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O35718 (SOCS3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 128. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·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
Protein EF-10
Gene names
Name:Socs3
Synonyms:Cis3, Cish3
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

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. 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. Ref.7 Ref.8 Ref.11 Ref.12 Ref.13

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 FGFR3 By similarity. Interacts with INSR. Interacts with BCL10; this interaction may interfere with BCL10-binding with PELI2. Ref.8 Ref.9 Ref.14

Tissue specificity

Low expression in lung, spleen and thymus. Expressed in Th2 but not TH1 cells. Ref.10

Developmental stage

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.

Induction

By a subset of cytokines including EPO, leptin, LIF, IL-2, IL-3, IL-4, IGF1, growth hormone and prolactin. Ref.13

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 By similarity.

Sequence similarities

Contains 1 SH2 domain.

Contains 1 SOCS box domain.

Ontologies

Keywords
   Biological processGrowth regulation
Ubl conjugation pathway
   DomainSH2 domain
   Molecular functionSignal transduction inhibitor
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processJAK-STAT cascade

Inferred from electronic annotation. Source: InterPro

branching involved in labyrinthine layer morphogenesis

Inferred from mutant phenotype PubMed 11481489. Source: MGI

negative regulation of apoptotic process

Inferred from electronic annotation. Source: InterPro

negative regulation of insulin receptor signaling pathway

Inferred from direct assay PubMed 15169905. Source: MGI

negative regulation of signal transduction

Inferred from genetic interaction PubMed 15358627. Source: MGI

placenta blood vessel development

Inferred from mutant phenotype PubMed 11481489. Source: MGI

positive regulation of cell differentiation

Inferred from direct assay PubMed 15358627. Source: MGI

protein ubiquitination

Inferred from electronic annotation. Source: UniProtKB-UniPathway

regulation of cell differentiation

Inferred from mutant phenotype PubMed 16185683. Source: MGI

regulation of growth

Inferred from electronic annotation. Source: UniProtKB-KW

regulation of protein phosphorylation

Inferred from direct assay PubMed 15169905. Source: MGI

spongiotrophoblast differentiation

Inferred from mutant phenotype PubMed 16185683. Source: MGI

trophoblast giant cell differentiation

Inferred from mutant phenotype PubMed 16185683. Source: MGI

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Il6stQ005603EBI-2659360,EBI-3862992

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 225225Suppressor of cytokine signaling 3
PRO_0000181244

Regions

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

Experimental info

Mutagenesis221L → A: No effect on LIF-induced signal transduction suppression. Ref.9
Mutagenesis221L → D: Abolishes binding to JAK2. No effect on binding to EPOR. Ref.9
Mutagenesis251F → A: Loss of LIF/EPO-induced signal transduction suppression. Abolishes binding to JAK2 and to EPOR. Ref.9
Mutagenesis301E → R: No effect on LIF-induced signal transduction suppression.
Mutagenesis451G → A: Abolishes binding to EPOR. No effect on binding to JAK2. Ref.9
Mutagenesis711R → K: Little effect on LIF-induced signal transduction suppression. Loss of EPO-induced signal transduction suppression. Abolishes binding to JAK2 and EPOR. Ref.9

Secondary structure

............................ 225
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
O35718 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: CD3859561D4CCDED

FASTA22524,776
        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 PGTPSFSLPP TEPSSEVPEQ PPAQALPGST PKRAYYIYSG GEKIPLVLSR 

