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Q62985

- SH2B1_RAT

UniProt

Q62985 - SH2B1_RAT

Protein

SH2B adapter protein 1

Gene

Sh2b1

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 95 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      Previous versions | rss
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    Functioni

    Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases, including the receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1, which in turn is phosphorylated by JAK2 on tyrosine residues. These phosphotyrosines form potential binding sites for other signaling proteins. GH also promotes serine/threonine phosphorylation of SH2B1 and these phosphorylated residues may serve to recruit other proteins to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP) signaling, binds to and potentiates the activation of JAK2 by globally enhancing downstream pathways. In response to leptin, binds simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-kinase pathway. Acts as positive regulator of NGF-mediated activation of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase activity of the cytokine receptor-associated tyrosine kinase JAK2 and of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2, the mechanism seems to involve dimerization of both, SH2B1 and JAK2. Enhances RET phosphorylation and kinase activity. Isoforms seem to be differentially involved in IGF-I and PDGF-induced mitogenesis By similarity.By similarity

    GO - Molecular functioni

    1. protein binding Source: IntAct
    2. signal transducer activity Source: InterPro

    GO - Biological processi

    1. cellular component movement Source: Ensembl
    2. intracellular signal transduction Source: InterPro
    3. lamellipodium assembly Source: Ensembl
    4. positive regulation of mitosis Source: Ensembl
    5. regulation of DNA biosynthetic process Source: Ensembl

    Enzyme and pathway databases

    ReactomeiREACT_195204. Signaling by Leptin.
    REACT_196232. Factors involved in megakaryocyte development and platelet production.
    REACT_196425. Growth hormone receptor signaling.
    REACT_199232. Prolactin receptor signaling.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    SH2B adapter protein 1
    Alternative name(s):
    FceRI gamma-chain-interacting protein SH2-B
    SH2 domain-containing protein 1B
    SH2-B PH domain-containing signaling mediator 1
    Gene namesi
    Name:Sh2b1
    Synonyms:Sh2-b, Sh2bpsm1
    OrganismiRattus norvegicus (Rat)
    Taxonomic identifieri10116 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
    ProteomesiUP000002494: Chromosome 1

    Organism-specific databases

    RGDi620132. Sh2b1.

    Subcellular locationi

    Cytoplasm 1 Publication. Membrane 1 Publication. Nucleus 1 Publication
    Note: Shuttles between the nucleus and the cytoplasm.

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB-SubCell
    2. membrane Source: UniProtKB-SubCell
    3. nucleus Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi96 – 961S → A: Reduces in vitro phosphorylation by MAPK1 and/or MAPK3. 1 Publication
    Mutagenesisi231 – 2311L → A: Abolishes nuclear localization; when associated with A-233. 1 Publication
    Mutagenesisi233 – 2331L → A: Abolishes nuclear localization; when associated with A-231. 1 Publication
    Mutagenesisi439 – 4391Y → F: Fails to enhance GH-induced membrane ruffling; when associated with F-494. 1 Publication
    Mutagenesisi439 – 4391Y → F: Reduces phosphorylation by JAK1, JAK2 and PDGFRA. 1 Publication
    Mutagenesisi494 – 4941Y → F: Fails to enhance GH-induced membrane ruffling; when associated with F-439. 1 Publication
    Mutagenesisi494 – 4941Y → F: Reduces phosphorylation by JAK1 and JAK2. 1 Publication
    Mutagenesisi555 – 5551R → E: Reduces interaction with JAK2 and abolishes JAK2 kinase activity; reduces GH-stimulated cell motility; abolishes interaction with PDGFRA. 2 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 756756SH2B adapter protein 1PRO_0000323611Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei88 – 881PhosphoserineBy similarity
    Modified residuei96 – 961Phosphoserine; by MAPK1 or MAPK3; in vitro1 Publication
    Modified residuei439 – 4391Phosphotyrosine; by JAK1, JAK2 and PDGFR1 Publication
    Modified residuei494 – 4941Phosphotyrosine; by JAK1, JAK21 Publication
    Modified residuei624 – 6241PhosphotyrosineBy similarity

    Post-translational modificationi

    Phosphorylated on tyrosine residues in response to treatment with growth hormone (GH), IFN-gamma (IFNG), BDNF, PDGF and FGF. Phosphorylated on tyrosine residues by JAK2 and JAK1. Phosphorylated on multiple serine and threonine residues in response to treatment with NGF. Phosphorylated on serine residues.5 Publications

    Keywords - PTMi

    Phosphoprotein

    Expressioni

    Tissue specificityi

    Isoform 1 is ubiquitously expressed. Expressed in epididymal adipose tissue, liver and skeletal muscle.1 Publication

    Gene expression databases

    GenevestigatoriQ62985.

