SH2B1_HUMAN
ID SH2B1_HUMAN Reviewed; 756 AA.
AC Q9NRF2; A8K2R7; Q96FK3; Q96SX3; Q9NRF1; Q9NRF3; Q9P2P7; Q9Y3Y3;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 3.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=SH2B adapter protein 1;
DE AltName: Full=Pro-rich, PH and SH2 domain-containing signaling mediator;
DE Short=PSM;
DE AltName: Full=SH2 domain-containing protein 1B;
GN Name=SH2B1; Synonyms=KIAA1299, SH2B;
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] (ISOFORMS 1; 2 AND 3), FUNCTION IN JAK2
RP ACTIVATION, SELF-ASSOCIATION, INTERACTION WITH JAK2; SH2B2; INSR AND IGF1R,
RP PHOSPHORYLATION, TISSUE SPECIFICITY, MUTAGENESIS OF PHE-29; ALA-34; ALA-38;
RP PHE-41; ALA-42; TYR-48; PHE-68; PHE-72 AND ARG-555, AND VARIANT ALA-484.
RX PubMed=15767667; DOI=10.1128/mcb.25.7.2607-2621.2005;
RA Nishi M., Werner E.D., Oh B.C., Frantz J.D., Dhe-Paganon S., Hansen L.,
RA Lee J., Shoelson S.E.;
RT "Kinase activation through dimerization by human SH2-B.";
RL Mol. Cell. Biol. 25:2607-2621(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ALA-541.
RC TISSUE=Brain;
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI. The
RT complete sequences of 150 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Teratocarcinoma, and Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 144-756 (ISOFORM 3), AND VARIANT ALA-484.
RC TISSUE=Mammary cancer;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 60-756 (ISOFORM 2).
RC TISSUE=Eye;
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 [7]
RP INTERACTION WITH INSR.
RX PubMed=9498552; DOI=10.1093/oxfordjournals.jbchem.a021868;
RA Riedel H., Wang J., Hansen H., Yousaf N.;
RT "PSM, an insulin-dependent, pro-rich, PH, SH2 domain containing partner of
RT the insulin receptor.";
RL J. Biochem. 122:1105-1113(1997).
RN [8]
RP FUNCTION, INTERACTION WITH INSR, AND PHOSPHORYLATION.
RX PubMed=9742218; DOI=10.1042/bj3350103;
RA Kotani K., Wilden P., Pillay T.S.;
RT "SH2-Balpha is an insulin-receptor adapter protein and substrate that
RT interacts with the activation loop of the insulin-receptor kinase.";
RL Biochem. J. 335:103-109(1998).
RN [9]
RP FUNCTION IN PDGF SIGNALING, AND INTERACTION WITH PDGFRA/B.
RX PubMed=9694882; DOI=10.1074/jbc.273.33.21239;
RA Rui L., Carter-Su C.;
RT "Platelet-derived growth factor (PDGF) stimulates the association of SH2-
RT Bbeta with PDGF receptor and phosphorylation of SH2-Bbeta.";
RL J. Biol. Chem. 273:21239-21245(1998).
RN [10]
RP INTERACTION WITH INSR AND ISR1.
RX PubMed=10594240; DOI=10.1007/s003359901183;
RA Nelms K., O'Neill T.J., Li S., Hubbard S.R., Gustafson T.A., Paul W.E.;
RT "Alternative splicing, gene localization, and binding of SH2-B to the
RT insulin receptor kinase domain.";
RL Mamm. Genome 10:1160-1167(1999).
RN [11]
RP INTERACTION WITH JAK1; JAK2 AND JAK3, AND PHOSPHORYLATION.
RX PubMed=11751854; DOI=10.1074/jbc.m109165200;
RA O'Brien K.B., O'Shea J.J., Carter-Su C.;
RT "SH2-B family members differentially regulate JAK family tyrosine
RT kinases.";
RL J. Biol. Chem. 277:8673-8681(2002).
RN [12]
RP FUNCTION IN FGF SIGNALING, AND INTERACTION WITH FGFR3.
RX PubMed=11827956; DOI=10.1074/jbc.m102777200;
RA Kong M., Wang C.S., Donoghue D.J.;
RT "Interaction of fibroblast growth factor receptor 3 and the adapter protein
RT SH2-B. A role in STAT5 activation.";
RL J. Biol. Chem. 277:15962-15970(2002).
RN [13]
RP FUNCTION IN NGF SIGNALING.
