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   27-MAR-2024, entry version 176.
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 T1D, 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: Type 1 diabetes mellitus (T1D) [MIM:222100]: A multifactorial
CC       disorder of glucose homeostasis that is characterized by susceptibility
CC       to ketoacidosis in the absence of insulin therapy. Clinical features
CC       are polydipsia, polyphagia and polyuria which result from
CC       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 may be associated with variants affecting
CC       the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the SH2B adapter family. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
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; 24.
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; 9606-ENSP00000345492; -.
DR   PeptideAtlas; Q9UQQ2; -.
DR   ProteomicsDB; 85571; -.
DR   Antibodypedia; 1179; 296 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   AGR; HGNC:29605; -.
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; WLRSRSM; -.
DR   OrthoDB; 2995825at2759; -.
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; 18 hits in 1158 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 178 other cell types or tissues.
DR   ExpressionAtlas; Q9UQQ2; baseline and differential.
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:0043409; P:negative regulation of MAPK cascade; ISS:ARUK-UCL.
DR   GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:ARUK-UCL.
DR   GO; GO:0090331; P:negative regulation of platelet aggregation; ISS:BHF-UCL.
DR   GO; GO:0046426; P:negative regulation of receptor signaling pathway via JAK-STAT; IMP:ARUK-UCL.
DR   GO; GO:1904893; P:negative regulation of receptor signaling pathway via STAT; ISS:ARUK-UCL.
DR   GO; GO:0060761; P:negative regulation of response to cytokine stimulus; IMP: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; cd01231; PH_SH2B_family; 1.
DR   CDD; cd10412; SH2_SH2B3; 1.
DR   Gene3D; 6.10.140.110; -; 1.
DR   Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1.
DR   Gene3D; 3.30.505.10; SH2 domain; 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; IPR035059; SH2B3_SH2.
DR   PANTHER; PTHR10872; SH2B ADAPTER PROTEIN; 1.
DR   PANTHER; PTHR10872:SF1; SH2B ADAPTER PROTEIN 3; 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; SSF50729; PH domain-like; 1.
DR   SUPFAM; SSF109805; Phenylalanine zipper; 1.
DR   SUPFAM; SSF55550; SH2 domain; 1.
DR   PROSITE; PS50001; SH2; 1.
DR   Genevisible; Q9UQQ2; HS.
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; uncertain 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; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:20843259"
FT                   /id="VAR_080829"
FT   VARIANT         262
FT                   /note="W -> R (risk factor for CELIAC13; risk factor for
FT                   T1D; 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
//