ID   GRAP_HUMAN              Reviewed;         217 AA.
AC   Q13588;
DT   15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   27-MAR-2024, entry version 173.
DE   RecName: Full=GRB2-related adapter protein {ECO:0000305};
GN   Name=GRAP {ECO:0000312|HGNC:HGNC:4562};
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=8647802; DOI=10.1074/jbc.271.21.12129;
RA   Feng G.-S., Ouyang Y.-B., Hu D.-P., Shi Z.-Q., Gentz R., Ni J.;
RT   "Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases
RT   to the Ras pathway.";
RL   J. Biol. Chem. 271:12129-12132(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P.,
RA   Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y.,
RA   LaBaer J.;
RT   "Cloning of human full open reading frames in Gateway(TM) system entry
RT   vector (pDONR201).";
RL   Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16625196; DOI=10.1038/nature04689;
RA   Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA   Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA   Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA   Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA   DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA   Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA   Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA   LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA   Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA   Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA   Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA   Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA   Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT   "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT   human lineage.";
RL   Nature 440:1045-1049(2006).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Blood, and 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   [6]
RP   INTERACTION WITH LAT.
RX   PubMed=9489702; DOI=10.1016/s0092-8674(00)80901-0;
RA   Zhang W., Sloan-Lancaster J., Kitchen J., Trible R.P., Samelson L.E.;
RT   "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to
RT   cellular activation.";
RL   Cell 92:83-92(1998).
RN   [7]
RP   INTERACTION WITH SHB.
RX   PubMed=9484780; DOI=10.1038/sj.onc.1201607;
RA   Welsh M., Songyang Z., Frantz J.D., Trueb T., Reedquist K.A., Karlsson T.,
RA   Miyazaki M., Cantley L.C., Band H., Shoelson S.E.;
RT   "Stimulation through the T cell receptor leads to interactions between SHB
RT   and several signaling proteins.";
RL   Oncogene 16:891-901(1998).
RN   [8]
RP   INVOLVEMENT IN DFNB114, FUNCTION, AND VARIANT DFNB114 LEU-104.
RX   PubMed=30610177; DOI=10.1073/pnas.1810951116;
RA   Li C., Bademci G., Subasioglu A., Diaz-Horta O., Zhu Y., Liu J.,
RA   Mitchell T.G., Abad C., Seyhan S., Duman D., Cengiz F.B., Tokgoz-Yilmaz S.,
RA   Blanton S.H., Farooq A., Walz K., Zhai R.G., Tekin M.;
RT   "Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked
RT   to sensorineural hearing loss.";
RL   Proc. Natl. Acad. Sci. U.S.A. 116:1347-1352(2019).
CC   -!- FUNCTION: Couples signals from receptor and cytoplasmic tyrosine
CC       kinases to the Ras signaling pathway. Plays a role in the inner ear and
CC       in hearing (PubMed:30610177). {ECO:0000269|PubMed:30610177}.
CC   -!- SUBUNIT: Associates through its SH2 domain with ligand-activated
CC       receptors for stem cell factor (KIT) and erythropoietin (EPOR). Also
CC       forms a stable complex with the Bcr-Abl oncoprotein. GRAP is associated
CC       with the Ras guanine nucleotide exchange factor SOS1, primarily through
CC       its N-terminal SH3 domain. Interacts with phosphorylated LAT upon TCR
CC       activation. Interacts with SHB. {ECO:0000269|PubMed:9484780,
CC       ECO:0000269|PubMed:9489702}.
CC   -!- INTERACTION:
CC       Q13588; O14672: ADAM10; NbExp=2; IntAct=EBI-2847510, EBI-1536151;
CC       Q13588; P50570-2: DNM2; NbExp=3; IntAct=EBI-2847510, EBI-10968534;
CC       Q13588; Q7L190: DPPA4; NbExp=3; IntAct=EBI-2847510, EBI-710457;
CC       Q13588; P42858: HTT; NbExp=12; IntAct=EBI-2847510, EBI-466029;
CC       Q13588; Q93062: RBPMS; NbExp=3; IntAct=EBI-2847510, EBI-740322;
CC       Q13588; Q04864-2: REL; NbExp=3; IntAct=EBI-2847510, EBI-10829018;
CC       Q13588; O94900: TOX; NbExp=3; IntAct=EBI-2847510, EBI-9088321;
CC       Q13588; P19474: TRIM21; NbExp=8; IntAct=EBI-2847510, EBI-81290;
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250|UniProtKB:Q08012};
CC       Peripheral membrane protein {ECO:0000250|UniProtKB:Q08012}. Synapse
CC       {ECO:0000250|UniProtKB:Q08012}. Note=Localizes at the presynaptic
CC       terminal. {ECO:0000250|UniProtKB:Q08012}.