    Interactioni

    Subunit structurei

    Self-associates. Homopentamer. Forms a heteromultimeric complex with SH2B2. Interacts with SH2B2. Isoform 1 interacts via its SH2 domain with JAK2. Isoform 2 interacts via its SH2 domain and its N-terminus with JAK2; the SH2 domain is required for the major interaction with JAK2 phosphorylated on tyrosine residues; the N-terminus provides a low-affinity binding to JAK2 independent of JAK2 phosphorylation. Isoform 1 interacts via its SH2 domain with INSR; the interaction requires receptor activation. Isoform 1 interacts with IGF1R; the interaction requires receptor activation. Isoform 2 interacts via its SH2 domain with FGFR3. Isoform 2 interacts with RET; the interaction requires RET kinase activity. Isoform 2 interacts with RAC1. Isoform 2 interacts with PDGFRA and/or PDGFRB; the interaction requires receptor activation. Interacts with ISR1 and ISR2. Probably part of a complex consisting of INSR, ISR1 and SH2B1. Probably part of a ternary complex consisting of SH2B1, JAK2 and ISR1 or ISR2 By similarity. May interact with FCER1G. Interacts (via SH2 domain) with NTRK1 (phosphorylated).By similarity10 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    RETP079493EBI-7395583,EBI-2480756From a different organism.

    Protein-protein interaction databases

    BioGridi250140. 3 interactions.
    IntActiQ62985. 2 interactions.
    MINTiMINT-1528512.

    Structurei

    3D structure databases

    ProteinModelPortaliQ62985.
    SMRiQ62985. Positions 247-381, 520-627.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini247 – 376130PHAdd
    BLAST
    Domaini527 – 62599SH2PROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni1 – 555555Interaction with JAK2 (low-affinity binding; independent of JAK2 phosphorylation)Add
    BLAST
    Regioni24 – 8562Required for self-associationBy similarityAdd
    BLAST
    Regioni85 – 196112Interaction with RAC1Add
    BLAST
    Regioni100 – 243144Required for NGF signalingAdd
    BLAST
    Regioni224 – 23310Required for nuclear localization

    Sequence similaritiesi

    Belongs to the SH2B adapter family.Curated
    Contains 1 PH domain.Curated
    Contains 1 SH2 domain.PROSITE-ProRule annotation

    Keywords - Domaini

    SH2 domain

    Phylogenomic databases

    GeneTreeiENSGT00530000063355.
    HOVERGENiHBG006707.
    KOiK12459.
    OMAiQEPNTSH.
    PhylomeDBiQ62985.

    Family and domain databases

    Gene3Di2.30.29.30. 1 hit.
    3.30.505.10. 1 hit.
    InterProiIPR001849. PH_domain.
    IPR011993. PH_like_dom.
    IPR015012. Phe_ZIP.
    IPR000980. SH2.
    [Graphical view]
    PfamiPF00169. PH. 1 hit.
    PF08916. Phe_ZIP. 1 hit.
    PF00017. SH2. 1 hit.
    [Graphical view]
    PRINTSiPR00401. SH2DOMAIN.
    SMARTiSM00233. PH. 1 hit.
    SM00252. SH2. 1 hit.
    [Graphical view]
    SUPFAMiSSF109805. SSF109805. 1 hit.
    SSF55550. SSF55550. 1 hit.
    PROSITEiPS50001. SH2. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: Q62985-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MNGAPSPEDG VFPSPPALPP PPPPSWQEFC ESHARAAALD LARRFRLYLA    50
    SHPQYAEPGA EAAFSGRFAE LFLQHFEAEV ARASGSLSPP VLAPLSPGVE 100
    IPPSHDLSLE SCRVGGPLAV LGPSRSSEDL AGPLPSSVSS STTSSKPKLK 150
    KRFSLRSVGR SVRGSVRGIL QWRGAVESPS QAGPLETTSG PPVLGGNSNS 200
    NSSGGAGTVG RALANDGTSP GERWTHRFER LRLSRGGGTL RDGAGVIQRE 250
    ELLSFMGAEE AAPDPAGVGR GGGAAGLTSG GGGQPQWQKC RLLLRSEGEG 300
    GGGSRLEFFV PPKASRPRLS IPCSTITDVR TATALEMPDR ENTFVVKVEG 350
    PSEYILETTD ALHVKAWVSD IQECLSPGPC PAISPRPMTL PLAPGTSFLT 400
    KDNTESLELP CLNHSESLPS QDLLLGPSES NDRLSQGAYG GLSDRPSASF 450
    SPSSASIAAS HFDSMELLPP ELPPRIPIEE GPPAGTVHPL STPYPPLDTP 500
    EAATGSFLFQ GEAEGGEGDQ PLSGYPWFHG MLSRLKAAQL VLEGGTSSHG 550
    VFLVRQSETR RGEYVLTFNF QGKAKHLRLS LNEEGQCRVQ HLWFQSIFDM 600
    LEHFRVHPIP LESGGSSDVV LVSYVPSQRQ QERSTSRDPT QPSEPPPWTD 650
    PPHPGAEEAS GAPEVAAATA AAAKERQEKE KAGGGGVQEE LVPMAELVPM 700
    AELEEAIAPG TEAQGGAGSS GDLEVSLMVQ LQQLPLGGNG EEGGHPRAIN 750
    NQYSFV 756
    Length:756
    Mass (Da):79,637
    Last modified:November 1, 1996 - v1
    Checksum:iD4FCF3086CF3DFE0
    GO
    Isoform 2 (identifier: Q62985-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         632-756: ERSTSRDPTQ...RAINNQYSFV → GREQAGSHAG...ASDCVTEHFP

    Show »
    Length:670
    Mass (Da):70,931
    Checksum:i868D9F7591C5E36D
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti211 – 2111R → K in AAC04575. (PubMed:9343427)Curated

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei632 – 756125ERSTS…QYSFV → GREQAGSHAGVCEGDRCYPD ASSTFLPFGASDCVTEHFP in isoform 2. 1 PublicationVSP_032045Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U57391 mRNA. Translation: AAC52601.1.
    AF047577 mRNA. Translation: AAC04575.1.
    RefSeqiNP_001041645.1. NM_001048180.1.
    NP_604451.2. NM_134456.3. [Q62985-1]
    XP_006230415.1. XM_006230353.1. [Q62985-1]
    XP_006230416.1. XM_006230354.1. [Q62985-1]
    UniGeneiRn.11069.

    Genome annotation databases

    EnsembliENSRNOT00000074274; ENSRNOP00000066048; ENSRNOG00000049181. [Q62985-1]
    GeneIDi89817.
    KEGGirno:89817.

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U57391 mRNA. Translation: AAC52601.1 .
    AF047577 mRNA. Translation: AAC04575.1 .
    RefSeqi NP_001041645.1. NM_001048180.1.
    NP_604451.2. NM_134456.3. [Q62985-1 ]
    XP_006230415.1. XM_006230353.1. [Q62985-1 ]
    XP_006230416.1. XM_006230354.1. [Q62985-1 ]
    UniGenei Rn.11069.

    3D structure databases

    ProteinModelPortali Q62985.
    SMRi Q62985. Positions 247-381, 520-627.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 250140. 3 interactions.
    IntActi Q62985. 2 interactions.
    MINTi MINT-1528512.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSRNOT00000074274 ; ENSRNOP00000066048 ; ENSRNOG00000049181 . [Q62985-1 ]
    GeneIDi 89817.
    KEGGi rno:89817.

    Organism-specific databases

    CTDi 25970.
    RGDi 620132. Sh2b1.

    Phylogenomic databases

    GeneTreei ENSGT00530000063355.
    HOVERGENi HBG006707.
    KOi K12459.
    OMAi QEPNTSH.
    PhylomeDBi Q62985.

    Enzyme and pathway databases

    Reactomei REACT_195204. Signaling by Leptin.
    REACT_196232. Factors involved in megakaryocyte development and platelet production.
    REACT_196425. Growth hormone receptor signaling.
    REACT_199232. Prolactin receptor signaling.

    Miscellaneous databases

    NextBioi 617706.
    PROi Q62985.

    Gene expression databases

    Genevestigatori Q62985.

