SH2B2_HUMAN
ID SH2B2_HUMAN Reviewed; 632 AA.
AC O14492; A0A0A0MTI2; A6ND74;
DT 15-AUG-2003, integrated into UniProtKB/Swiss-Prot.
DT 23-SEP-2008, sequence version 2.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=SH2B adapter protein 2;
DE AltName: Full=Adapter protein with pleckstrin homology and Src homology 2 domains;
DE AltName: Full=SH2 and PH domain-containing adapter protein APS;
GN Name=SH2B2; Synonyms=APS;
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 {ECO:0000312|EMBL:BAA22514.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, INTERACTION WITH GRB2; KIT
RP AND SHC1, AND PHOSPHORYLATION AT TYR-629.
RC TISSUE=B-cell {ECO:0000269|PubMed:9233773};
RX PubMed=9233773; DOI=10.1038/sj.onc.1201163;
RA Yokouchi M., Suzuki R., Masuhara M., Komiya S., Inoue A., Yoshimura A.;
RT "Cloning and characterization of APS, an adaptor molecule containing PH and
RT SH2 domains that is tyrosine phosphorylated upon B-cell receptor
RT stimulation.";
RL Oncogene 15:7-15(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4] {ECO:0000305}
RP FUNCTION, PHOSPHORYLATION, AND INTERACTION WITH CBL AND EPOR.
RX PubMed=10374881; DOI=10.1038/sj.leu.2401397;
RA Wakioka T., Sasaki A., Mitsui K., Yokouchi M., Inoue A., Komiya S.,
RA Yoshimura A.;
RT "APS, an adaptor protein containing pleckstrin homology (PH) and Src
RT homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration
RT with c-Cbl.";
RL Leukemia 13:760-767(1999).
RN [5] {ECO:0000305}
RP FUNCTION, PHOSPHORYLATION, INTERACTION WITH CBL AND PDGFR, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=9989826; DOI=10.1038/sj.onc.1202326;
RA Yokouchi M., Wakioka T., Sakamoto H., Yasukawa H., Ohtsuka S., Sasaki A.,
RA Ohtsubo M., Valius M., Inoue A., Komiya S., Yoshimura A.;
RT "APS, an adaptor protein containing PH and SH2 domains, is associated with
RT the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis.";
RL Oncogene 18:759-767(1999).
RN [6] {ECO:0000305}
RP FUNCTION, AND INTERACTION WITH VAV1 AND VAV3.
RX PubMed=12400014; DOI=10.1038/sj.onc.1205927;
RA Yabana N., Shibuya M.;
RT "Adaptor protein APS binds the NH2-terminal autoinhibitory domain of
RT guanine nucleotide exchange factor Vav3 and augments its activity.";
RL Oncogene 21:7720-7729(2002).
RN [7]
RP REVIEW ON ROLE IN KIT SIGNALING.
RX PubMed=16129412; DOI=10.1016/j.bbrc.2005.08.055;
RA Roskoski R. Jr.;
RT "Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor.";
RL Biochem. Biophys. Res. Commun. 337:1-13(2005).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 21-85, FUNCTION, AND SUBUNIT.
RX PubMed=15378031; DOI=10.1038/nsmb829;
RA Dhe-Paganon S., Werner E.D., Nishi M., Hansen L., Chi Y.-I., Shoelson S.E.;
RT "A phenylalanine zipper mediates APS dimerization.";
RL Nat. Struct. Mol. Biol. 11:968-974(2004).
CC -!- FUNCTION: Adapter protein for several members of the tyrosine kinase
CC receptor family. Involved in multiple signaling pathways. May be
CC involved in coupling from immunoreceptor to Ras signaling. Acts as a
CC negative regulator of cytokine signaling in collaboration with CBL.
CC Binds to EPOR and suppresses EPO-induced STAT5 activation, possibly
CC through a masking effect on STAT5 docking sites in EPOR. Suppresses
CC PDGF-induced mitogenesis. May induce cytoskeletal reorganization via
CC interaction with VAV3. {ECO:0000269|PubMed:10374881,
CC ECO:0000269|PubMed:12400014, ECO:0000269|PubMed:15378031,
CC ECO:0000269|PubMed:9989826}.
CC -!- SUBUNIT: Homodimer. Interacts with KIT/c-KIT, SHC1, EPOR, PDGFR, VAV1
CC and VAV3. Interacts (via N-terminal region) with SHC1. Interacts (via
CC the phosphorylated C-terminus) with GRB2. Interacts (via its SH2
CC domain) with EPOR, INSR and KIT. Interacts with GRB2 after B-cell
CC antigen receptor stimulation. Interacts (via PH domain) with VAV3.
CC Interacts with NTRK1, NTRK2 and NTRK3 (phosphorylated); after
CC stimulation of the receptor by its extracellular ligand and subsequent
CC autophosphorylation of the receptor. Binds INSR, GRB2, ASB6 and CAP.
