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.
 16-OCT-2019, entry version 133.
 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:
     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; 2.
 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 10 organ(s), highest expression level in skeletal muscle tissue.
 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; IEA:Ensembl.
 GO; GO:0045840; P:positive regulation of mitotic nuclear division; IEA:Ensembl.
 GO; GO:2000278; P:regulation of DNA biosynthetic process; IEA:Ensembl.
 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; Complete proteome; Cytoplasm; Membrane;
 Methylation; Nucleus; Phosphoprotein; Reference proteome; SH2 domain.
 CHAIN         1    756       SH2B adapter protein 1.
                              /FTId=PRO_0000323611.
 DOMAIN      247    376       PH.
 DOMAIN      527    625       SH2. {ECO:0000255|PROSITE-
                              ProRule:PRU00191}.
 REGION        1    555       Interaction with JAK2 (low-affinity
                              binding; independent of JAK2
                              phosphorylation).
 REGION       24     85       Required for self-association.
                              {ECO:0000250}.
 REGION       85    196       Interaction with RAC1.
                              {ECO:0000269|PubMed:11786545}.
 REGION      100    243       Required for NGF signaling.
 REGION      224    233       Required for nuclear localization.
 MOD_RES      88     88       Phosphoserine.
                              {ECO:0000250|UniProtKB:Q91ZM2}.
 MOD_RES      96     96       Phosphoserine; by MAPK1 or MAPK3; in
                              vitro. {ECO:0000269|PubMed:10473609}.
 MOD_RES     270    270       Omega-N-methylarginine.
                              {ECO:0000250|UniProtKB:Q9NRF2}.
 MOD_RES     417    417       Phosphoserine.
                              {ECO:0000250|UniProtKB:Q91ZM2}.
 MOD_RES     420    420       Phosphoserine.
                              {ECO:0000250|UniProtKB:Q91ZM2}.
 MOD_RES     439    439       Phosphotyrosine; by JAK1, JAK2 and PDGFR.
                              {ECO:0000269|PubMed:12551917}.
 MOD_RES     494    494       Phosphotyrosine; by JAK1, JAK2.
                              {ECO:0000269|PubMed:12551917}.
 VAR_SEQ     632    756       ERSTSRDPTQPSEPPPWTDPPHPGAEEASGAPEVAAATAAA
                              AKERQEKEKAGGGGVQEELVPMAELVPMAELEEAIAPGTEA
                              QGGAGSSGDLEVSLMVQLQQLPLGGNGEEGGHPRAINNQYS
                              FV -> GREQAGSHAGVCEGDRCYPDASSTFLPFGASDCVT
                              EHFP (in isoform 2).
                              {ECO:0000303|PubMed:9343427}.
                              /FTId=VSP_032045.
 MUTAGEN      96     96       S->A: Reduces in vitro phosphorylation by
                              MAPK1 and/or MAPK3.
                              {ECO:0000269|PubMed:10473609}.
 MUTAGEN     231    231       L->A: Abolishes nuclear localization;
                              when associated with A-233.
                              {ECO:0000269|PubMed:15082760}.
 MUTAGEN     233    233       L->A: Abolishes nuclear localization;
                              when associated with A-231.
                              {ECO:0000269|PubMed:15082760}.
 MUTAGEN     439    439       Y->F: Fails to enhance GH-induced
                              membrane ruffling; when associated with
                              F-494. {ECO:0000269|PubMed:12551917}.
 MUTAGEN     439    439       Y->F: Reduces phosphorylation by JAK1,
                              JAK2 and PDGFRA.
                              {ECO:0000269|PubMed:12551917}.
 MUTAGEN     494    494       Y->F: Fails to enhance GH-induced
                              membrane ruffling; when associated with
                              F-439. {ECO:0000269|PubMed:12551917}.
 MUTAGEN     494    494       Y->F: Reduces phosphorylation by JAK1 and
                              JAK2. {ECO:0000269|PubMed:12551917}.
 MUTAGEN     555    555       R->E: Reduces interaction with JAK2 and
                              abolishes JAK2 kinase activity; reduces
                              GH-stimulated cell motility; abolishes
                              interaction with PDGFRA.
                              {ECO:0000269|PubMed:10377387,
                              ECO:0000269|PubMed:10757801}.
 CONFLICT    211    211       R -> K (in Ref. 2; AAC04575).
                              {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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