    Family and domain databases

    Gene3Di 2.30.29.30. 1 hit.
    3.30.505.10. 1 hit.
    InterProi IPR001849. PH_domain.
    IPR011993. PH_like_dom.
    IPR015012. Phe_ZIP.
    IPR000980. SH2.
    [Graphical view ]
    Pfami PF00169. PH. 1 hit.
    PF08916. Phe_ZIP. 1 hit.
    PF00017. SH2. 1 hit.
    [Graphical view ]
    PRINTSi PR00401. SH2DOMAIN.
    SMARTi SM00233. PH. 1 hit.
    SM00252. SH2. 1 hit.
    [Graphical view ]
    SUPFAMi SSF109805. SSF109805. 1 hit.
    SSF55550. SSF55550. 1 hit.
    PROSITEi PS50001. SH2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "The yeast tribrid system -- genetic detection of trans-phosphorylated ITAM-SH2-interactions."
      Osborne M.A., Dalton S., Kochan J.P.
      Biotechnology (N.Y.) 13:1474-1478(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH FCER1G.
      Tissue: Mast cell.
    2. "Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling."
      Rui L., Mathews L.S., Hotta K., Gustafson T.A., Carter-Su C.
      Mol. Cell. Biol. 17:6633-6644(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, PHOSPHORYLATION, INTERACTION WITH JAK2.
      Tissue: Kidney.
    3. "SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase."
      Kotani K., Wilden P., Pillay T.S.
      Biochem. J. 335:103-109(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY.
    4. "Platelet-derived growth factor (PDGF) stimulates the association of SH2-Bbeta with PDGF receptor and phosphorylation of SH2-Bbeta."
      Rui L., Carter-Su C.
      J. Biol. Chem. 273:21239-21245(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PDGFRA/B.
    5. "Identification and characterization of novel substrates of Trk receptors in developing neurons."
      Qian X., Riccio A., Zhang Y., Ginty D.D.
      Neuron 21:1017-1029(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN NGF SIGNALING, INTERACTION WITH NTRK1, PHOSPHORYLATION.
    6. "SH2-B, a membrane-associated adapter, is phosphorylated on multiple serines/threonines in response to nerve growth factor by kinases within the MEK/ERK cascade."
      Rui L., Herrington J., Carter-Su C.
      J. Biol. Chem. 274:26485-26492(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN NGF SIGNALING, PHOSPHORYLATION AT SER-96, MUTAGENESIS OF SER-96.
    7. "Identification of SH2-bbeta as a potent cytoplasmic activator of the tyrosine kinase Janus kinase 2."
      Rui L., Carter-Su C.
      Proc. Natl. Acad. Sci. U.S.A. 96:7172-7177(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN JAK2 ACTIVATION, MUTAGENESIS OF ARG-555.
    8. "Differential binding to and regulation of JAK2 by the SH2 domain and N-terminal region of SH2-bbeta."
      Rui L., Gunter D.R., Herrington J., Carter-Su C.
      Mol. Cell. Biol. 20:3168-3177(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH JAK2, MUTAGENESIS OF ARG-555.
    9. "SH2-B and APS are multimeric adapters that augment TrkA signaling."
      Qian X., Ginty D.D.
      Mol. Cell. Biol. 21:1613-1620(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBUNIT, INTERACTION WITH SH2B2.
    10. "SH2-B family members differentially regulate JAK family tyrosine kinases."
      O'Brien K.B., O'Shea J.J., Carter-Su C.
      J. Biol. Chem. 277:8673-8681(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH JAK1; JAK2 AND JAK3, PHOSPHORYLATION.
    11. "SH2-Bbeta is a Rac-binding protein that regulates cell motility."
      Diakonova M., Gunter D.R., Herrington J., Carter-Su C.
      J. Biol. Chem. 277:10669-10677(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN ACTIN REORGANIZATION, INTERACTION WITH RAC1.
    12. "Interaction of fibroblast growth factor receptor 3 and the adapter protein SH2-B. A role in STAT5 activation."
      Kong M., Wang C.S., Donoghue D.J.
      J. Biol. Chem. 277:15962-15970(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH FGFR3.
    13. "YXXL motifs in SH2-Bbeta are phosphorylated by JAK2, JAK1, and platelet-derived growth factor receptor and are required for membrane ruffling."
      O'Brien K.B., Argetsinger L.S., Diakonova M., Carter-Su C.
      J. Biol. Chem. 278:11970-11978(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT TYR-439 AND TYR-494, MUTAGENESIS OF TYR-439 AND TYR-494.
    14. "Adapter protein SH2-B beta undergoes nucleocytoplasmic shuttling: implications for nerve growth factor induction of neuronal differentiation."
      Chen L., Carter-Su C.
      Mol. Cell. Biol. 24:3633-3647(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, MUTAGENESIS OF LEU-231 AND LEU-233.
    15. "Interaction of SH2-Bbeta with RET is involved in signaling of GDNF-induced neurite outgrowth."
      Zhang Y., Zhu W., Wang Y.G., Liu X.J., Jiao L., Liu X., Zhang Z.H., Lu C.L., He C.
      J. Cell Sci. 119:1666-1676(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN GDNF SIGNALING, INTERACTION WITH RET.

    Entry informationi

    Entry nameiSH2B1_RAT
    AccessioniPrimary (citable) accession number: Q62985
    Secondary accession number(s): O55072
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: March 18, 2008
    Last sequence update: November 1, 1996
    Last modified: October 1, 2014
    This is version 95 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3