GRB2-associated and regulator of MAPK protein 1 (GRB2-associated and regulator of MAPK1)

 GARE1_HUMAN             Reviewed;         876 AA.
 Q9H706; Q0VAG3; Q0VAG4; Q8ND03; Q9BSF5;
 06-FEB-2007, integrated into UniProtKB/Swiss-Prot.
 06-FEB-2007, sequence version 2.
 17-JUN-2020, entry version 142.
 RecName: Full=GRB2-associated and regulator of MAPK protein 1;
 AltName: Full=GRB2-associated and regulator of MAPK1;
 Name=GAREM1; Synonyms=C18orf11, FAM59A, GAREM;
 Homo sapiens (Human).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
 Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
 Homo.
 NCBI_TaxID=9606;
 [1]
 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
 TISSUE=Colon;
 PubMed=14702039; DOI=10.1038/ng1285;
 Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
 Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
 Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
 Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
 Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
 Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
 Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
 Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
 Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
 Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
 Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
 Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
 Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
 Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
 Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
 Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
 Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
 Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
 Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
 Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
 Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
 Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
 Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
 Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
 Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
 Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
 Isogai T., Sugano S.;
 "Complete sequencing and characterization of 21,243 full-length human
 cDNAs.";
 Nat. Genet. 36:40-45(2004).
 [2]
 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
 TISSUE=Testis;
 PubMed=17974005; DOI=10.1186/1471-2164-8-399;
 Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
 Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
 Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
 Wiemann S., Schupp I.;
 "The full-ORF clone resource of the German cDNA consortium.";
 BMC Genomics 8:399-399(2007).
 [3]
 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
 TISSUE=Lung;
 PubMed=15489334; DOI=10.1101/gr.2596504;
 The MGC Project Team;
 "The status, quality, and expansion of the NIH full-length cDNA project:
 the Mammalian Gene Collection (MGC).";
 Genome Res. 14:2121-2127(2004).
 [4]
 FUNCTION, INTERACTION WITH EGFR; GRB2 AND PTPN11, ALTERNATIVE SPLICING
 (ISOFORMS 1 AND 2), PHOSPHORYLATION AT TYR-453 AND TYR-105, MUTAGENESIS OF
 TYR-105 AND TYR-453, AND TISSUE SPECIFICITY.
 PubMed=19509291; DOI=10.1074/jbc.m109.021139;
 Tashiro K., Tsunematsu T., Okubo H., Ohta T., Sano E., Yamauchi E.,
 Taniguchi H., Konishi H.;
 "GAREM, a novel adaptor protein for growth factor receptor-bound protein 2,
 contributes to cellular transformation through the activation of
 extracellular signal-regulated kinase signaling.";
 J. Biol. Chem. 284:20206-20214(2009).
 [5]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-610 AND SER-614, AND
 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 TISSUE=Cervix carcinoma;
 PubMed=23186163; DOI=10.1021/pr300630k;
 Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
 Mohammed S.;
 "Toward a comprehensive characterization of a human cancer cell
 phosphoproteome.";
 J. Proteome Res. 12:260-271(2013).
 [6]
 STRUCTURE BY NMR OF 2-165.
 RIKEN structural genomics initiative (RSGI);
 "Solution structure of the SAM_PNT-domain of the hypothetical protein
 LOC64762.";
 Submitted (OCT-2006) to the PDB data bank.
 -!- FUNCTION: [Isoform 1]: Acts as an adapter protein that plays a role in
     intracellular signaling cascades triggered either by the cell surface
     activated epidermal growth factor receptor and/or cytoplasmic protein
     tyrosine kinases. Promotes activation of the MAPK/ERK signaling
     pathway. Plays a role in the regulation of cell proliferation.
     {ECO:0000269|PubMed:19509291}.
 -!- SUBUNIT: Isoform 1 interacts with EGFR. Isoform 1 interacts (via
     proline-rich domain and phosphorylated at Tyr-105 and Tyr-453) with
     GRB2 (via SH3 domains); the interaction occurs upon EGF stimulation.
