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Protein

Suppressor of cytokine signaling 3

Gene

Socs3

Organism
Mus musculus (Mouse)
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. 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 (By similarity). Seems to recognize IL6ST.By similarity5 Publications

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: CAFA
  • protein kinase inhibitor activity Source: GO_Central

GO - Biological processi

  • branching involved in labyrinthine layer morphogenesis Source: MGI
  • cellular response to leukemia inhibitory factor Source: MGI
  • cytokine-mediated signaling pathway Source: GO_Central
  • JAK-STAT cascade Source: InterPro
  • negative regulation of apoptotic process Source: InterPro
  • negative regulation of inflammatory response Source: MGI
  • negative regulation of insulin receptor signaling pathway Source: MGI
  • negative regulation of JAK-STAT cascade Source: MGI
  • negative regulation of protein kinase activity Source: GO_Central
  • negative regulation of signal transduction Source: MGI
  • negative regulation of tyrosine phosphorylation of STAT protein Source: MGI
  • placenta blood vessel development Source: MGI
  • positive regulation of cell differentiation Source: MGI
  • protein ubiquitination Source: UniProtKB-UniPathway
  • regulation of cell differentiation Source: MGI
  • regulation of growth Source: UniProtKB-KW
  • regulation of protein phosphorylation Source: MGI
  • spongiotrophoblast differentiation Source: MGI
  • trophoblast giant cell differentiation Source: MGI

Keywordsi

Molecular functionSignal transduction inhibitor
Biological processGrowth regulation, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-MMU-1059683 Interleukin-6 signaling
R-MMU-877300 Interferon gamma signaling
R-MMU-877312 Regulation of IFNG signaling
R-MMU-8849474 PTK6 Activates STAT3
R-MMU-8951664 Neddylation
R-MMU-909733 Interferon alpha/beta signaling
R-MMU-983168 Antigen processing: Ubiquitination & Proteasome degradation
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
Protein EF-10
Gene namesi
Name:Socs3
Synonyms:Cis3, Cish3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi

Organism-specific databases

MGIiMGI:1201791 Socs3

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

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi22L → A: No effect on LIF-induced signal transduction suppression. 1 Publication1
Mutagenesisi22L → D: Abolishes binding to JAK2. No effect on binding to EPOR. 1 Publication1
Mutagenesisi25F → A: Loss of LIF/EPO-induced signal transduction suppression. Abolishes binding to JAK2 and to EPOR. 1 Publication1
Mutagenesisi30E → R: No effect on LIF-induced signal transduction suppression. 1
Mutagenesisi45G → A: Abolishes binding to EPOR. No effect on binding to JAK2. 1 Publication1
Mutagenesisi71R → K: Little effect on LIF-induced signal transduction suppression. Loss of EPO-induced signal transduction suppression. Abolishes binding to JAK2 and EPOR. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001812441 – 225Suppressor of cytokine signaling 3Add BLAST225

Post-translational modificationi

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

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiO35718
PRIDEiO35718

PTM databases

iPTMnetiO35718
PhosphoSitePlusiO35718

Expressioni

Tissue specificityi

Low expression in lung, spleen and thymus. Expressed in Th2 but not TH1 cells.1 Publication

Developmental stagei

In the developing brain, expressed at low levels from E10 stages to young adulthood (P25) with peak levels from E14 to P8. In the cortex, first expressed uniformly in all cells at E14. Not expressed in the retina. Highly expressed in fetal liver progenitors at E12.5.

Inductioni

By a subset of cytokines including EPO, leptin, LIF, IL-2, IL-3, IL-4, IGF1, growth hormone and prolactin.1 Publication

Gene expression databases

BgeeiENSMUSG00000053113
CleanExiMM_SOCS3
GenevisibleiO35718 MM

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 (By similarity). Binds specific activated tyrosine residues of the leptin, EPO, IL12, GSCF and gp130 receptors (PubMed:10882725). Interaction with CSNK1E stabilizes SOCS3 protein (By similarity). Component of the probable ECS(SOCS3) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, elongin BC complex and SOCS3 (By similarity). Interacts with CUL5, RNF7, ELOB and ELOC (By similarity). Interacts with FGFR3 (By similarity). Interacts with INSR (PubMed:10821852). Interacts with BCL10; this interaction may interfere with BCL10-binding with PELI2 (PubMed:15213237). Interacts with NOD2 (via CARD domain); the interaction promotes NOD2 degradation (PubMed:23019338).By similarity5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Il6stQ005602EBI-2659360,EBI-3862992

GO - Molecular functioni

  • phosphotyrosine residue binding Source: CAFA

Protein-protein interaction databases

BioGridi198718, 13 interactors
DIPiDIP-29137N
IntActiO35718, 11 interactors
MINTiO35718
STRINGi10090.ENSMUSP00000059129

Structurei

Secondary structure

1225
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi32 – 43Combined sources12
Beta strandi45 – 48Combined sources4
Helixi53 – 61Combined sources9
Beta strandi67 – 72Combined sources6
Beta strandi79 – 86Combined sources8
Beta strandi89 – 96Combined sources8
Helixi98 – 100Combined sources3
Beta strandi102 – 104Combined sources3
Beta strandi117 – 119Combined sources3
Helixi120 – 126Combined sources7
Beta strandi137 – 139Combined sources3
Beta strandi165 – 167Combined sources3
Beta strandi174 – 176Combined sources3
Helixi189 – 199Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2BBUNMR-A22-185[»]
2HMHX-ray2.00A15-185[»]
2JZ3NMR-A186-225[»]
4GL9X-ray3.90E/F/G/H22-128[»]
E/F/G/H179-185[»]
DisProtiDP00446
ProteinModelPortaliO35718
SMRiO35718
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO35718

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
InParanoidiO35718
KOiK04696
OMAiKRTYYIY
OrthoDBiEOG091G0NEU
PhylomeDBiO35718
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.

O35718-1 [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 PGTPSFSLPP TEPSSEVPEQ
160 170 180 190 200
PPAQALPGST PKRAYYIYSG GEKIPLVLSR PLSSNVATLQ HLCRKTVNGH
210 220
LDSYEKVTQL PGPIREFLDQ YDAPL
Length:225
Mass (Da):24,776
Last modified:January 1, 1998 - v1
Checksum:iCD3859561D4CCDED
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U88328 mRNA Translation: AAB62403.1
AF314501 Genomic DNA Translation: AAK60601.1
AK047165 mRNA Translation: BAC32977.1
AK139241 mRNA Translation: BAE23929.1
AK152468 mRNA Translation: BAE31244.1
AK152514 mRNA Translation: BAE31277.1
AK157708 mRNA Translation: BAE34161.1
AK159395 mRNA Translation: BAE35049.1
AK170406 mRNA Translation: BAE41773.1
AK172399 mRNA Translation: BAE42985.1
BC052031 mRNA Translation: AAH52031.1
AF117732 Genomic DNA Translation: AAD18024.1
U72673 mRNA Translation: AAB51035.1 Sequence problems.
CCDSiCCDS25697.1
RefSeqiNP_031733.1, NM_007707.3
XP_011247009.1, XM_011248707.2
UniGeneiMm.3468

Genome annotation databases

EnsembliENSMUST00000054002; ENSMUSP00000059129; ENSMUSG00000053113
GeneIDi12702
KEGGimmu:12702
UCSCiuc007moi.2 mouse

Entry informationi

Entry nameiSOCS3_MOUSE
AccessioniPrimary (citable) accession number: O35718
Secondary accession number(s): P97803, Q3U7X5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 16, 2002
Last sequence update: January 1, 1998
Last modified: May 23, 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

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references

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