       190        200        210        220 
PLSSNVATLQ HLCRKTVNGH LDSYEKVTQL PGPIREFLDQ YDAPL 

« Hide

References

« Hide 'large scale' references
[1]"A family of cytokine-inducible inhibitors of signaling."
Starr R., Willson T.A., Viney E.M., Murray L.J.L., Rayner J.R., Jenkins B.J., Gonda T.J., Alexander W.S., Metcalf D., Nicola N.A., Hilton D.J.
Nature 387:917-921(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Lung and Thymus.
[2]"Murine SOCS3 gene structure."
Le Provost F., Henninghausen L.
Submitted (OCT-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6J and NOD.
Tissue: Bone marrow, Cerebellum and Spleen.
[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].
Strain: C57BL/6.
Tissue: Brain.
[5]"Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of the murine SOCS-3 promoter."
Auernhammer C.J., Bousquet C., Melmed S.
Proc. Natl. Acad. Sci. U.S.A. 96:6964-6969(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-30.
Strain: ICR X Swiss Webster.
[6]"E2a-Pbx1 induces aberrant expression of tissue-specific and developmentally regulated genes when expressed in NIH 3T3 fibroblasts."
Fu X., Kamps M.P.
Mol. Cell. Biol. 17:1503-1512(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 221-225.
Strain: BALB/c.
[7]"Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction."
Nicholson S.E., Willson T.A., Farley A., Starr R., Zhang J.-G., Baca M., Alexander W.S., Metcalf D., Hilton D.J., Nicola N.A.
EMBO J. 18:375-385(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN LIF AND IL6 SIGNALING.
[8]"SOCS-3 is an insulin-induced negative regulator of insulin signaling."
Emanuelli B., Peraldi P., Filloux C., Sawka-Verhelle D., Hilton D., Van Obberghen E.
J. Biol. Chem. 275:15985-15991(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INHIBITION OF INSR KINASE ACTIVITY, INTERACTION WITH INSR.
[9]"CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2."
Sasaki A., Yasukawa H., Shouda T., Kitamura T., Dikic I., Yoshimura A.
J. Biol. Chem. 275:29338-29347(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH EPOR AND JAK2, MUTAGENESIS OF LEU-22; PHE-25; GLY-45 AND ARG-71.
[10]"Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation."
Seki Y., Hayashi K., Matsumoto A., Seki N., Tsukada J., Ransom J., Naka T., Kishimoto T., Yoshimura A., Kubo M.
Proc. Natl. Acad. Sci. U.S.A. 99:13003-13008(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[11]"SOCS3 is essential in the regulation of fetal liver erythropoiesis."
Marine J.-C., McKay C., Wang D., Topham D.J., Parganas E., Nakajima H., Pendeville H., Yasukawa H., Sasaki A., Yoshimura A., Ihle J.N.
Cell 98:617-627(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ERYTHROPOIESIS.
[12]"SOCS3 negatively regulates IL-6 signaling in vivo."
Croker B.A., Krebs D.L., Zhang J.-G., Wormald S., Willson T.A., Stanley E.G., Robb L., Greenhalgh C.J., Foerster I., Clausen B.E., Nicola N.A., Metcalf D., Hilton D.J., Roberts A.W., Alexander W.S.
Nat. Immunol. 4:540-545(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: ROLE IN IL-6 SIGNALING.
[13]"SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses."
Seki Y., Inoue H., Nagata N., Hayashi K., Fukuyama S., Matsumoto K., Komine O., Hamano S., Himeno K., Inagaki-Ohara K., Cacalano N., O'Garra A., Oshida T., Saito H., Johnston J.A., Yoshimura A., Kubo M.
Nat. Med. 9:1047-1054(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: ROLE IN ALLERGIC RESPONSE, INDUCTION BY IL-4.
[14]"BCL10 mediates lipopolysaccharide/toll-like receptor-4 signaling through interaction with Pellino2."
Liu Y., Dong W., Chen L., Xiang R., Xiao H., De G., Wang Z., Qi Y.
J. Biol. Chem. 279:37436-37444(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BCL10.
[15]"The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability."
Babon J.J., McManus E.J., Yao S., DeSouza D.P., Mielke L.A., Sprigg N.S., Willson T.A., Hilton D.J., Nicola N.A., Baca M., Nicholson S.E., Norton R.S.
Mol. Cell 22:205-216(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 22-185.
[16]"Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3."
Bergamin E., Wu J., Hubbard S.R.
Structure 14:1285-1292(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 15-185 IN COMPLEX WITH PHOSPHORYLATED IL6ST.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
RefSeqNP_031733.1. NM_007707.3.
XP_006532173.1. XM_006532110.1.
UniGeneMm.3468.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2BBUNMR-A22-185[»]
2HMHX-ray2.00A15-185[»]
2JZ3NMR-A186-225[»]
4GL9X-ray3.90E/F/G/H22-185[»]
DisProtDP00446.
ProteinModelPortalO35718.
SMRO35718. Positions 30-185.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198718. 11 interactions.
DIPDIP-29137N.
IntActO35718. 9 interactions.
MINTMINT-2569503.
STRING10090.ENSMUSP00000059129.

PTM databases

PhosphoSiteO35718.

Proteomic databases

PRIDEO35718.

Protocols and materials databases

DNASU12702.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000054002; ENSMUSP00000059129; ENSMUSG00000053113.
GeneID12702.
KEGGmmu:12702.
UCSCuc007moi.2. mouse.

Organism-specific databases

CTD9021.
MGIMGI:1201791. Socs3.

Phylogenomic databases

eggNOGNOG281730.
GeneTreeENSGT00740000115151.
HOGENOMHOG000236320.
HOVERGENHBG105645.
InParanoidO35718.
KOK04696.
OMAKRTYYIY.
OrthoDBEOG7TXKHR.
PhylomeDBO35718.
TreeFamTF321368.

Enzyme and pathway databases

ReactomeREACT_169390. Signaling by Leptin.
REACT_188257. Signal Transduction.
REACT_98458. Immune System.
UniPathwayUPA00143.

Gene expression databases

BgeeO35718.
CleanExMM_SOCS3.
GenevestigatorO35718.

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

EvolutionaryTraceO35718.
NextBio281958.
PROO35718.
SOURCESearch...

Entry information

Entry nameSOCS3_MOUSE
AccessionPrimary (citable) accession number: O35718
Secondary accession number(s): P97803, Q3U7X5
Entry history
Integrated into UniProtKB/Swiss-Prot: April 16, 2002
Last sequence update: January 1, 1998
Last modified: April 16, 2014
This is version 128 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot