SH2B adapter protein 1 (FceRI gamma-chain-interacting protein SH2-B) (SH2 domain-containing protein 1B) (SH2-B PH domain-containing signaling mediator 1)

 SH2B1_RAT               Reviewed;         756 AA.
 Q62985; O55072;
 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
 01-NOV-1996, sequence version 1.
 22-APR-2020, entry version 136.
 RecName: Full=SH2B adapter protein 1;
 AltName: Full=FceRI gamma-chain-interacting protein SH2-B;
 AltName: Full=SH2 domain-containing protein 1B;
 AltName: Full=SH2-B PH domain-containing signaling mediator 1;
 Name=Sh2b1; Synonyms=Sh2-b, Sh2bpsm1;
 Rattus norvegicus (Rat).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
 Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
 Murinae; Rattus.
 NCBI_TaxID=10116;
 [1]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND INTERACTION WITH FCER1G.
 TISSUE=Mast cell;
 PubMed=9636306; DOI=10.1038/nbt1295-1474;
 Osborne M.A., Dalton S., Kochan J.P.;
 "The yeast tribrid system -- genetic detection of trans-phosphorylated
 ITAM-SH2-interactions.";
 Biotechnology (N.Y.) 13:1474-1478(1995).
 [2]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, PHOSPHORYLATION, AND
 INTERACTION WITH JAK2.
 TISSUE=Kidney;
 PubMed=9343427; DOI=10.1128/mcb.17.11.6633;
 Rui L., Mathews L.S., Hotta K., Gustafson T.A., Carter-Su C.;
 "Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2
 involved in growth hormone signaling.";
 Mol. Cell. Biol. 17:6633-6644(1997).
 [3]
 TISSUE SPECIFICITY.
 PubMed=9742218; DOI=10.1042/bj3350103;
 Kotani K., Wilden P., Pillay T.S.;
 "SH2-Balpha is an insulin-receptor adapter protein and substrate that
 interacts with the activation loop of the insulin-receptor kinase.";
 Biochem. J. 335:103-109(1998).
 [4]
 INTERACTION WITH PDGFRA/B.
 PubMed=9694882; DOI=10.1074/jbc.273.33.21239;
 Rui L., Carter-Su C.;
 "Platelet-derived growth factor (PDGF) stimulates the association of SH2-
 Bbeta with PDGF receptor and phosphorylation of SH2-Bbeta.";
 J. Biol. Chem. 273:21239-21245(1998).
 [5]
 FUNCTION IN NGF SIGNALING, INTERACTION WITH NTRK1, AND PHOSPHORYLATION.
 PubMed=9856458; DOI=10.1016/s0896-6273(00)80620-0;
 Qian X., Riccio A., Zhang Y., Ginty D.D.;
 "Identification and characterization of novel substrates of Trk receptors
 in developing neurons.";
 Neuron 21:1017-1029(1998).
 [6]
 FUNCTION IN NGF SIGNALING, PHOSPHORYLATION AT SER-96, AND MUTAGENESIS OF
 SER-96.
 PubMed=10473609; DOI=10.1074/jbc.274.37.26485;
 Rui L., Herrington J., Carter-Su C.;
 "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.";
 J. Biol. Chem. 274:26485-26492(1999).
 [7]
 FUNCTION IN JAK2 ACTIVATION, AND MUTAGENESIS OF ARG-555.
 PubMed=10377387; DOI=10.1073/pnas.96.13.7172;
 Rui L., Carter-Su C.;
 "Identification of SH2-bbeta as a potent cytoplasmic activator of the
 tyrosine kinase Janus kinase 2.";
 Proc. Natl. Acad. Sci. U.S.A. 96:7172-7177(1999).
 [8]
 FUNCTION, INTERACTION WITH JAK2, AND MUTAGENESIS OF ARG-555.
