[Graphical view]

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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti81 – 811T → A in BAA22430 (PubMed:9266833).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti125 – 1251H → Y.1 Publication
Corresponds to variant rs1061489 [ dbSNP | Ensembl ].
VAR_030033

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.
UCSCiuc002jvl.2. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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.

3D structure databases

ProteinModelPortaliO14543.
SMRiO14543. Positions 30-185.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114488. 72 interactions.
IntActiO14543. 35 interactions.
MINTiMINT-149732.
STRINGi9606.ENSP00000330341.

PTM databases

PhosphoSiteiO14543.

Proteomic databases

PaxDbiO14543.
PRIDEiO14543.

Protocols and materials databases

DNASUi9021.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000330871; ENSP00000330341; ENSG00000184557.
GeneIDi9021.
KEGGihsa:9021.
UCSCiuc002jvl.2. human.

Organism-specific databases

CTDi9021.
GeneCardsiGC17M076352.
HGNCiHGNC:19391. SOCS3.
HPAiCAB012220.
MIMi604176. gene.
neXtProtiNX_O14543.
PharmGKBiPA134885765.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG281730.
HOGENOMiHOG000236320.
HOVERGENiHBG105645.
InParanoidiO14543.
KOiK04696.
OMAiKRTYYIY.
PhylomeDBiO14543.
TreeFamiTF321368.

Enzyme and pathway databases

UniPathwayiUPA00143.
ReactomeiREACT_111133. Growth hormone receptor signaling.
REACT_169118. Signaling by Leptin.
REACT_24980. Regulation of IFNG signaling.
REACT_25078. Interferon gamma signaling.
REACT_25162. Interferon alpha/beta signaling.
REACT_25216. Regulation of IFNA signaling.
REACT_27307. Interleukin-6 signaling.
REACT_75842. Antigen processing: Ubiquitination & Proteasome degradation.
SignaLinkiO14543.

Miscellaneous databases

ChiTaRSiSOCS3. human.
GeneWikiiSOCS3.
GenomeRNAii9021.
NextBioi33797.
PROiO14543.
SOURCEiSearch...

Gene expression databases

BgeeiO14543.
CleanExiHS_SOCS3.
ExpressionAtlasiO14543. baseline and differential.
GenevisibleiO14543. HS.

Family and domain databases

Gene3Di3.30.505.10. 2 hits.
InterProiIPR000980. SH2.
IPR028413. SOCS.
IPR028414. SOCS3.
IPR001496. SOCS_C.
[Graphical view]
PANTHERiPTHR10385. PTHR10385. 1 hit.
PTHR10385:SF4. PTHR10385:SF4. 1 hit.
PfamiPF00017. SH2. 1 hit.
PF07525. SOCS_box. 1 hit.
[Graphical view]
SMARTiSM00252. SH2. 1 hit.
SM00253. SOCS. 1 hit.
SM00969. SOCS_box. 1 hit.
[Graphical view]
SUPFAMiSSF55550. SSF55550. 1 hit.
PROSITEiPS50001. SH2. 1 hit.
PS50225. SOCS. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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. 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. 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.
  12. "Proteasomal degradation of Nod2 protein mediates tolerance to bacterial cell wall components."
    Lee K.H., Biswas A., Liu Y.J., Kobayashi K.S.
    J. Biol. Chem. 287:39800-39811(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NOD2.

Entry informationi

Entry nameiSOCS3_HUMAN
AccessioniPrimary (citable) accession number: O14543
Secondary accession number(s): O14509
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 16, 2002
Last sequence update: January 1, 1998
Last modified: June 24, 2015
This is version 137 of the entry and version 1 of the sequence. [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
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.