CC   -!- DISEASE: Deafness, autosomal recessive, 114 (DFNB114) [MIM:618456]: A
CC       form of non-syndromic deafness characterized by congenital profound
CC       sensorineural hearing loss. Sensorineural deafness results from damage
CC       to the neural receptors of the inner ear, the nerve pathways to the
CC       brain, or the area of the brain that receives sound information.
CC       {ECO:0000269|PubMed:30610177}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the GRB2/sem-5/DRK family. {ECO:0000305}.
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DR   EMBL; U52518; AAC50541.1; -; mRNA.
DR   EMBL; BT019981; AAV38784.1; -; mRNA.
DR   EMBL; CR541941; CAG46739.1; -; mRNA.
DR   EMBL; CR541966; CAG46764.1; -; mRNA.
DR   EMBL; AC003957; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC007952; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC035856; AAH35856.1; -; mRNA.
DR   EMBL; BC063035; AAH63035.1; -; mRNA.
DR   CCDS; CCDS11202.1; -.
DR   RefSeq; NP_001317077.1; NM_001330148.1.
DR   RefSeq; NP_006604.1; NM_006613.3.
DR   RefSeq; XP_016879518.1; XM_017024029.1.
DR   AlphaFoldDB; Q13588; -.
DR   SMR; Q13588; -.
DR   BioGRID; 115973; 13.
DR   IntAct; Q13588; 12.
DR   MINT; Q13588; -.
DR   STRING; 9606.ENSP00000284154; -.
DR   iPTMnet; Q13588; -.
DR   PhosphoSitePlus; Q13588; -.
DR   BioMuta; GRAP; -.
DR   DMDM; 3913785; -.
DR   MassIVE; Q13588; -.
DR   MaxQB; Q13588; -.
DR   PaxDb; 9606-ENSP00000284154; -.
DR   PeptideAtlas; Q13588; -.
DR   ProteomicsDB; 59585; -.
DR   Antibodypedia; 25855; 200 antibodies from 31 providers.
DR   DNASU; 10750; -.
DR   Ensembl; ENST00000284154.10; ENSP00000284154.5; ENSG00000154016.14.
DR   GeneID; 10750; -.
DR   KEGG; hsa:10750; -.
DR   MANE-Select; ENST00000284154.10; ENSP00000284154.5; NM_006613.4; NP_006604.1.
DR   UCSC; uc002guy.4; human.
DR   AGR; HGNC:4562; -.
DR   CTD; 10750; -.
DR   DisGeNET; 10750; -.
DR   GeneCards; GRAP; -.
DR   HGNC; HGNC:4562; GRAP.
DR   HPA; ENSG00000154016; Tissue enhanced (lymphoid).
DR   MalaCards; GRAP; -.
DR   MIM; 604330; gene.
DR   MIM; 618456; phenotype.
DR   neXtProt; NX_Q13588; -.
DR   OpenTargets; ENSG00000154016; -.
DR   Orphanet; 90636; Rare autosomal recessive non-syndromic sensorineural deafness type DFNB.
DR   PharmGKB; PA28958; -.
DR   VEuPathDB; HostDB:ENSG00000154016; -.
DR   eggNOG; KOG3601; Eukaryota.
DR   GeneTree; ENSGT00940000156254; -.
DR   HOGENOM; CLU_073617_1_0_1; -.
DR   InParanoid; Q13588; -.
DR   OMA; NKGDMLK; -.
DR   OrthoDB; 25371at2759; -.
DR   PhylomeDB; Q13588; -.
DR   TreeFam; TF354288; -.
DR   PathwayCommons; Q13588; -.
DR   Reactome; R-HSA-1433557; Signaling by SCF-KIT.
DR   SignaLink; Q13588; -.
DR   SIGNOR; Q13588; -.