 PubMed=10757801; DOI=10.1128/mcb.20.9.3168-3177.2000;
 Rui L., Gunter D.R., Herrington J., Carter-Su C.;
 "Differential binding to and regulation of JAK2 by the SH2 domain and N-
 terminal region of SH2-bbeta.";
 Mol. Cell. Biol. 20:3168-3177(2000).
 [9]
 FUNCTION, SUBUNIT, AND INTERACTION WITH SH2B2.
 PubMed=11238898; DOI=10.1128/mcb.21.5.1613-1620.2001;
 Qian X., Ginty D.D.;
 "SH2-B and APS are multimeric adapters that augment TrkA signaling.";
 Mol. Cell. Biol. 21:1613-1620(2001).
 [10]
 INTERACTION WITH JAK1; JAK2 AND JAK3, AND PHOSPHORYLATION.
 PubMed=11751854; DOI=10.1074/jbc.m109165200;
 O'Brien K.B., O'Shea J.J., Carter-Su C.;
 "SH2-B family members differentially regulate JAK family tyrosine
 kinases.";
 J. Biol. Chem. 277:8673-8681(2002).
 [11]
 FUNCTION IN ACTIN REORGANIZATION, AND INTERACTION WITH RAC1.
 PubMed=11786545; DOI=10.1074/jbc.m111138200;
 Diakonova M., Gunter D.R., Herrington J., Carter-Su C.;
 "SH2-Bbeta is a Rac-binding protein that regulates cell motility.";
 J. Biol. Chem. 277:10669-10677(2002).
 [12]
 INTERACTION WITH FGFR3.
 PubMed=11827956; DOI=10.1074/jbc.m102777200;
 Kong M., Wang C.S., Donoghue D.J.;
 "Interaction of fibroblast growth factor receptor 3 and the adapter protein
 SH2-B. A role in STAT5 activation.";
 J. Biol. Chem. 277:15962-15970(2002).
 [13]
 PHOSPHORYLATION AT TYR-439 AND TYR-494, AND MUTAGENESIS OF TYR-439 AND
 TYR-494.
 PubMed=12551917; DOI=10.1074/jbc.m210765200;
 O'Brien K.B., Argetsinger L.S., Diakonova M., Carter-Su C.;
 "YXXL motifs in SH2-Bbeta are phosphorylated by JAK2, JAK1, and platelet-
 derived growth factor receptor and are required for membrane ruffling.";
 J. Biol. Chem. 278:11970-11978(2003).
 [14]
 SUBCELLULAR LOCATION, AND MUTAGENESIS OF LEU-231 AND LEU-233.
 PubMed=15082760; DOI=10.1128/mcb.24.9.3633-3647.2004;
 Chen L., Carter-Su C.;
 "Adapter protein SH2-B beta undergoes nucleocytoplasmic shuttling:
 implications for nerve growth factor induction of neuronal
 differentiation.";
 Mol. Cell. Biol. 24:3633-3647(2004).
 [15]
 FUNCTION IN GDNF SIGNALING, AND INTERACTION WITH RET.
 PubMed=16569669; DOI=10.1242/jcs.02845;
 Zhang Y., Zhu W., Wang Y.G., Liu X.J., Jiao L., Liu X., Zhang Z.H.,
 Lu C.L., He C.;
 "Interaction of SH2-Bbeta with RET is involved in signaling of GDNF-induced
 neurite outgrowth.";
 J. Cell Sci. 119:1666-1676(2006).
 [16]
 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 PubMed=22673903; DOI=10.1038/ncomms1871;
 Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
 Olsen J.V.;
 "Quantitative maps of protein phosphorylation sites across 14 different rat
 organs and tissues.";
 Nat. Commun. 3:876-876(2012).
 -!- FUNCTION: 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). {ECO:0000250, ECO:0000269|PubMed:10377387,
     ECO:0000269|PubMed:10473609, ECO:0000269|PubMed:10757801,
     ECO:0000269|PubMed:11238898, ECO:0000269|PubMed:11786545,
     ECO:0000269|PubMed:16569669, ECO:0000269|PubMed:9343427,
     ECO:0000269|PubMed:9856458}.
