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O14543

- SOCS3_HUMAN

UniProt

O14543 - SOCS3_HUMAN

Protein

Suppressor of cytokine signaling 3

Gene

SOCS3

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 129 (01 Oct 2014)
      Sequence version 1 (01 Jan 1998)
      Previous versions | rss
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    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

    Pathwayi

    GO - Molecular functioni

    1. protein binding Source: IntAct
    2. protein kinase inhibitor activity Source: ProtInc

    GO - Biological processi

    1. branching involved in labyrinthine layer morphogenesis Source: Ensembl
    2. cytokine-mediated signaling pathway Source: Reactome
    3. interferon-gamma-mediated signaling pathway Source: Reactome
    4. JAK-STAT cascade Source: ProtInc
    5. JAK-STAT cascade involved in growth hormone signaling pathway Source: Reactome
    6. negative regulation of apoptotic process Source: ProtInc
    7. negative regulation of insulin receptor signaling pathway Source: Ensembl
    8. negative regulation of protein kinase activity Source: GOC
    9. placenta blood vessel development Source: Ensembl
    10. positive regulation of cell differentiation Source: Ensembl
    11. protein ubiquitination Source: UniProtKB-UniPathway
    12. regulation of growth Source: UniProtKB-KW
    13. regulation of interferon-gamma-mediated signaling pathway Source: Reactome
    14. regulation of type I interferon-mediated signaling pathway Source: Reactome
    15. spongiotrophoblast differentiation Source: Ensembl
    16. trophoblast giant cell differentiation Source: Ensembl
    17. type I interferon signaling pathway Source: Reactome

    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_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: Chromosome 17

    Organism-specific databases

    HGNCiHGNC:19391. SOCS3.

    Subcellular locationi

    GO - Cellular componenti

    1. cytosol Source: Reactome

    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

    ArrayExpressiO14543.
    BgeeiO14543.
    CleanExiHS_SOCS3.
    GenevestigatoriO14543.

    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. 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. Interacts with BCL10; this interaction may interfere with BCL10-binding with PELI2 By similarity.By similarity

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    GAB1Q134804EBI-714146,EBI-517684
    KITP107213EBI-714146,EBI-1379503
    MAP1SQ66K746EBI-714146,EBI-2133734

    Protein-protein interaction databases

    BioGridi114488. 68 interactions.
    IntActiO14543. 28 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

    MVTHSKFPAA GMSRPLDTSL RLKTFSSKSE YQLVVNAVRK LQESGFYWSA    50
    VTGGEANLLL SAEPAGTFLI RDSSDQRHFF TLSVKTQSGT KNLRIQCEGG 100
    SFSLQSDPRS TQPVPRFDCV LKLVHHYMPP PGAPSFPSPP TEPSSEVPEQ 150
    PSAQPLPGSP PRRAYYIYSG GEKIPLVLSR PLSSNVATLQ HLCRKTVNGH 200
    LDSYEKVTQL PGPIREFLDQ YDAPL 225
    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:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AB004904 mRNA. Translation: BAA22430.1 .
    AB006967 mRNA. Translation: BAA22537.1 .
    AF159854 mRNA. Translation: AAD42231.1 .
    BC060858 mRNA. Translation: AAH60858.1 .
    CCDSi CCDS11756.1.
    PIRi JC5627.
    JC5761.
    RefSeqi NP_003946.3. NM_003955.4.
    UniGenei Hs.527973.
    Hs.703620.

    3D structure databases

    ProteinModelPortali O14543.
    SMRi O14543. Positions 30-185.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 114488. 68 interactions.
    IntActi O14543. 28 interactions.
    MINTi MINT-149732.
    STRINGi 9606.ENSP00000330341.

    PTM databases

    PhosphoSitei O14543.

    Proteomic databases

    PaxDbi O14543.
    PRIDEi O14543.

    Protocols and materials databases

    DNASUi 9021.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000330871 ; ENSP00000330341 ; ENSG00000184557 .
    GeneIDi 9021.
    KEGGi hsa:9021.
    UCSCi uc002jvl.2. human.

    Organism-specific databases

    CTDi 9021.
    GeneCardsi GC17M076352.
    HGNCi HGNC:19391. SOCS3.
    HPAi CAB012220.
    MIMi 604176. gene.
    neXtProti NX_O14543.
    PharmGKBi PA134885765.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG281730.
    HOGENOMi HOG000236320.
    HOVERGENi HBG105645.
    InParanoidi O14543.
    KOi K04696.
    OMAi KRTYYIY.
    PhylomeDBi O14543.
    TreeFami TF321368.

    Enzyme and pathway databases

    UniPathwayi UPA00143 .
    Reactomei REACT_111133. Growth hormone receptor signaling.
    REACT_169118. Signaling by Leptin.
    REACT_24980. Regulation of IFNG signaling.
    REACT_25078. Interferon gamma signaling.
    REACT_25216. Regulation of IFNA signaling.
    REACT_27307. Interleukin-6 signaling.
    REACT_75842. Antigen processing: Ubiquitination & Proteasome degradation.
    SignaLinki O14543.

    Miscellaneous databases

    GeneWikii SOCS3.
    GenomeRNAii 9021.
    NextBioi 33797.
    PROi O14543.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O14543.
    Bgeei O14543.
    CleanExi HS_SOCS3.
    Genevestigatori O14543.

    Family and domain databases

    Gene3Di 3.30.505.10. 2 hits.
    InterProi IPR000980. SH2.
    IPR028413. SOCS.
    IPR028414. SOCS3.
    IPR001496. SOCS_C.
    [Graphical view ]
    PANTHERi PTHR10385. PTHR10385. 1 hit.
    PTHR10385:SF4. PTHR10385:SF4. 1 hit.
    Pfami PF00017. SH2. 1 hit.
    PF07525. SOCS_box. 1 hit.
    [Graphical view ]
    SMARTi SM00252. SH2. 1 hit.
    SM00253. SOCS. 1 hit.
    SM00969. SOCS_box. 1 hit.
    [Graphical view ]
    SUPFAMi SSF55550. SSF55550. 1 hit.
    PROSITEi PS50001. SH2. 1 hit.
    PS50225. SOCS. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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.

    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: October 1, 2014
    This is version 129 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