SH2B3_HUMAN
ID SH2B3_HUMAN Reviewed; 575 AA.
AC Q9UQQ2; B9EGG5; O95184;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-APR-2001, sequence version 2.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=SH2B adapter protein 3;
DE AltName: Full=Lymphocyte adapter protein;
DE AltName: Full=Lymphocyte-specific adapter protein Lnk;
DE AltName: Full=Signal transduction protein Lnk;
GN Name=SH2B3; Synonyms=LNK;
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].
RX PubMed=10799879; DOI=10.4049/jimmunol.164.10.5199;
RA Li Y., He X., Schembri-King J., Jakes S., Hayashi J.;
RT "Cloning and characterization of human Lnk, an adaptor protein with
RT pleckstrin homology and Src homology 2 domains that can inhibit T cell
RT activation.";
RL J. Immunol. 164:5199-5206(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bartholomew M.A., Morse M.A., Vivier R.G., Blanchard A.D., Boyhan A.,
RA Tite J.P., Fuller K.J., Lewis A.P., Sims M.J.;
RT "Characterisation of human Lnk a lymphocyte adaptor protein with a multiple
RT domain structure.";
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.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]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [5]
RP INVOLVEMENT IN SUSCEPTIBILITY TO IDDM, AND VARIANT ARG-262.
RX PubMed=17554260; DOI=10.1038/ng2068;
RG Genetics of type 1 diabetes in Finland;
RG The Wellcome Trust case control consortium;
RA Todd J.A., Walker N.M., Cooper J.D., Smyth D.J., Downes K., Plagnol V.,
RA Bailey R., Nejentsev S., Field S.F., Payne F., Lowe C.E., Szeszko J.S.,
RA Hafler J.P., Zeitels L., Yang J.H.M., Vella A., Nutland S., Stevens H.E.,
RA Schuilenburg H., Coleman G., Maisuria M., Meadows W., Smink L.J., Healy B.,
RA Burren O.S., Lam A.A.C., Ovington N.R., Allen J., Adlem E., Leung H.-T.,
RA Wallace C., Howson J.M.M., Guja C., Ionescu-Tirgoviste C., Simmonds M.J.,
RA Heward J.M., Gough S.C.L., Dunger D.B., Wicker L.S., Clayton D.G.;
RT "Robust associations of four new chromosome regions from genome-wide
RT analyses of type 1 diabetes.";
RL Nat. Genet. 39:857-864(2007).
RN [6]
RP INVOLVEMENT IN SUSCEPTIBILITY TO CELIAC13, AND VARIANT ARG-262.
RX PubMed=18311140; DOI=10.1038/ng.102;
RA Hunt K.A., Zhernakova A., Turner G., Heap G.A.R., Franke L.,
RA Bruinenberg M., Romanos J., Dinesen L.C., Ryan A.W., Panesar D.,
RA Gwilliam R., Takeuchi F., McLaren W.M., Holmes G.K.T., Howdle P.D.,
RA Walters J.R.F., Sanders D.S., Playford R.J., Trynka G., Mulder C.J.,
RA Mearin M.L., Verbeek W.H.M., Trimble V., Stevens F.M., O'Morain C.,
RA Kennedy N.P., Kelleher D., Pennington D.J., Strachan D.P., McArdle W.L.,
RA Mein C.A., Wapenaar M.C., Deloukas P., McGinnis R., McManus R.,
RA Wijmenga C., van Heel D.A.;
RT "Newly identified genetic risk variants for celiac disease related to the
RT immune response.";
RL Nat. Genet. 40:395-402(2008).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-150, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-103; SER-120 AND SER-150, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=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 [9]
RP VARIANTS 208-GLU--LEU-575 DEL AND VAL-215.
RX PubMed=20843259; DOI=10.1056/nejmc1006966;
RA Lasho T.L., Pardanani A., Tefferi A.;
RT "LNK mutations in JAK2 mutation-negative erythrocytosis.";
RL N. Engl. J. Med. 363:1189-1190(2010).
CC -!- FUNCTION: Links T-cell receptor activation signal to phospholipase C-
CC gamma-1, GRB2 and phosphatidylinositol 3-kinase. {ECO:0000250}.
CC -!- SUBUNIT: Binds to the tyrosine-phosphorylated TCR zeta chain via its
CC SH2 domain.
CC -!- INTERACTION:
CC Q9UQQ2; P00533: EGFR; NbExp=2; IntAct=EBI-7879749, EBI-297353;
CC Q9UQQ2; P21860: ERBB3; NbExp=2; IntAct=EBI-7879749, EBI-720706;
CC Q9UQQ2; P10721: KIT; NbExp=2; IntAct=EBI-7879749, EBI-1379503;
CC Q9UQQ2; P08581: MET; NbExp=2; IntAct=EBI-7879749, EBI-1039152;
CC -!- TISSUE SPECIFICITY: Preferentially expressed by lymphoid cell lines.
CC -!- PTM: Tyrosine phosphorylated by LCK.
