ID SOCS3_HUMAN Reviewed; 225 AA. AC O14543; O14509; DT 16-APR-2002, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 27-MAR-2024, entry version 200. DE RecName: Full=Suppressor of cytokine signaling 3 {ECO:0000305}; DE Short=SOCS-3; DE AltName: Full=Cytokine-inducible SH2 protein 3; DE Short=CIS-3; DE AltName: Full=STAT-induced STAT inhibitor 3; DE Short=SSI-3; GN Name=SOCS3 {ECO:0000312|HGNC:HGNC:19391}; Synonyms=CIS3, SSI3; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT TYR-125. RC TISSUE=T-cell lymphoma; RX PubMed=9266833; DOI=10.1006/bbrc.1997.7080; RA Minamoto S., Ikegame K., Ueno K., Narazaki M., Naka T., Yamamoto H., RA Matsumoto T., Saito H., Hosoe S., Kishimoto T.; RT "Cloning and functional analysis of new members of STAT induced STAT RT inhibitor (SSI) family: SSI-2 and SSI-3."; RL Biochem. Biophys. Res. Commun. 237:79-83(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9344848; DOI=10.1006/bbrc.1997.7484; RA Masuhara M., Sakamoto H., Matsumoto A., Suzuki R., Yasukawa H., Mitsui K., RA Wakioka T., Tanimura S., Sasaki A., Misawa H., Yokouchi M., Ohtsubo M., RA Yoshimura A.; RT "Cloning and characterization of novel CIS family genes."; RL Biochem. Biophys. Res. Commun. 239:439-446(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Skeletal muscle; RX PubMed=11071852; DOI=10.1006/bbrc.2000.3762; RA Dey B.R., Furlanetto R.W., Nissley P.; RT "Suppressor of cytokine signaling (SOCS)-3 protein interacts with the RT insulin-like growth factor-I receptor."; RL Biochem. Biophys. Res. Commun. 278:38-43(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP INTERACTION WITH JAK2, AND MUTAGENESIS OF LEU-22; PHE-25; GLU-30; TYR-31; RP VAL-34; LEU-41; GLY-45 AND ARG-71. RX PubMed=10421843; DOI=10.1046/j.1365-2443.1999.00263.x; RA Sasaki A., Yasukawa H., Suzuki A., Kamizono S., Syoda T., Kinjyo I., RA Sasaki M., Johnston J.A., Yoshimura A.; RT "Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine RT kinase by binding through the N-terminal kinase inhibitory region as well RT as SH2 domain."; RL Genes Cells 4:339-351(1999). RN [6] RP INTERACTION WITH EPOR, AND MUTAGENESIS OF GLY-53; LEU-58; LEU-93 AND RP ARG-94. RX PubMed=12027890; DOI=10.1046/j.1432-1033.2002.02916.x; RA Hoertner M., Nielsch U., Mayr L.M., Heinrich P.C., Haan S.; RT "A new high affinity binding site for suppressor of cytokine signaling-3 on RT the erythropoietin receptor."; RL Eur. J. Biochem. 269:2516-2526(2002). RN [7] RP INTERACTION WITH IL12RB2, AND MUTAGENESIS OF ARG-71. RX PubMed=14559241; DOI=10.1016/j.bbrc.2003.09.140; RA Yamamoto K., Yamaguchi M., Miyasaka N., Miura O.; RT "SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 RT domain to the STAT4 docking site in the IL-12 receptor beta2 subunit."; RL Biochem. Biophys. Res. Commun. 310:1188-1193(2003). RN [8] RP INTERACTION WITH CSNK1E, AND PROTEIN STABILIZATION. RX PubMed=15070676; DOI=10.1182/blood-2003-08-2768; RA Okamura A., Iwata N., Nagata A., Tamekane A., Shimoyama M., Gomyo H., RA Yakushijin K., Urahama N., Hamaguchi M., Fukui C., Chihara K., Ito M., RA Matsui T.; RT "Involvement of casein kinase Iepsilon in cytokine-induced granulocytic RT differentiation."; RL Blood 103:2997-3004(2004). RN [9] RP FUNCTION IN AN E3 UBIQUITIN-PROTEIN LIGASE COMPLEX, AND INTERACTION WITH RP CUL5; RNF7; ELOB AND ELOC. RX PubMed=15601820; DOI=10.1101/gad.1252404; RA Kamura T., Maenaka K., Kotoshiba S., Matsumoto M., Kohda D., Conaway R.C., RA Conaway J.W., Nakayama K.I.; RT "VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 RT and Cul5-Rbx2 modules of ubiquitin ligases."; RL Genes Dev. 18:3055-3065(2004). RN [10] RP POSSIBLE INVOLVEMENT IN ATOPIC DERMATITIS. RX PubMed=16685656; DOI=10.1086/504272; RA Ekelund E., Saeaef A., Tengvall-Linder M., Melen E., Link J., Barker J., RA Reynolds N.J., Meggitt S.J., Kere J., Wahlgren C.