RX PubMed=14565960; DOI=10.1074/jbc.m310040200;
RA Wang X., Chen L., Maures T.J., Herrington J., Carter-Su C.;
RT "SH2-B is a positive regulator of nerve growth factor-mediated activation
RT of the Akt/Forkhead pathway in PC12 cells.";
RL J. Biol. Chem. 279:133-141(2004).
RN [14]
RP FUNCTION IN GDNF SIGNALING, AND INTERACTION WITH RET.
RX PubMed=16569669; DOI=10.1242/jcs.02845;
RA Zhang Y., Zhu W., Wang Y.G., Liu X.J., Jiao L., Liu X., Zhang Z.H.,
RA Lu C.L., He C.;
RT "Interaction of SH2-Bbeta with RET is involved in signaling of GDNF-induced
RT neurite outgrowth.";
RL J. Cell Sci. 119:1666-1676(2006).
RN [15]
RP FUNCTION IN RET SIGNALING, AND INTERACTION WITH PRKAR1A/RET.
RX PubMed=17471236; DOI=10.1038/sj.onc.1210480;
RA Donatello S., Fiorino A., Degl'Innocenti D., Alberti L., Miranda C.,
RA Gorla L., Bongarzone I., Rizzetti M.G., Pierotti M.A., Borrello M.G.;
RT "SH2B1beta adaptor is a key enhancer of RET tyrosine kinase signaling.";
RL Oncogene 26:6546-6559(2007).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-96, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-96, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [20]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-270, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Colon carcinoma;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
CC -!- FUNCTION: Adapter protein for several members of the tyrosine kinase
CC receptor family. Involved in multiple signaling pathways mediated by
CC Janus kinase (JAK) and receptor tyrosine kinases, including the
CC receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve
CC growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial
CC cell line-derived neurotrophic factor (GDNF), platelet-derived growth
CC factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone
CC (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1,
CC which in turn is phosphorylated by JAK2 on tyrosine residues. These
CC phosphotyrosines form potential binding sites for other signaling
CC proteins. GH also promotes serine/threonine phosphorylation of SH2B1
CC and these phosphorylated residues may serve to recruit other proteins
CC to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP)
CC signaling, binds to and potentiates the activation of JAK2 by globally
CC enhancing downstream pathways. In response to leptin, binds
CC simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation
CC of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine
CC phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-
CC kinase pathway. Acts as positive regulator of NGF-mediated activation
CC of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of
CC AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase
CC activity of the cytokine receptor-associated tyrosine kinase JAK2 and
CC of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2,
CC the mechanism seems to involve dimerization of both, SH2B1 and JAK2.
CC Enhances RET phosphorylation and kinase activity. Isoforms seem to be
CC differentially involved in IGF-I and PDGF-induced mitogenesis (By
CC similarity). {ECO:0000250, ECO:0000269|PubMed:11827956,
CC ECO:0000269|PubMed:14565960, ECO:0000269|PubMed:15767667,
CC ECO:0000269|PubMed:16569669, ECO:0000269|PubMed:17471236,
CC ECO:0000269|PubMed:9694882, ECO:0000269|PubMed:9742218}.
CC -!- SUBUNIT: Self-associates. Homopentamer (By similarity). Forms a
CC heteromultimeric complex with SH2B2 (By similarity). Interacts with
CC SH2B2. Isoform 1 interacts via its SH2 domain with JAK2. Isoform 2
CC interacts via its SH2 domain and its N-terminus with JAK2; the SH2
CC domain is required for the major interaction with JAK2 phosphorylated
CC on tyrosine residues; the N-terminus provides a low-affinity binding to
CC JAK2 independent of JAK2 phosphorylation. Isoform 3 interacts via its
CC SH2 domain with JAK2. Isoform 1 interacts via its SH2 domain with INSR;
CC the interaction requires receptor activation. Isoform 3 interacts via
CC its SH2 domain with INSR; the interaction requires receptor activation
CC and requires INSR phosphorylation at 'Tyr-1185'. Isoform 1 interacts
CC with IGF1R; the interaction requires receptor activation. Isoform 2
CC interacts with PRKAR1A/RET (PTC2) fusion protein; the interaction
CC requires RET 'Tyr-905' and Tyr-981'. Isoform 2 interacts via its SH2
CC domain with FGFR3; the interaction requires FGFR3 'Tyr-724' and 'Tyr-
CC 760'. Isoform 2 interacts with RET; the interaction requires RET kinase
CC activity and RET 'Tyr-981'. Isoform 2 interacts with RAC1. Isoform 2
CC interacts with PDGFRA and/or PDGFRB; the interaction requires receptor
CC activation. Interacts with ISR1 and ISR2. Isoform 3 is probably part of
CC a complex consisting of INSR, ISR1 and SH2B1. Probably part of a
CC ternary complex consisting of SH2B1, JAK2 and ISR1 or ISR2. May
CC interact with FCER1G (By similarity). Interacts (via SH2 domain) with
CC NTRK1 (phosphorylated) (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC Q9NRF2; P00533: EGFR; NbExp=4; IntAct=EBI-310491, EBI-297353;
CC Q9NRF2; P06213: INSR; NbExp=6; IntAct=EBI-310491, EBI-475899;
CC Q9NRF2; P42227: Stat3; Xeno; NbExp=5; IntAct=EBI-310491, EBI-602878;
CC Q9NRF2-2; P62993: GRB2; NbExp=3; IntAct=EBI-10691662, EBI-401755;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Membrane {ECO:0000305}.