CC -!- DISEASE: Celiac disease 13 (CELIAC13) [MIM:612011]: A multifactorial,
CC chronic disorder of the small intestine caused by intolerance to
CC gluten. It is characterized by immune-mediated enteropathy associated
CC with failed intestinal absorption, and malnutrition. In predisposed
CC individuals, the ingestion of gluten-containing food such as wheat and
CC rye induces a flat jejunal mucosa with infiltration of lymphocytes.
CC {ECO:0000269|PubMed:18311140}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- DISEASE: Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A
CC multifactorial disorder of glucose homeostasis that is characterized by
CC susceptibility to ketoacidosis in the absence of insulin therapy.
CC Clinical features are polydipsia, polyphagia and polyuria which result
CC from hyperglycemia-induced osmotic diuresis and secondary thirst. These
CC derangements result in long-term complications that affect the eyes,
CC kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:17554260}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SH2B adapter family. {ECO:0000305}.
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DR EMBL; AF055581; AAC71695.1; -; mRNA.
DR EMBL; AJ012793; CAB42642.1; -; mRNA.
DR EMBL; CH471054; EAW97955.1; -; Genomic_DNA.
DR EMBL; BC136451; AAI36452.1; -; mRNA.
DR CCDS; CCDS9153.1; -.
DR RefSeq; NP_001278353.1; NM_001291424.1.
DR RefSeq; NP_005466.1; NM_005475.2.
DR AlphaFoldDB; Q9UQQ2; -.
DR SMR; Q9UQQ2; -.
DR BioGRID; 115336; 20.
DR IntAct; Q9UQQ2; 39.
DR MINT; Q9UQQ2; -.
DR STRING; 9606.ENSP00000345492; -.
DR DrugBank; DB06589; Pazopanib.
DR iPTMnet; Q9UQQ2; -.
DR PhosphoSitePlus; Q9UQQ2; -.
DR BioMuta; SH2B3; -.
DR DMDM; 13628527; -.
DR EPD; Q9UQQ2; -.
DR jPOST; Q9UQQ2; -.
DR MassIVE; Q9UQQ2; -.
DR MaxQB; Q9UQQ2; -.
DR PaxDb; Q9UQQ2; -.
DR PeptideAtlas; Q9UQQ2; -.
DR PRIDE; Q9UQQ2; -.
DR ProteomicsDB; 85571; -.
DR Antibodypedia; 1179; 270 antibodies from 36 providers.
DR DNASU; 10019; -.
DR Ensembl; ENST00000341259.7; ENSP00000345492.2; ENSG00000111252.11.
DR GeneID; 10019; -.
DR KEGG; hsa:10019; -.
DR MANE-Select; ENST00000341259.7; ENSP00000345492.2; NM_005475.3; NP_005466.1.
DR UCSC; uc001tse.3; human.
DR CTD; 10019; -.
DR DisGeNET; 10019; -.
DR GeneCards; SH2B3; -.
DR HGNC; HGNC:29605; SH2B3.
DR HPA; ENSG00000111252; Tissue enhanced (bone).
DR MalaCards; SH2B3; -.
DR MIM; 222100; phenotype.
DR MIM; 605093; gene.
DR MIM; 612011; phenotype.
DR neXtProt; NX_Q9UQQ2; -.
DR OpenTargets; ENSG00000111252; -.
DR Orphanet; 3318; Essential thrombocythemia.
DR Orphanet; 391366; Growth retardation-mild developmental delay-chronic hepatitis syndrome.
DR PharmGKB; PA145148124; -.
DR VEuPathDB; HostDB:ENSG00000111252; -.
DR eggNOG; ENOG502QS89; Eukaryota.
DR GeneTree; ENSGT00950000183191; -.
DR HOGENOM; CLU_014885_3_0_1; -.
DR InParanoid; Q9UQQ2; -.
DR OMA; HADVTHF; -.
DR OrthoDB; 556279at2759; -.
DR PhylomeDB; Q9UQQ2; -.
DR TreeFam; TF323184; -.
DR PathwayCommons; Q9UQQ2; -.
DR Reactome; R-HSA-1433559; Regulation of KIT signaling.
DR Reactome; R-HSA-9706369; Negative regulation of FLT3.
DR Reactome; R-HSA-983231; Factors involved in megakaryocyte development and platelet production.
DR SignaLink; Q9UQQ2; -.
DR SIGNOR; Q9UQQ2; -.
DR BioGRID-ORCS; 10019; 16 hits in 1080 CRISPR screens.
DR ChiTaRS; SH2B3; human.
DR GeneWiki; SH2B3; -.
DR GenomeRNAi; 10019; -.
DR Pharos; Q9UQQ2; Tbio.
DR PRO; PR:Q9UQQ2; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q9UQQ2; protein.
DR Bgee; ENSG00000111252; Expressed in monocyte and 177 other tissues.
DR ExpressionAtlas; Q9UQQ2; baseline and differential.
DR Genevisible; Q9UQQ2; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:1990782; F:protein tyrosine kinase binding; ISS:BHF-UCL.
DR GO; GO:0030159; F:signaling receptor complex adaptor activity; ISS:BHF-UCL.