-F., Pershagen G., RA Wickman M., Nordenskjoeld M., Kockum I., Bradley M.; RT "Elevated expression and genetic association links the SOCS3 gene to atopic RT dermatitis."; RL Am. J. Hum. Genet. 78:1060-1065(2006). RN [11] RP INTERACTION WITH FGFR3. RX PubMed=16410555; DOI=10.1242/jcs.02740; RA Ben-Zvi T., Yayon A., Gertler A., Monsonego-Ornan E.; RT "Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and RT modulate fibroblast growth factor receptor signaling."; RL J. Cell Sci. 119:380-387(2006). RN [12] RP INTERACTION WITH NOD2. RX PubMed=23019338; DOI=10.1074/jbc.m112.410027; RA Lee K.H., Biswas A., Liu Y.J., Kobayashi K.S.; RT "Proteasomal degradation of Nod2 protein mediates tolerance to bacterial RT cell wall components."; RL J. Biol. Chem. 287:39800-39811(2012). CC -!- FUNCTION: SOCS family proteins form part of a classical negative CC feedback system that regulates cytokine signal transduction. SOCS3 is CC involved in negative regulation of cytokines that signal through the CC JAK/STAT pathway. Inhibits cytokine signal transduction by binding to CC tyrosine kinase receptors including IL6ST/gp130, LIF, erythropoietin, CC insulin, IL12, GCSF and leptin receptors. Binding to JAK2 inhibits its CC kinase activity and regulates IL6 signaling. Suppresses fetal liver CC erythropoiesis. Regulates onset and maintenance of allergic responses CC mediated by T-helper type 2 cells (By similarity). Probable substrate CC recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box CC protein) E3 ubiquitin-protein ligase complex which mediates the CC ubiquitination and subsequent proteasomal degradation of target CC proteins (PubMed:15601820). {ECO:0000250|UniProtKB:O35718, CC ECO:0000269|PubMed:15601820}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Interacts with multiple activated proteins of the tyrosine CC kinase signaling pathway including IGF1 receptor, insulin receptor and CC JAK2. Binding to JAK2 is mediated through the KIR and SH2 domains to a CC phosphorylated tyrosine residue within the JAK2 JH1 domain CC (PubMed:10421843). Binds specific activated tyrosine residues of the CC leptin, EPO, IL12, GSCF and gp130 receptors (PubMed:12027890, CC PubMed:14559241). Interaction with CSNK1E stabilizes SOCS3 protein CC (PubMed:15070676). Component of the probable ECS(SOCS3) E3 ubiquitin- CC protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC CC complex and SOCS3 (PubMed:15601820). Interacts with CUL5, RNF7, ELOB CC and ELOC (PubMed:15601820). Interacts with CUL2 (PubMed:15601820). CC Interacts with FGFR3 (PubMed:16410555). Interacts with INSR (By CC similarity). Interacts with BCL10; this interaction may interfere with CC BCL10-binding with PELI2 (By similarity). Interacts with NOD2 (via CARD CC domain); the interaction promotes NOD2 degradation (PubMed:23019338). CC {ECO:0000250|UniProtKB:O35718, ECO:0000269|PubMed:10421843, CC ECO:0000269|PubMed:12027890, ECO:0000269|PubMed:14559241, CC ECO:0000269|PubMed:15070676, ECO:0000269|PubMed:15601820, CC ECO:0000269|PubMed:16410555, ECO:0000269|PubMed:23019338}. CC -!