CC Nucleus {ECO:0000250}. Note=Shuttles between the nucleus and the
CC cytoplasm. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Alpha;
CC IsoId=Q9NRF2-1; Sequence=Displayed;
CC Name=2; Synonyms=Beta;
CC IsoId=Q9NRF2-2; Sequence=VSP_032027;
CC Name=3; Synonyms=Gamma;
CC IsoId=Q9NRF2-3; Sequence=VSP_032028;
CC -!- TISSUE SPECIFICITY: Widely expressed with highest levels in skeletal
CC muscle and ovary. {ECO:0000269|PubMed:15767667}.
CC -!- PTM: Phosphorylated on tyrosine residues in response to receptor kinase
CC stimulation. Phosphorylated by RET. {ECO:0000269|PubMed:11751854,
CC ECO:0000269|PubMed:15767667, ECO:0000269|PubMed:9742218}.
CC -!- SIMILARITY: Belongs to the SH2B adapter family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH10704.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA92537.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAB55148.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF227967; AAF73912.1; -; mRNA.
DR EMBL; AF227968; AAF73913.1; -; mRNA.
DR EMBL; AF227969; AAF73914.1; -; mRNA.
DR EMBL; AB037720; BAA92537.1; ALT_INIT; mRNA.
DR EMBL; AK027488; BAB55148.1; ALT_INIT; mRNA.
DR EMBL; AK290332; BAF83021.1; -; mRNA.
DR EMBL; AL049924; CAB43208.1; -; mRNA.
DR EMBL; AL713760; CAD28530.1; -; mRNA.
DR EMBL; AC133550; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC010704; AAH10704.1; ALT_INIT; mRNA.
DR CCDS; CCDS32424.1; -. [Q9NRF2-2]
DR CCDS; CCDS53996.1; -. [Q9NRF2-1]
DR CCDS; CCDS53997.1; -. [Q9NRF2-3]
DR PIR; T08662; T08662.
DR RefSeq; NP_001139267.1; NM_001145795.1. [Q9NRF2-1]
DR RefSeq; NP_001139268.1; NM_001145796.1. [Q9NRF2-2]
DR RefSeq; NP_001139269.1; NM_001145797.1. [Q9NRF2-3]
DR RefSeq; NP_001139284.1; NM_001145812.1. [Q9NRF2-2]
DR RefSeq; NP_001295222.1; NM_001308293.1. [Q9NRF2-1]
DR RefSeq; NP_001295223.1; NM_001308294.1.
DR RefSeq; NP_056318.2; NM_015503.2. [Q9NRF2-2]
DR RefSeq; XP_016878603.1; XM_017023114.1.
DR RefSeq; XP_016878604.1; XM_017023115.1.
DR RefSeq; XP_016878605.1; XM_017023116.1.
DR PDB; 5W3R; X-ray; 1.39 A; A=519-628.
DR PDBsum; 5W3R; -.
DR AlphaFoldDB; Q9NRF2; -.
DR SMR; Q9NRF2; -.
DR BioGRID; 117455; 26.
DR IntAct; Q9NRF2; 17.
DR MINT; Q9NRF2; -.
DR STRING; 9606.ENSP00000321221; -.
DR iPTMnet; Q9NRF2; -.
DR PhosphoSitePlus; Q9NRF2; -.