DR GO; GO:0005173; F:stem cell factor receptor binding; ISS:BHF-UCL.
DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; IBA:GO_Central.
DR GO; GO:1990869; P:cellular response to chemokine; ISS:ARUK-UCL.
DR GO; GO:0036016; P:cellular response to interleukin-3; ISS:ARUK-UCL.
DR GO; GO:0035162; P:embryonic hemopoiesis; ISS:BHF-UCL.
DR GO; GO:0048821; P:erythrocyte development; IMP:ARUK-UCL.
DR GO; GO:0060218; P:hematopoietic stem cell differentiation; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0035855; P:megakaryocyte development; ISS:ARUK-UCL.
DR GO; GO:0035702; P:monocyte homeostasis; ISS:BHF-UCL.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:ARUK-UCL.
DR GO; GO:0070100; P:negative regulation of chemokine-mediated signaling pathway; ISS:ARUK-UCL.
DR GO; GO:1900235; P:negative regulation of Kit signaling pathway; ISS:BHF-UCL.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; ISS:ARUK-UCL.
DR GO; GO:0090331; P:negative regulation of platelet aggregation; ISS:BHF-UCL.
DR GO; GO:0051898; P:negative regulation of protein kinase B signaling; ISS:ARUK-UCL.
DR GO; GO:0046426; P:negative regulation of receptor signaling pathway via JAK-STAT; IMP:ARUK-UCL.
DR GO; GO:0060761; P:negative regulation of response to cytokine stimulus; IMP:ARUK-UCL.
DR GO; GO:0042532; P:negative regulation of tyrosine phosphorylation of STAT protein; ISS:ARUK-UCL.
DR GO; GO:0001780; P:neutrophil homeostasis; ISS:BHF-UCL.
DR GO; GO:0038163; P:thrombopoietin-mediated signaling pathway; IDA:ARUK-UCL.
DR CDD; cd10412; SH2_SH2B3; 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; IPR030522; SH2B3.
DR InterPro; IPR035059; SH2B3_SH2.
DR PANTHER; PTHR10872; PTHR10872; 1.
DR PANTHER; PTHR10872:SF1; PTHR10872:SF1; 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 Diabetes mellitus; Phosphoprotein; Reference proteome; SH2 domain.
FT CHAIN 1..575
FT /note="SH2B adapter protein 3"
FT /id="PRO_0000084454"
FT DOMAIN 194..307
FT /note="PH"
FT DOMAIN 364..462
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT REGION 1..23
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 83..136
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 150..176
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 322..346
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 503..525
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 546..575
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..17
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 322..342
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 546..563
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 13
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O09039"
FT MOD_RES 103
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 120
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 150
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 330
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O09039"
FT VARIANT 182
FT /note="F -> L (in dbSNP:rs7972796)"
FT /id="VAR_046210"
FT VARIANT 208..575
FT /note="Missing (found in a patient with isolated
FT erythrocytosis; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:20843259"
FT /id="VAR_080828"
FT VARIANT 215
FT /note="A -> V (found in a patient with isolated
FT erythrocytosis; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:20843259"
FT /id="VAR_080829"
FT VARIANT 262
FT /note="W -> R (associated with susceptibility to CELIAC13
FT and IDDM; dbSNP:rs3184504)"
FT /evidence="ECO:0000269|PubMed:17554260,
FT ECO:0000269|PubMed:18311140"
FT /id="VAR_024168"
FT CONFLICT 309
FT /note="G -> GR (in Ref. 2; CAB42642)"
FT /evidence="ECO:0000305"
FT CONFLICT 491
FT /note="H -> P (in Ref. 2; CAB42642)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 575 AA; 63225 MW; EE30B9E21E0009E5 CRC64;
MNGPALQPSS PSSAPSASPA AAPRGWSEFC ELHAVAAARE LARQYWLFAR EHPQHAPLRA
ELVSLQFTDL FQRYFCREVR DGRAPGRDYR DTGRGPPAKA EASPEPGPGP AAPGLPKARS
SEELAPPRPP GPCSFQHFRR SLRHIFRRRS AGELPAAHTA AAPGTPGEAA ETPARPGLAK
KFLPWSLARE PPPEALKEAV LRYSLADEAS MDSGARWQRG RLALRRAPGP DGPDRVLELF
DPPKSSRPKL QAACSSIQEV RWCTRLEMPD NLYTFVLKVK DRTDIIFEVG DEQQLNSWMA
ELSECTGRGL ESTEAEMHIP SALEPSTSSS PRGSTDSLNQ GASPGGLLDP ACQKTDHFLS
CYPWFHGPIS RVKAAQLVQL QGPDAHGVFL VRQSETRRGE YVLTFNFQGI AKHLRLSLTE
RGQCRVQHLH FPSVVDMLHH FQRSPIPLEC GAACDVRLSS YVVVVSQPPG SCNTVLFPFS
LPHWDSESLP HWGSELGLPH LSSSGCPRGL SPEGLPGRSS PPEQIFHLVP SPEELANSLQ
HLEHEPVNRA RDSDYEMDSS SRSHLRAIDN QYTPL