 -!- SUBUNIT: 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). {ECO:0000250, ECO:0000269|PubMed:10757801,
     ECO:0000269|PubMed:11238898, ECO:0000269|PubMed:11751854,
     ECO:0000269|PubMed:11786545, ECO:0000269|PubMed:11827956,
     ECO:0000269|PubMed:16569669, ECO:0000269|PubMed:9343427,
     ECO:0000269|PubMed:9636306, ECO:0000269|PubMed:9694882,
     ECO:0000269|PubMed:9856458}.
 -!- INTERACTION:
     Q62985; P07949: RET; Xeno; NbExp=3; IntAct=EBI-7395583, EBI-2480756;
 -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15082760}. Membrane
     {ECO:0000305|PubMed:15082760}. Nucleus {ECO:0000269|PubMed:15082760}.
     Note=Shuttles between the nucleus and the cytoplasm.
 -!- ALTERNATIVE PRODUCTS:
     Event=Alternative splicing; Named isoforms=2;
     Name=1;
       IsoId=Q62985-1; Sequence=Displayed;
     Name=2;
       IsoId=Q62985-2; Sequence=VSP_032045;
 -!- TISSUE SPECIFICITY: Isoform 1 is ubiquitously expressed. Expressed in
     epididymal adipose tissue, liver and skeletal muscle.
     {ECO:0000269|PubMed:9742218}.
 -!- PTM: 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. {ECO:0000269|PubMed:10473609,
     ECO:0000269|PubMed:11751854, ECO:0000269|PubMed:12551917,
     ECO:0000269|PubMed:9343427, ECO:0000269|PubMed:9856458}.
 -!- SIMILARITY: Belongs to the SH2B adapter family. {ECO:0000305}.
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 EMBL; U57391; AAC52601.1; -; mRNA.
 EMBL; AF047577; AAC04575.1; -; mRNA.
 RefSeq; NP_001041645.1; NM_001048180.1.
 RefSeq; NP_604451.2; NM_134456.3. [Q62985-1]
 RefSeq; XP_006230415.1; XM_006230353.3. [Q62985-1]
 RefSeq; XP_006230416.1; XM_006230354.3. [Q62985-1]
 SMR; Q62985; -.
 BioGrid; 250140; 5.
 IntAct; Q62985; 37.
 MINT; Q62985; -.
 STRING; 10116.ENSRNOP00000066048; -.
 iPTMnet; Q62985; -.
 PaxDb; Q62985; -.
 PRIDE; Q62985; -.
 Ensembl; ENSRNOT00000074274; ENSRNOP00000066048; ENSRNOG00000049181. [Q62985-1]
 GeneID; 89817; -.
 KEGG; rno:89817; -.
 CTD; 25970; -.
 RGD; 620132; Sh2b1.
 eggNOG; ENOG410IMWK; Eukaryota.
 eggNOG; ENOG41102PH; LUCA.
 GeneTree; ENSGT00950000183191; -.
 InParanoid; Q62985; -.
 KO; K12459; -.
 OMA; MLEHFRM; -.
 OrthoDB; 556279at2759; -.
 PhylomeDB; Q62985; -.
 Reactome; R-RNO-1170546; Prolactin receptor signaling.
 Reactome; R-RNO-982772; Growth hormone receptor signaling.
 Reactome; R-RNO-983231; Factors involved in megakaryocyte development and platelet production.
 PRO; PR:Q62985; -.
 Proteomes; UP000002494; Chromosome 1.
 Bgee; ENSRNOG00000049181; Expressed in skeletal muscle tissue and 9 other tissues.
 ExpressionAtlas; Q62985; baseline and differential.
 Genevisible; Q62985; RN.
 GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
 GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
 GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
 GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; IBA:GO_Central.
 GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
 GO; GO:0030032; P:lamellipodium assembly; ISO:RGD.