DR BioMuta; SH2B1; -.
DR DMDM; 313104186; -.
DR EPD; Q9NRF2; -.
DR jPOST; Q9NRF2; -.
DR MassIVE; Q9NRF2; -.
DR MaxQB; Q9NRF2; -.
DR PaxDb; Q9NRF2; -.
DR PeptideAtlas; Q9NRF2; -.
DR PRIDE; Q9NRF2; -.
DR ProteomicsDB; 82346; -. [Q9NRF2-1]
DR ProteomicsDB; 82347; -. [Q9NRF2-2]
DR ProteomicsDB; 82348; -. [Q9NRF2-3]
DR Antibodypedia; 26583; 289 antibodies from 31 providers.
DR DNASU; 25970; -.
DR Ensembl; ENST00000322610.12; ENSP00000321221.7; ENSG00000178188.15. [Q9NRF2-1]
DR Ensembl; ENST00000337120.9; ENSP00000337163.5; ENSG00000178188.15. [Q9NRF2-2]
DR Ensembl; ENST00000359285.9; ENSP00000352232.5; ENSG00000178188.15. [Q9NRF2-3]
DR Ensembl; ENST00000395532.8; ENSP00000378903.4; ENSG00000178188.15. [Q9NRF2-2]
DR Ensembl; ENST00000618521.4; ENSP00000481709.1; ENSG00000178188.15. [Q9NRF2-1]
DR Ensembl; ENST00000684370.1; ENSP00000507475.1; ENSG00000178188.15. [Q9NRF2-1]
DR GeneID; 25970; -.
DR KEGG; hsa:25970; -.
DR MANE-Select; ENST00000684370.1; ENSP00000507475.1; NM_001387430.1; NP_001374359.1.
DR UCSC; uc002dri.4; human. [Q9NRF2-1]
DR CTD; 25970; -.
DR DisGeNET; 25970; -.
DR GeneCards; SH2B1; -.
DR HGNC; HGNC:30417; SH2B1.
DR HPA; ENSG00000178188; Low tissue specificity.
DR MalaCards; SH2B1; -.
DR MIM; 608937; gene.
DR neXtProt; NX_Q9NRF2; -.
DR OpenTargets; ENSG00000178188; -.
DR Orphanet; 261222; Distal 16p11.2 microdeletion syndrome.
DR Orphanet; 261197; Proximal 16p11.2 microdeletion syndrome.
DR Orphanet; 329249; Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency.
DR PharmGKB; PA145148084; -.
DR VEuPathDB; HostDB:ENSG00000178188; -.
DR eggNOG; ENOG502QT43; Eukaryota.
DR GeneTree; ENSGT00950000183191; -.
DR HOGENOM; CLU_014885_4_0_1; -.
DR InParanoid; Q9NRF2; -.
DR OMA; GILQWRS; -.
DR PhylomeDB; Q9NRF2; -.
DR TreeFam; TF323184; -.
DR PathwayCommons; Q9NRF2; -.
DR Reactome; R-HSA-1170546; Prolactin receptor signaling. [Q9NRF2-2]
DR Reactome; R-HSA-2586552; Signaling by Leptin. [Q9NRF2-2]
DR Reactome; R-HSA-982772; Growth hormone receptor signaling. [Q9NRF2-2]
DR Reactome; R-HSA-983231; Factors involved in megakaryocyte development and platelet production.
DR SignaLink; Q9NRF2; -.
DR SIGNOR; Q9NRF2; -.
DR BioGRID-ORCS; 25970; 41 hits in 1077 CRISPR screens.
DR ChiTaRS; SH2B1; human.
DR GeneWiki; SH2B1; -.
DR GenomeRNAi; 25970; -.
DR Pharos; Q9NRF2; Tbio.
DR PRO; PR:Q9NRF2; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q9NRF2; protein.
DR Bgee; ENSG00000178188; Expressed in right hemisphere of cerebellum and 175 other tissues.
DR ExpressionAtlas; Q9NRF2; baseline and differential.
DR Genevisible; Q9NRF2; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; IBA:GO_Central.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0030032; P:lamellipodium assembly; IEA:Ensembl.
DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IEA:Ensembl.
DR GO; GO:0060391; P:positive regulation of SMAD protein signal transduction; IGI:MGI.
DR GO; GO:2000278; P:regulation of DNA biosynthetic process; IEA:Ensembl.