CC Insulin stimulation leads to dissociation of CAP. Binds CBS only when
CC SH2B2/APS has become phosphorylated. INSR binding does not depend on
CC the phosphorylation of SH2B2/APS (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC O14492; P22681: CBL; NbExp=7; IntAct=EBI-7507432, EBI-518228;
CC O14492-2; Q9NWX5: ASB6; NbExp=6; IntAct=EBI-19952306, EBI-6425205;
CC O14492-2; P49759-3: CLK1; NbExp=3; IntAct=EBI-19952306, EBI-11981867;
CC O14492-2; P49761: CLK3; NbExp=3; IntAct=EBI-19952306, EBI-745579;
CC O14492-2; Q9UII6: DUSP13; NbExp=3; IntAct=EBI-19952306, EBI-749800;
CC O14492-2; Q9H5Z6-2: FAM124B; NbExp=3; IntAct=EBI-19952306, EBI-11986315;
CC O14492-2; Q86YD7: FAM90A1; NbExp=3; IntAct=EBI-19952306, EBI-6658203;
CC O14492-2; P08631-2: HCK; NbExp=3; IntAct=EBI-19952306, EBI-9834454;
CC O14492-2; Q9UBH0: IL36RN; NbExp=3; IntAct=EBI-19952306, EBI-465156;
CC O14492-2; Q8TAP4-4: LMO3; NbExp=3; IntAct=EBI-19952306, EBI-11742507;
CC O14492-2; Q9H213: MAGEH1; NbExp=3; IntAct=EBI-19952306, EBI-473834;
CC O14492-2; Q96EZ8: MCRS1; NbExp=3; IntAct=EBI-19952306, EBI-348259;
CC O14492-2; Q9HB20: PLEKHA3; NbExp=3; IntAct=EBI-19952306, EBI-11079894;
CC O14492-2; Q9NRW1: RAB6B; NbExp=3; IntAct=EBI-19952306, EBI-1760079;
CC O14492-2; Q08117-2: TLE5; NbExp=3; IntAct=EBI-19952306, EBI-11741437;
CC O14492-2; Q9H1K6: TLNRD1; NbExp=3; IntAct=EBI-19952306, EBI-12344941;
CC O14492-2; O75604: USP2; NbExp=3; IntAct=EBI-19952306, EBI-743272;
CC O14492-2; Q96IQ9: ZNF414; NbExp=3; IntAct=EBI-19952306, EBI-744257;
CC O14492-2; Q8TAU3: ZNF417; NbExp=3; IntAct=EBI-19952306, EBI-740727;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9989826}. Cell
CC membrane {ECO:0000269|PubMed:9989826}. Note=Cytoplasmic before PDGF
CC stimulation. After PDGF stimulation, localized at the cell membrane and
CC peripheral region.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O14492-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O14492-2; Sequence=VSP_059358;
CC -!- TISSUE SPECIFICITY: Expressed in spleen, prostate, testis, uterus,
CC small intestine and skeletal muscle. Among hematopoietic cell lines,
CC expressed exclusively in B-cells. Not expressed in most tumor cell
CC lines. {ECO:0000269|PubMed:9233773, ECO:0000269|PubMed:9989826}.
CC -!- PTM: Tyrosine phosphorylated by JAK2, KIT and other kinases activated
CC by B-cell receptor in response to stimulation with cytokines, IL3, IL5,
CC PDGF, IGF1, IGF2, CSF2/GM-CSF and cross-linking of the B-cell receptor
CC complex. {ECO:0000250|UniProtKB:Q9JID9, ECO:0000269|PubMed:10374881,
CC ECO:0000269|PubMed:9233773, ECO:0000269|PubMed:9989826}.
CC -!- SIMILARITY: Belongs to the SH2B adapter family. {ECO:0000305}.
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DR EMBL; AB000520; BAA22514.1; -; mRNA.
DR EMBL; AC005088; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC091390; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471197; EAW50232.1; -; Genomic_DNA.
DR CCDS; CCDS78264.1; -. [O14492-1]
DR RefSeq; NP_066189.3; NM_020979.4. [O14492-2]
DR RefSeq; XP_005277034.1; XM_005276977.4.
DR RefSeq; XP_005277036.1; XM_005276979.3.
DR PDB; 1Q2H; X-ray; 1.70 A; A/B/C=21-85.
DR PDBsum; 1Q2H; -.
DR AlphaFoldDB; O14492; -.
DR SMR; O14492; -.
DR BioGRID; 115850; 43.
DR IntAct; O14492; 24.
DR MINT; O14492; -.
DR STRING; 9606.ENSP00000440273; -.
DR BindingDB; O14492; -.
DR iPTMnet; O14492; -.
DR PhosphoSitePlus; O14492; -.
DR BioMuta; SH2B2; -.
DR EPD; O14492; -.
DR jPOST; O14492; -.
DR MassIVE; O14492; -.
DR MaxQB; O14492; -.
DR PeptideAtlas; O14492; -.
DR PRIDE; O14492; -.
DR ProteomicsDB; 48035; -.
DR DNASU; 10603; -.
DR Ensembl; ENST00000444095.3; ENSP00000401883.3; ENSG00000160999.11. [O14492-1]
DR Ensembl; ENST00000536178.3; ENSP00000440273.3; ENSG00000160999.11. [O14492-2]
DR GeneID; 10603; -.