 GO; GO:0045840; P:positive regulation of mitotic nuclear division; ISO:RGD.
 GO; GO:0060391; P:positive regulation of SMAD protein signal transduction; IEA:Ensembl.
 GO; GO:2000278; P:regulation of DNA biosynthetic process; ISO:RGD.
 CDD; cd10346; SH2_SH2B_family; 1.
 Gene3D; 2.30.29.30; -; 1.
 Gene3D; 3.30.505.10; -; 1.
 InterPro; IPR011993; PH-like_dom_sf.
 InterPro; IPR001849; PH_domain.
 InterPro; IPR015012; Phe_ZIP.
 InterPro; IPR036290; Phe_ZIP_sf.
 InterPro; IPR000980; SH2.
 InterPro; IPR036860; SH2_dom_sf.
 InterPro; IPR030523; SH2B.
 InterPro; IPR030521; SH2B1.
 InterPro; IPR035057; SH2B1_SH2.
 PANTHER; PTHR10872; PTHR10872; 1.
 PANTHER; PTHR10872:SF3; PTHR10872:SF3; 1.
 Pfam; PF00169; PH; 1.
 Pfam; PF08916; Phe_ZIP; 1.
 Pfam; PF00017; SH2; 1.
 PRINTS; PR00401; SH2DOMAIN.
 SMART; SM00233; PH; 1.
 SMART; SM00252; SH2; 1.
 SUPFAM; SSF109805; SSF109805; 1.
 SUPFAM; SSF55550; SSF55550; 1.
 PROSITE; PS50001; SH2; 1.
 1: Evidence at protein level;
 Alternative splicing; Cytoplasm; Membrane; Methylation; Nucleus;
 Phosphoprotein; Reference proteome; SH2 domain.
 CHAIN           1..756
                 /note="SH2B adapter protein 1"
                 /id="PRO_0000323611"
 DOMAIN          247..376
                 /note="PH"
 DOMAIN          527..625
                 /note="SH2"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
 REGION          1..555
                 /note="Interaction with JAK2 (low-affinity binding;
                 independent of JAK2 phosphorylation)"
 REGION          24..85
                 /note="Required for self-association"
                 /evidence="ECO:0000250"
 REGION          85..196
                 /note="Interaction with RAC1"
                 /evidence="ECO:0000269|PubMed:11786545"
 REGION          100..243
                 /note="Required for NGF signaling"
 REGION          224..233
                 /note="Required for nuclear localization"
 MOD_RES         88
                 /note="Phosphoserine"
                 /evidence="ECO:0000250|UniProtKB:Q91ZM2"
 MOD_RES         96
                 /note="Phosphoserine; by MAPK1 or MAPK3; in vitro"
                 /evidence="ECO:0000269|PubMed:10473609"
 MOD_RES         270
                 /note="Omega-N-methylarginine"
                 /evidence="ECO:0000250|UniProtKB:Q9NRF2"
 MOD_RES         417
                 /note="Phosphoserine"
                 /evidence="ECO:0000250|UniProtKB:Q91ZM2"
 MOD_RES         420
                 /note="Phosphoserine"
                 /evidence="ECO:0000250|UniProtKB:Q91ZM2"
 MOD_RES         439
                 /note="Phosphotyrosine; by JAK1, JAK2 and PDGFR"
                 /evidence="ECO:0000269|PubMed:12551917"
 MOD_RES         494
                 /note="Phosphotyrosine; by JAK1, JAK2"
                 /evidence="ECO:0000269|PubMed:12551917"
 VAR_SEQ         632..756
                 /note="ERSTSRDPTQPSEPPPWTDPPHPGAEEASGAPEVAAATAAAAKERQEKEKAG
                 GGGVQEELVPMAELVPMAELEEAIAPGTEAQGGAGSSGDLEVSLMVQLQQLPLGGNGEE
                 GGHPRAINNQYSFV -> GREQAGSHAGVCEGDRCYPDASSTFLPFGASDCVTEHFP
                 (in isoform 2)"
                 /evidence="ECO:0000303|PubMed:9343427"
                 /id="VSP_032045"
 MUTAGEN         96
                 /note="S->A: Reduces in vitro phosphorylation by MAPK1
                 and/or MAPK3."