DR CDD; cd10346; SH2_SH2B_family; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR015012; Phe_ZIP.
DR InterPro; IPR036290; Phe_ZIP_sf.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR030523; SH2B.
DR InterPro; IPR030521; SH2B1.
DR InterPro; IPR035057; SH2B1_SH2.
DR PANTHER; PTHR10872; PTHR10872; 1.
DR PANTHER; PTHR10872:SF3; PTHR10872:SF3; 1.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF08916; Phe_ZIP; 1.
DR Pfam; PF00017; SH2; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00233; PH; 1.
DR SMART; SM00252; SH2; 1.
DR SUPFAM; SSF109805; SSF109805; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Membrane; Methylation;
KW Nucleus; Phosphoprotein; Reference proteome; SH2 domain.
FT CHAIN 1..756
FT /note="SH2B adapter protein 1"
FT /id="PRO_0000323593"
FT DOMAIN 267..376
FT /note="PH"
FT DOMAIN 527..625
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT REGION 1..555
FT /note="Interaction with JAK2 (low-affinity binding;
FT independent of JAK2 phosphorylation)"
FT /evidence="ECO:0000250"
FT REGION 1..27
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 24..85
FT /note="Required for self-association"
FT REGION 85..196
FT /note="Interaction with RAC1"
FT /evidence="ECO:0000250"
FT REGION 100..243
FT /note="Required for NGF signaling"
FT /evidence="ECO:0000250"
FT REGION 123..154
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 169..222
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 224..233
FT /note="Required for nuclear localization"
FT /evidence="ECO:0000250"
FT REGION 263..286
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 420..455
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 468..491
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 626..688
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 709..756
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 10..27
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 129..148
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 181..208
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 420..437
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 637..653
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 88
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q91ZM2"
FT MOD_RES 96
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18220336,
FT ECO:0007744|PubMed:18669648"
FT MOD_RES 270
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 417
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q91ZM2"
FT MOD_RES 420
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q91ZM2"
FT MOD_RES 439
FT /note="Phosphotyrosine; by JAK1, JAK2 and PDGFR"
FT /evidence="ECO:0000250|UniProtKB:Q62985"
FT MOD_RES 494
FT /note="Phosphotyrosine; by JAK1, JAK2"
FT /evidence="ECO:0000250|UniProtKB:Q62985"
FT VAR_SEQ 633..756
FT /note="EPTTSHDPPQPPEPPSWTDPPQPGAEEASRAPEVAAAAAAAAKERQEKEKAG
FT GGGVPEELVPVVELVPVVELEEAIAPGSEAQGAGSGGDAGVPPMVQLQQSPLGGDGEEG
FT GHPRAINNQYSFV -> GREQAGSHAGVCEGDGCHPDASCTLMPFGASDCVTDHLP
FT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10718198,
FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:15767667, ECO:0000303|PubMed:17974005"
FT /id="VSP_032027"
FT VAR_SEQ 633..756
FT /note="EPTTSHDPPQPPEPPSWTDPPQPGAEEASRAPEVAAAAAAAAKERQEKEKAG
FT GGGVPEELVPVVELVPVVELEEAIAPGSEAQGAGSGGDAGVPPMVQLQQSPLGGDGEEG
FT GHPRAINNQYSFV -> GEQSRSAGEEVPVHPRSEAGSRLGAMRGCAREMDATPMPPAP
FT SCPSERVTV (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15767667,
FT ECO:0000303|PubMed:17974005"
FT /id="VSP_032028"
FT VARIANT 484
FT /note="T -> A (in dbSNP:rs7498665)"
FT /evidence="ECO:0000269|PubMed:15767667,
FT ECO:0000269|PubMed:17974005"
FT /id="VAR_039550"
FT VARIANT 541
FT /note="V -> A (in dbSNP:rs17850682)"
FT /evidence="ECO:0000269|PubMed:10718198"
FT /id="VAR_039551"
FT MUTAGEN 29
FT /note="F->R: Abolishes self-association and interaction
FT with INSR and IGF1R."
FT /evidence="ECO:0000269|PubMed:15767667"
FT MUTAGEN 34
FT /note="A->D: Abolishes self-association and interaction
FT with INSR and IGF1R."
FT /evidence="ECO:0000269|PubMed:15767667"
FT MUTAGEN 38
FT /note="A->D: Abolishes self-association and interaction
FT with INSR and IGF1R."