- INTERACTION: CC O14543; P51451: BLK; NbExp=3; IntAct=EBI-714146, EBI-2105445; CC O14543; Q13480: GAB1; NbExp=4; IntAct=EBI-714146, EBI-517684; CC O14543; Q8N8K9: KIAA1958; NbExp=6; IntAct=EBI-714146, EBI-10181113; CC O14543; P10721: KIT; NbExp=3; IntAct=EBI-714146, EBI-1379503; CC O14543; Q66K74: MAP1S; NbExp=6; IntAct=EBI-714146, EBI-2133734; CC O14543; I6L996: PTK2; NbExp=3; IntAct=EBI-714146, EBI-10181089; CC O14543; O95863: SNAI1; NbExp=3; IntAct=EBI-714146, EBI-1045459; CC O14543; P42681: TXK; NbExp=3; IntAct=EBI-714146, EBI-7877438; CC O14543; P07947: YES1; NbExp=6; IntAct=EBI-714146, EBI-515331; CC -!- TISSUE SPECIFICITY: Widely expressed with high expression in heart, CC placenta, skeletal muscle, peripheral blood leukocytes, fetal and adult CC lung, and fetal liver and kidney. Lower levels in thymus. CC -!- DOMAIN: The ESS and SH2 domains are required for JAK phosphotyrosine CC binding. Further interaction with the KIR domain is necessary for CC signal and kinase inhibition. CC -!- DOMAIN: The SOCS box domain mediates the interaction with the Elongin CC BC complex, an adapter module in different E3 ubiquitin ligase CC complexes. {ECO:0000250}. CC -!- PTM: Phosphorylated on tyrosine residues after stimulation by the CC cytokines, IL-2, EPO or IGF1. CC -!- DISEASE: Note=There is some evidence that SOCS3 may be a susceptibility CC gene for atopic dermatitis linked to 17q25. SOCS3 messenger RNA is CC significantly more highly expressed in skin from patients with atopic CC dermatitis than in skin from healthy controls. Furthermore, a genetic CC association between atopic dermatitis and a haplotype in the SOCS3 gene CC has been found in two independent groups of patients. CC {ECO:0000269|PubMed:16685656}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44124/SOCS3"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB004904; BAA22430.1; -; mRNA. DR EMBL; AB006967; BAA22537.1; -; mRNA. DR EMBL; AF159854; AAD42231.1; -; mRNA. DR EMBL; BC060858; AAH60858.1; -; mRNA. DR CCDS; CCDS11756.1; -. DR PIR; JC5627; JC5627. DR PIR; JC5761; JC5761. DR RefSeq; NP_003946.3; NM_003955.4. DR AlphaFoldDB; O14543; -. DR BMRB; O14543; -. DR SMR; O14543; -. DR BioGRID; 114488; 99. DR CORUM; O14543; -. DR IntAct; O14543; 57. DR MINT; O14543; -. DR STRING; 9606.ENSP00000330341; -. DR GlyGen; O14543; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O14543; -. DR PhosphoSitePlus; O14543; -. DR BioMuta; SOCS3; -. DR EPD; O14543; -. DR MassIVE; O14543; -. DR PaxDb; 9606-ENSP00000330341; -. DR PeptideAtlas; O14543; -. DR Antibodypedia; 3206; 958 antibodies from 44 providers. DR DNASU; 9021; -. DR Ensembl; ENST00000330871.3; ENSP00000330341.2; ENSG00000184557.4. DR GeneID; 9021; -. DR KEGG; hsa:9021; -. DR MANE-Select; ENST00000330871.3; ENSP00000330341.2; NM_003955.5; NP_003946.3. DR AGR; HGNC:19391; -. DR CTD; 9021; -. DR DisGeNET; 9021; -. DR GeneCards; SOCS3; -. DR HGNC; HGNC:19391; SOCS3. DR HPA; ENSG00000184557; Tissue enhanced (adipose). DR MalaCards; SOCS3; -. DR MIM; 604176; gene. DR neXtProt; NX_O14543; -. DR OpenTargets; ENSG00000184557; -. DR PharmGKB; PA134885765; -. DR VEuPathDB; HostDB:ENSG00000184557; -. DR eggNOG; KOG4566; Eukaryota. DR GeneTree; ENSGT00940000159620; -. DR HOGENOM; CLU_079452_3_0_1; -. DR InParanoid; O14543; -. DR OMA; KLVHYYM; -. DR OrthoDB; 5362214at2759; -. DR PhylomeDB; O14543; -. DR TreeFam; TF321368; -. DR PathwayCommons; O14543; -. DR Reactome; R-HSA-1059683; Interleukin-6 signaling. DR Reactome; R-HSA-2586552; Signaling by Leptin. DR Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling. DR Reactome; R-HSA-877300; Interferon gamma signaling. DR Reactome; R-HSA-877312; Regulation of IFNG signaling. DR Reactome; R-HSA-8849474; PTK6 Activates STAT3. DR Reactome; R-HSA-8939242; RUNX1 regulates transcription of genes involved in differentiation of keratinocytes. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-909733; Interferon alpha/beta signaling. DR Reactome; R-HSA-912694; Regulation of IFNA/IFNB signaling. DR Reactome; R-HSA-9674555; Signaling by CSF3 (G-CSF). DR Reactome; R-HSA-9705462; Inactivation of CSF3 (G-CSF) signaling. DR Reactome; R-HSA-982772; Growth hormone receptor signaling. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; O14543; -. DR SIGNOR; O14543; -. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 9021; 129 hits in 1202 CRISPR screens. DR ChiTaRS; SOCS3; human. DR GeneWiki; SOCS3; -. DR GenomeRNAi; 9021; -. DR Pharos; O14543; Tbio. DR PRO; PR:O14543; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; O14543; Protein. DR Bgee; ENSG00000184557; Expressed in mucosa of stomach and 184 other cell types or tissues. DR ExpressionAtlas; O14543; baseline and differential. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:UniProt. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005942; C:phosphatidylinositol 3-kinase complex; IBA:GO_Central. DR GO; GO:0046935; F:1-phosphatidylinositol-3-kinase regulator activity; IBA:GO_Central. DR GO; GO:0035198; F:miRNA binding; IEA:Ensembl. DR GO; GO:0001784; F:phosphotyrosine residue binding; IEA:Ensembl. DR GO; GO:0004860; F:protein kinase inhibitor activity; TAS:ProtInc. DR GO; GO:0030292; F:protein tyrosine kinase inhibitor activity; IDA:UniProt. DR GO; GO:0060670; P:branching involved in labyrinthine layer morphogenesis; IEA:Ensembl. DR GO; GO:0097398; P:cellular response to interleukin-17; IEA:Ensembl. DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro. DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:ProtInc. DR GO; GO:0050728; P:negative regulation of inflammatory response; IEA:Ensembl. DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IEA:Ensembl. DR GO; GO:0046426; P:negative regulation of receptor signaling pathway via JAK-STAT; IMP:BHF-UCL. DR GO; GO:0042532; P:negative regulation of tyrosine phosphorylation of STAT protein; IMP:BHF-UCL. DR GO; GO:0046854; P:phosphatidylinositol phosphate biosynthetic process; IBA:GO_Central. DR GO; GO:0060674; P:placenta blood vessel development; IEA:Ensembl. DR GO; GO:0045597; P:positive regulation of cell differentiation; IEA:Ensembl. DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway. DR GO; GO:0072540; P:T-helper 17 cell lineage commitment; TAS:UniProt. DR CDD; cd10384; SH2_SOCS3; 1. DR CDD; cd03737; SOCS_SOCS3; 1. DR Gene3D; 3.30.505.10; SH2 domain; 1. DR Gene3D; 1.10.750.20; SOCS box; 1. DR InterPro; IPR000980; SH2. DR InterPro; IPR036860; SH2_dom_sf. DR InterPro; IPR035863; SOCS3_SH2. DR InterPro; IPR028414; SOCS3_SOCS_box. DR InterPro; IPR001496; SOCS_box. DR InterPro; IPR036036; SOCS_box-like_dom_sf. DR PANTHER; PTHR10155; PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT; 1. DR PANTHER; PTHR10155:SF11; SUPPRESSOR OF CYTOKINE SIGNALING 3; 1. DR Pfam; PF00017; SH2; 1. DR SMART; SM00252; SH2; 1. DR SMART; SM00253; SOCS; 1. DR SMART; SM00969; SOCS_box; 1. DR SUPFAM; SSF55550; SH2 domain; 1. DR SUPFAM; SSF158235; SOCS box-like; 1. DR PROSITE; PS50001; SH2; 1. DR PROSITE; PS50225; SOCS; 1. DR Genevisible; O14543; HS. PE 1: Evidence at protein level; KW Growth regulation; Pharmaceutical; Phosphoprotein; Reference proteome; KW SH2 domain; Signal