DR   BioGRID-ORCS; 10750; 62 hits in 1141 CRISPR screens.
DR   ChiTaRS; GRAP; human.
DR   GeneWiki; GRAP; -.
DR   GenomeRNAi; 10750; -.
DR   Pharos; Q13588; Tbio.
DR   PRO; PR:Q13588; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; Q13588; Protein.
DR   Bgee; ENSG00000154016; Expressed in spleen and 101 other cell types or tissues.
DR   ExpressionAtlas; Q13588; baseline and differential.
DR   GO; GO:0008180; C:COP9 signalosome; IBA:GO_Central.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005654; C:nucleoplasm; IBA:GO_Central.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:0098793; C:presynapse; ISS:UniProtKB.
DR   GO; GO:0005154; F:epidermal growth factor receptor binding; IBA:GO_Central.
DR   GO; GO:0001784; F:phosphotyrosine residue binding; IBA:GO_Central.
DR   GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR   GO; GO:0007265; P:Ras protein signal transduction; TAS:ProtInc.
DR   GO; GO:0043408; P:regulation of MAPK cascade; IBA:GO_Central.
DR   GO; GO:0007605; P:sensory perception of sound; IDA:UniProtKB.
DR   GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR   CDD; cd09941; SH2_Grb2_like; 1.
DR   CDD; cd11951; SH3_GRAP_C; 1.
DR   CDD; cd11948; SH3_GRAP_N; 1.
DR   Gene3D; 3.30.505.10; SH2 domain; 1.
DR   Gene3D; 2.30.30.40; SH3 Domains; 2.
DR   InterPro; IPR035645; GRAP_N_SH3.
DR   InterPro; IPR043539; Grb2-like.
DR   InterPro; IPR000980; SH2.
DR   InterPro; IPR036860; SH2_dom_sf.
DR   InterPro; IPR036028; SH3-like_dom_sf.
DR   InterPro; IPR001452; SH3_domain.
DR   PANTHER; PTHR46037:SF2; GRB2-RELATED ADAPTER PROTEIN; 1.
DR   PANTHER; PTHR46037; PROTEIN ENHANCER OF SEVENLESS 2B; 1.
DR   Pfam; PF00017; SH2; 1.
DR   Pfam; PF00018; SH3_1; 2.
DR   PRINTS; PR00499; P67PHOX.
DR   PRINTS; PR00401; SH2DOMAIN.
DR   PRINTS; PR00452; SH3DOMAIN.
DR   SMART; SM00252; SH2; 1.
DR   SMART; SM00326; SH3; 2.
DR   SUPFAM; SSF55550; SH2 domain; 1.
DR   SUPFAM; SSF50044; SH3-domain; 2.
DR   PROSITE; PS50001; SH2; 1.
DR   PROSITE; PS50002; SH3; 2.
DR   Genevisible; Q13588; HS.
PE   1: Evidence at protein level;
KW   Deafness; Disease variant; Membrane; Non-syndromic deafness;
KW   Reference proteome; Repeat; SH2 domain; SH3 domain; Synapse.
FT   CHAIN           1..217
FT                   /note="GRB2-related adapter protein"
FT                   /id="PRO_0000088206"
FT   DOMAIN          1..58
FT                   /note="SH3 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT   DOMAIN          60..154
FT                   /note="SH2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT   DOMAIN          158..217
FT                   /note="SH3 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT   VARIANT         104
FT                   /note="Q -> L (in DFNB114; dbSNP:rs370564476)"
FT                   /evidence="ECO:0000269|PubMed:30610177"
FT                   /id="VAR_082111"
SQ   SEQUENCE   217 AA;  25337 MW;  09FEC2F3BAC0FAF8 CRC64;
     MESVALYSFQ ATESDELAFN KGDTLKILNM EDDQNWYKAE LRGVEGFIPK NYIRVKPHPW
     YSGRISRQLA EEILMKRNHL GAFLIRESES SPGEFSVSVN YGDQVQHFKV LREASGKYFL
     WEEKFNSLNE LVDFYRTTTI AKKRQIFLRD EEPLLKSPGA CFAQAQFDFS AQDPSQLSFR
     RGDIIEVLER PDPHWWRGRS CGRVGFFPRS YVQPVHL
//