DR MANE-Select; ENST00000444095.3; ENSP00000401883.3; NM_001359228.2; NP_001346157.1.
DR UCSC; uc033aba.2; human.
DR CTD; 10603; -.
DR DisGeNET; 10603; -.
DR GeneCards; SH2B2; -.
DR HGNC; HGNC:17381; SH2B2.
DR MIM; 605300; gene.
DR neXtProt; NX_O14492; -.
DR OpenTargets; ENSG00000160999; -.
DR PharmGKB; PA145148106; -.
DR eggNOG; ENOG502QT43; Eukaryota.
DR GeneTree; ENSGT00950000183191; -.
DR InParanoid; O14492; -.
DR OMA; KMEGERF; -.
DR OrthoDB; 556279at2759; -.
DR PhylomeDB; O14492; -.
DR PathwayCommons; O14492; -.
DR Reactome; R-HSA-1433559; Regulation of KIT signaling.
DR Reactome; R-HSA-983231; Factors involved in megakaryocyte development and platelet production.
DR SignaLink; O14492; -.
DR SIGNOR; O14492; -.
DR BioGRID-ORCS; 10603; 11 hits in 272 CRISPR screens.
DR ChiTaRS; SH2B2; human.
DR EvolutionaryTrace; O14492; -.
DR GeneWiki; SH2B2; -.
DR GenomeRNAi; 10603; -.
DR Pharos; O14492; Tbio.
DR PRO; PR:O14492; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; O14492; protein.
DR Bgee; ENSG00000160999; Expressed in triceps brachii and 195 other tissues.
DR ExpressionAtlas; O14492; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0042169; F:SH2 domain binding; IDA:UniProtKB.
DR GO; GO:0035591; F:signaling adaptor activity; IDA:UniProtKB.
DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; IBA:GO_Central.
DR GO; GO:0050851; P:antigen receptor-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0050853; P:B cell receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR CDD; cd10411; SH2_SH2B2; 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; IPR030520; SH2B2.
DR InterPro; IPR035058; SH2B2_SH2.
DR PANTHER; PTHR10872; PTHR10872; 1.
DR PANTHER; PTHR10872:SF4; PTHR10872:SF4; 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; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cytoplasm; Membrane;
KW Phosphoprotein; Reference proteome; SH2 domain.
FT CHAIN 1..632
FT /note="SH2B adapter protein 2"
FT /id="PRO_0000064647"
FT DOMAIN 193..306
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145,
FT ECO:0000305"
FT DOMAIN 417..515
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191,
FT ECO:0000305"
FT REGION 381..409
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 516..537
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 558..632
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 381..400
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 519..535
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 562..579
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 52
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9JID9"
FT MOD_RES 141
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JID9"
FT MOD_RES 310
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JID9"
FT MOD_RES 629
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:9233773"
FT VAR_SEQ 1
FT /note="M -> MDPSYCPAHGFPSQDPLWPLSSQQWSSAHYSEPAAGGCDGTEAM
FT (in isoform 2)"
FT /id="VSP_059358"
FT CONFLICT 111
FT /note="P -> S (in Ref. 1; BAA22514)"
FT /evidence="ECO:0000305"
FT HELIX 23..48
FT /evidence="ECO:0007829|PDB:1Q2H"
FT HELIX 50..52
FT /evidence="ECO:0007829|PDB:1Q2H"
FT HELIX 57..82
FT /evidence="ECO:0007829|PDB:1Q2H"
SQ SEQUENCE 632 AA; 67738 MW; 823DF1699D404227 CRC64;
MNGAGPGPAA AAPVPVPVPV PDWRQFCELH AQAAAVDFAH KFCRFLRDNP AYDTPDAGAS
FSRHFAANFL DVFGEEVRRV LVAGPTTRGA AVSAEAMEPE LADTSALKAA PYGHSRSSED
VSTHAATKAR VRKGFSLRNM SLCVVDGVRD MWHRRASPEP DAAAAPRTAE PRDKWTRRLR
LSRTLAAKVE LVDIQREGAL RFMVADDAAA GSGGSAQWQK CRLLLRRAVA EERFRLEFFV
PPKASRPKVS IPLSAIIEVR TTMPLEMPEK DNTFVLKVEN GAEYILETID SLQKHSWVAD
IQGCVDPGDS EEDTELSCTR GGCLASRVAS CSCELLTDAV DLPRPPETTA VGAVVTAPHS
RGRDAVRESL IHVPLETFLQ TLESPGGSGS DSNNTGEQGA ETDPEAEPEL ELSDYPWFHG
TLSRVKAAQL VLAGGPRNHG LFVIRQSETR PGEYVLTFNF QGKAKHLRLS LNGHGQCHVQ
HLWFQSVLDM LRHFHTHPIP LESGGSADIT LRSYVRAQDP PPEPGPTPPA APASPACWSD
SPGQHYFSSL AAAACPPASP SDAAGASSSS ASSSSAASGP APPRPVEGQL SARSRSNSAE
RLLEAVAATA AEEPPEAAPG RARAVENQYS FY