FT /evidence="ECO:0000269|PubMed:15767667"
FT MUTAGEN 41
FT /note="F->A: Abolishes self-association and interaction
FT with INSR and IGF1R."
FT /evidence="ECO:0000269|PubMed:15767667"
FT MUTAGEN 42
FT /note="A->D: Abolishes self-association and interaction
FT with INSR and IGF1R."
FT /evidence="ECO:0000269|PubMed:15767667"
FT MUTAGEN 48
FT /note="Y->A: Abolishes self-association and interaction
FT with INSR and IGF1R."
FT /evidence="ECO:0000269|PubMed:15767667"
FT MUTAGEN 68
FT /note="F->A: Abolishes self-association and interaction
FT with INSR and IGF1R."
FT /evidence="ECO:0000269|PubMed:15767667"
FT MUTAGEN 72
FT /note="F->A: Abolishes self-association and interaction
FT with INSR and IGF1R."
FT /evidence="ECO:0000269|PubMed:15767667"
FT MUTAGEN 555
FT /note="R->A: Abolishes self-association and interaction
FT with INSR and IGF1R."
FT /evidence="ECO:0000269|PubMed:15767667"
FT CONFLICT 197
FT /note="N -> D (in Ref. 3; BAF83021)"
FT /evidence="ECO:0000305"
FT CONFLICT 519
FT /note="D -> G (in Ref. 3; BAF83021)"
FT /evidence="ECO:0000305"
FT HELIX 522..524
FT /evidence="ECO:0007829|PDB:5W3R"
FT STRAND 528..531
FT /evidence="ECO:0007829|PDB:5W3R"
FT HELIX 534..542
FT /evidence="ECO:0007829|PDB:5W3R"
FT HELIX 545..548
FT /evidence="ECO:0007829|PDB:5W3R"
FT STRAND 551..556
FT /evidence="ECO:0007829|PDB:5W3R"
FT STRAND 558..560
FT /evidence="ECO:0007829|PDB:5W3R"
FT STRAND 564..570
FT /evidence="ECO:0007829|PDB:5W3R"
FT STRAND 573..581
FT /evidence="ECO:0007829|PDB:5W3R"
FT STRAND 587..589
FT /evidence="ECO:0007829|PDB:5W3R"
FT STRAND 592..596
FT /evidence="ECO:0007829|PDB:5W3R"
FT HELIX 597..606
FT /evidence="ECO:0007829|PDB:5W3R"
FT STRAND 614..616
FT /evidence="ECO:0007829|PDB:5W3R"
SQ SEQUENCE 756 AA; 79366 MW; CF680B57114CB1D3 CRC64;
MNGAPSPEDG ASPSSPPLPP PPPPSWREFC ESHARAAALD FARRFRLYLA SHPQYAGPGA
EAAFSRRFAE LFLQHFEAEV ARASGSLSPP ILAPLSPGAE ISPHDLSLES CRVGGPLAVL
GPSRSSEDLA GPLPSSVSSS STTSSKPKLK KRFSLRSVGR SVRGSVRGIL QWRGTVDPPS
SAGPLETSSG PPVLGGNSNS NSSGGAGTVG RGLVSDGTSP GERWTHRFER LRLSRGGGAL
KDGAGMVQRE ELLSFMGAEE AAPDPAGVGR GGGVAGPPSG GGGQPQWQKC RLLLRSEGEG
GGGSRLEFFV PPKASRPRLS IPCSSITDVR TTTALEMPDR ENTFVVKVEG PSEYIMETVD
AQHVKAWVSD IQECLSPGPC PATSPRPMTL PLAPGTSFLT RENTDSLELS CLNHSESLPS
QDLLLGPSES NDRLSQGAYG GLSDRPSASI SPSSASIAAS HFDSMELLPP ELPPRIPIEE
GPPTGTVHPL SAPYPPLDTP ETATGSFLFQ GEPEGGEGDQ PLSGYPWFHG MLSRLKAAQL
VLTGGTGSHG VFLVRQSETR RGEYVLTFNF QGKAKHLRLS LNEEGQCRVQ HLWFQSIFDM
LEHFRVHPIP LESGGSSDVV LVSYVPSSQR QQEPTTSHDP PQPPEPPSWT DPPQPGAEEA
SRAPEVAAAA AAAAKERQEK EKAGGGGVPE ELVPVVELVP VVELEEAIAP GSEAQGAGSG
GDAGVPPMVQ LQQSPLGGDG EEGGHPRAIN NQYSFV