transduction inhibitor; Ubl conjugation pathway. FT CHAIN 1..225 FT /note="Suppressor of cytokine signaling 3" FT /id="PRO_0000181243" FT DOMAIN 46..142 FT /note="SH2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191" FT DOMAIN 177..224 FT /note="SOCS box" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00194" FT REGION 22..33 FT /note="Kinase inhibitory region (KIR)" FT REGION 34..45 FT /note="Extended SH2 subdomain (ESS)" FT REGION 131..162 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 131..146 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VARIANT 125 FT /note="H -> Y (in dbSNP:rs1061489)" FT /evidence="ECO:0000269|PubMed:9266833" FT /id="VAR_030033" FT MUTAGEN 22 FT /note="L->A,F: Little effect on EPO-induced STAT5 signaling FT suppression." FT /evidence="ECO:0000269|PubMed:10421843" FT MUTAGEN 22 FT /note="L->D: Complete loss of EPO-induced STAT5 signaling FT suppression. No suppression of JAK2 phosphorylation." FT /evidence="ECO:0000269|PubMed:10421843" FT MUTAGEN 25 FT /note="F->A: Complete loss of EPO-induced STAT5 signaling FT suppression. Abolishes binding to JH1." FT /evidence="ECO:0000269|PubMed:10421843" FT MUTAGEN 30 FT /note="E->R: Partial loss of EPO-induced STAT5 signaling FT suppression. No effect on LIF-induced signaling FT suppression. Abolishes binding to JH1. Inhibits JAK2 FT phosphorylation." FT /evidence="ECO:0000269|PubMed:10421843" FT MUTAGEN 31 FT /note="Y->A: Complete loss of EPO-induced STAT5 signaling FT suppression. No effect on LIF-induced STAT3 signaling. FT Abolishes binding to JH1." FT /evidence="ECO:0000269|PubMed:10421843" FT MUTAGEN 31 FT /note="Y->F: Little effect on EPO-induced signaling FT suppression." FT /evidence="ECO:0000269|PubMed:10421843" FT MUTAGEN 34 FT /note="V->E: Complete loss of EPO/LIF-induced signaling FT suppression." FT /evidence="ECO:0000269|PubMed:10421843" FT MUTAGEN 41 FT /note="L->R: Complete loss of EPO/LIF-induced signaling FT inhibition. Abolishes binding to JH1." FT /evidence="ECO:0000269|PubMed:10421843" FT MUTAGEN 45 FT /note="G->A: Little effect on EPO/LIF signaling." FT /evidence="ECO:0000269|PubMed:10421843" FT MUTAGEN 53 FT /note="G->V: No effect on binding to Y429/Y431 FT phosphorylated EPOR." FT /evidence="ECO:0000269|PubMed:12027890" FT MUTAGEN 58 FT /note="L->A: Impaired binding to Y429/Y431 phosphorylated FT EPOR." FT /evidence="ECO:0000269|PubMed:12027890" FT MUTAGEN 71 FT /note="R->E: Complete loss of EPO/LIF-induced signaling FT suppression. No inhibition of JAK2 phosphorylation." FT /evidence="ECO:0000269|PubMed:10421843, FT ECO:0000269|PubMed:14559241" FT MUTAGEN 71 FT /note="R->K: No effect on EPO/LIF-induced signaling FT suppression. Partial suppression of JAK2 phosphorylation. FT No effect on binding to JH1. Loss of binding to IL12RB2." FT /evidence="ECO:0000269|PubMed:10421843, FT ECO:0000269|PubMed:14559241" FT MUTAGEN 93 FT /note="L->A: Impaired binding to Y429/Y431 phosphorylated FT EPOR." FT /evidence="ECO:0000269|PubMed:12027890" FT MUTAGEN 94 FT /note="R->E: Greatly impaired binding to Y429/Y431 FT phosphorylated EPOR." FT /evidence="ECO:0000269|PubMed:12027890" FT CONFLICT 81 FT /note="T -> A (in Ref. 1; BAA22430)" FT /evidence="ECO:0000305" SQ SEQUENCE 225 AA; 24770 MW; 08581DC411EFFF19 CRC64; MVTHSKFPAA GMSRPLDTSL RLKTFSSKSE YQLVVNAVRK LQESGFYWSA VTGGEANLLL SAEPAGTFLI RDSSDQRHFF TLSVKTQSGT KNLRIQCEGG SFSLQSDPRS TQPVPRFDCV LKLVHHYMPP PGAPSFPSPP TEPSSEVPEQ PSAQPLPGSP PRRAYYIYSG GEKIPLVLSR PLSSNVATLQ HLCRKTVNGH LDSYEKVTQL PGPIREFLDQ YDAPL //