O14543 (SOCS3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	SOCS3
Synonyms:	CIS3, SSI3

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	225 AA.
Sequence status	Complete.
Protein existence	Evidence 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. 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	Note=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.
Pharmaceutical use	Could be used as a possible therapeutic agent for treating rheumatoid arthritis.
Sequence similarities	Contains 1 SH2 domain. Contains 1 SOCS box domain.

Ontologies

Keywords
Biological process	Growth regulation Ubl conjugation pathway
Coding sequence diversity	Polymorphism
Domain	SH2 domain
Molecular function	Signal transduction inhibitor
PTM	Phosphoprotein
Technical term	Complete proteome Pharmaceutical Reference proteome
Gene Ontology (GO)
Biological process	JAK-STAT cascade Traceable author statement. Source: ProtInc anti-apoptosis Traceable author statement. Source: ProtInc interferon-gamma-mediated signaling pathway Traceable author statement. Source: Reactome 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 type I interferon-mediated signaling pathway Traceable author statement. Source: Reactome
Cellular component	cytosol Traceable author statement. Source: Reactome
Molecular function	protein kinase inhibitor activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 225	225	Suppressor of cytokine signaling 3		PRO_0000181243
Regions
	Domain	46 – 142	97	SH2
	Domain	177 – 224	48	SOCS box
	Region	22 – 33	12	Kinase inhibitory region (KIR)
	Region	34 – 45	12	Extended SH2 subdomain (ESS)
Natural variations
	Natural variant	125	1	H → Y. Ref.1 Corresponds to variant rs1061489 [ dbSNP | Ensembl ].		VAR_030033
Experimental info
	Mutagenesis	22	1	L → A or F: Little effect on EPO-induced STAT5 signaling suppression. Ref.5
	Mutagenesis	22	1	L → D: Complete loss of EPO-induced STAT5 signaling suppression. No suppression of JAK2 phosphorylation. Ref.5
	Mutagenesis	25	1	F → A: Complete loss of EPO-induced STAT5 signaling suppression. Abolishes binding to JH1. Ref.5
	Mutagenesis	30	1	E → 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
	Mutagenesis	31	1	Y → A: Complete loss of EPO-induced STAT5 signaling suppression. No effect on LIF-induced STAT3 signaling. Abolishes binding to JH1. Ref.5
	Mutagenesis	31	1	Y → F: Little effect on EPO-induced signaling suppression. Ref.5
	Mutagenesis	34	1	V → E: Complete loss of EPO/LIF-induced signaling suppression. Ref.5
	Mutagenesis	41	1	L → R: Complete loss of EPO/LIF-induced signaling inhibition. Abolishes binding to JH1. Ref.5
	Mutagenesis	45	1	G → A: Little effect on EPO/LIF signaling. Ref.5
	Mutagenesis	53	1	G → V: No effect on binding to Y429/Y431 phosphorylated EPOR. Ref.6
	Mutagenesis	58	1	L → A: Impaired binding to Y429/Y431 phosphorylated EPOR. Ref.6
	Mutagenesis	71	1	R → E: Complete loss of EPO/LIF-induced signaling suppression. No inhibition of JAK2 phosphorylation. Ref.5 Ref.7
	Mutagenesis	71	1	R → 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
	Mutagenesis	93	1	L → A: Impaired binding to Y429/Y431 phosphorylated EPOR. Ref.6
	Mutagenesis	94	1	R → E: Greatly impaired binding to Y429/Y431 phosphorylated EPOR. Ref.6
	Sequence conflict	81	1	T → A in BAA22430. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	O14543 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: 08581DC411EFFF19	FASTA	225	24,770
	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

References

	« Hide 'large scale' referencesShow '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: 9266833] [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: 9344848] [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: 11071852] [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: 15489334] [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: 10421843] [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: 12027890] [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: 14559241] [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: 15070676] [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: 15601820] [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: 16685656] [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: 16410555] [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.
IPI	IPI00297349.
PIR	JC5627. JC5761.
RefSeq	NP_003946.3. NM_003955.3.
UniGene	Hs.527973.
3D structure databases
ProteinModelPortal	O14543.
SMR	O14543. Positions 30-185.
ModBase	Search...
Protein-protein interaction databases
IntAct	O14543. 15 interactions.
MINT	MINT-149732.
STRING	O14543.
PTM databases
PhosphoSite	O14543.
Proteomic databases
PRIDE	O14543.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000330871; ENSP00000330341; ENSG00000184557.
GeneID	9021.
KEGG	hsa:9021.
UCSC	uc002jvl.1. human.
Organism-specific databases
CTD	9021.
GeneCards	GC17M076352.
H-InvDB	HIX0039019.
HGNC	HGNC:19391. SOCS3.
HPA	CAB012220.
MIM	604176. gene.
neXtProt	NX_O14543.
PharmGKB	PA134885765.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG15955.
HOGENOM	HBG715092.
HOVERGEN	HBG105645.
InParanoid	O14543.
OMA	NVASLQH.
OrthoDB	EOG48D0WC.
PhylomeDB	O14543.
Enzyme and pathway databases
Pathway_Interaction_DB	epopathway. EPO signaling pathway. il2_1pathway. IL2-mediated signaling events. il23pathway. IL23-mediated signaling events. il4_2pathway. IL4-mediated signaling events. il6_7pathway. IL6-mediated signaling events. ptp1bpathway. Signaling events mediated by PTP1B.
Reactome	REACT_6900. Immune System.
Gene expression databases
ArrayExpress	O14543.
Bgee	O14543.
CleanEx	HS_SOCS3.
Genevestigator	O14543.
GermOnline	ENSG00000184557. Homo sapiens.
Family and domain databases
InterPro	IPR000980. SH2. IPR001496. SOCS_C. [Graphical view]
Gene3D	G3DSA:3.30.505.10. SH2. 1 hit.
KO	K04696.
Pfam	PF00017. SH2. 1 hit. PF07525. SOCS_box. 1 hit. [Graphical view]
SMART	SM00252. SH2. 1 hit. SM00253. SOCS. 1 hit. SM00969. SOCS_box. 1 hit. [Graphical view]
PROSITE	PS50001. SH2. 1 hit. PS50225. SOCS. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	33797.
SOURCE	Search...

Entry information

Entry name

SOCS3_HUMAN

Accession

Primary (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:	January 25, 2012
This is version 104 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.