                 /evidence="ECO:0000269|PubMed:10473609"
 MUTAGEN         231
                 /note="L->A: Abolishes nuclear localization; when
                 associated with A-233."
                 /evidence="ECO:0000269|PubMed:15082760"
 MUTAGEN         233
                 /note="L->A: Abolishes nuclear localization; when
                 associated with A-231."
                 /evidence="ECO:0000269|PubMed:15082760"
 MUTAGEN         439
                 /note="Y->F: Fails to enhance GH-induced membrane ruffling;
                 when associated with F-494."
                 /evidence="ECO:0000269|PubMed:12551917"
 MUTAGEN         439
                 /note="Y->F: Reduces phosphorylation by JAK1, JAK2 and
                 PDGFRA."
                 /evidence="ECO:0000269|PubMed:12551917"
 MUTAGEN         494
                 /note="Y->F: Fails to enhance GH-induced membrane ruffling;
                 when associated with F-439."
                 /evidence="ECO:0000269|PubMed:12551917"
 MUTAGEN         494
                 /note="Y->F: Reduces phosphorylation by JAK1 and JAK2."
                 /evidence="ECO:0000269|PubMed:12551917"
 MUTAGEN         555
                 /note="R->E: Reduces interaction with JAK2 and abolishes
                 JAK2 kinase activity; reduces GH-stimulated cell motility;
                 abolishes interaction with PDGFRA."
                 /evidence="ECO:0000269|PubMed:10377387,
                 ECO:0000269|PubMed:10757801"
 CONFLICT        211
                 /note="R -> K (in Ref. 2; AAC04575)"
                 /evidence="ECO:0000305"
 SEQUENCE   756 AA;  79637 MW;  D4FCF3086CF3DFE0 CRC64;
 MNGAPSPEDG VFPSPPALPP PPPPSWQEFC ESHARAAALD LARRFRLYLA SHPQYAEPGA
 EAAFSGRFAE LFLQHFEAEV ARASGSLSPP VLAPLSPGVE IPPSHDLSLE SCRVGGPLAV
 LGPSRSSEDL AGPLPSSVSS STTSSKPKLK KRFSLRSVGR SVRGSVRGIL QWRGAVESPS
 QAGPLETTSG PPVLGGNSNS NSSGGAGTVG RALANDGTSP GERWTHRFER LRLSRGGGTL
 RDGAGVIQRE ELLSFMGAEE AAPDPAGVGR GGGAAGLTSG GGGQPQWQKC RLLLRSEGEG
 GGGSRLEFFV PPKASRPRLS IPCSTITDVR TATALEMPDR ENTFVVKVEG PSEYILETTD
 ALHVKAWVSD IQECLSPGPC PAISPRPMTL PLAPGTSFLT KDNTESLELP CLNHSESLPS
 QDLLLGPSES NDRLSQGAYG GLSDRPSASF SPSSASIAAS HFDSMELLPP ELPPRIPIEE
 GPPAGTVHPL STPYPPLDTP EAATGSFLFQ GEAEGGEGDQ PLSGYPWFHG MLSRLKAAQL
 VLEGGTSSHG VFLVRQSETR RGEYVLTFNF QGKAKHLRLS LNEEGQCRVQ HLWFQSIFDM
 LEHFRVHPIP LESGGSSDVV LVSYVPSQRQ QERSTSRDPT QPSEPPPWTD PPHPGAEEAS
 GAPEVAAATA AAAKERQEKE KAGGGGVQEE LVPMAELVPM AELEEAIAPG TEAQGGAGSS
 GDLEVSLMVQ LQQLPLGGNG EEGGHPRAIN NQYSFV

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