     Isoform 1 interacts (phosphorylated at Tyr-453) with PTPN11; the
     interaction increases MAPK/ERK activity and does not affect the
     GRB2/SOS complex formation. Isoform 2 does not interact with GRB2.
     {ECO:0000269|PubMed:19509291}.
 -!- INTERACTION:
     Q9H706; O75791: GRAP2; NbExp=4; IntAct=EBI-3440103, EBI-740418;
     Q9H706; P62993: GRB2; NbExp=11; IntAct=EBI-3440103, EBI-401755;
     Q9H706; O43639: NCK2; NbExp=3; IntAct=EBI-3440103, EBI-713635;
 -!- ALTERNATIVE PRODUCTS:
     Event=Alternative splicing; Named isoforms=3;
     Name=1;
       IsoId=Q9H706-1; Sequence=Displayed;
     Name=2; Synonyms=GAREM(S);
       IsoId=Q9H706-2; Sequence=VSP_023047;
     Name=3;
       IsoId=Q9H706-3; Sequence=VSP_023048;
 -!- TISSUE SPECIFICITY: Isoform 1 is ubiquitously expressed.
     {ECO:0000269|PubMed:19509291}.
 -!- PTM: On EGF stimulation, phosphorylated on Tyr-105 and Tyr-453.
     {ECO:0000269|PubMed:19509291}.
 -!- SIMILARITY: Belongs to the GAREM family. {ECO:0000305}.
 -!- SEQUENCE CAUTION:
     Sequence=CAD39149.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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 EMBL; AK025263; BAB15094.1; -; mRNA.
 EMBL; AL834491; CAD39149.1; ALT_INIT; mRNA.
 EMBL; BC005074; AAH05074.1; -; mRNA.
 EMBL; BC121067; AAI21068.1; -; mRNA.
 EMBL; BC121068; AAI21069.1; -; mRNA.
 CCDS; CCDS11905.1; -. [Q9H706-3]
 CCDS; CCDS56057.1; -. [Q9H706-1]
 RefSeq; NP_001229338.1; NM_001242409.1. [Q9H706-1]
 RefSeq; NP_073588.1; NM_022751.2. [Q9H706-3]
 PDB; 2DKZ; NMR; -; A=801-871.
 PDBsum; 2DKZ; -.
 SMR; Q9H706; -.
 BioGRID; 122275; 9.
 IntAct; Q9H706; 22.
 STRING; 9606.ENSP00000269209; -.
 iPTMnet; Q9H706; -.
 PhosphoSitePlus; Q9H706; -.
 BioMuta; GAREM1; -.
 DMDM; 125991851; -.
 jPOST; Q9H706; -.
 MassIVE; Q9H706; -.
 MaxQB; Q9H706; -.
 PaxDb; Q9H706; -.
 PeptideAtlas; Q9H706; -.
 PRIDE; Q9H706; -.
 ProteomicsDB; 81068; -. [Q9H706-1]
 ProteomicsDB; 81069; -. [Q9H706-2]
 ProteomicsDB; 81070; -. [Q9H706-3]
 Antibodypedia; 41891; 108 antibodies.
 Ensembl; ENST00000269209; ENSP00000269209; ENSG00000141441. [Q9H706-1]
 Ensembl; ENST00000399218; ENSP00000382165; ENSG00000141441. [Q9H706-3]
 GeneID; 64762; -.
 KEGG; hsa:64762; -.
 UCSC; uc002kxk.3; human. [Q9H706-1]
 CTD; 64762; -.
 DisGeNET; 64762; -.
 EuPathDB; HostDB:ENSG00000141441.15; -.
 GeneCards; GAREM1; -.
 HGNC; HGNC:26136; GAREM1.
 HPA; ENSG00000141441; Tissue enhanced (pancreas).
 MIM; 617998; gene.
 neXtProt; NX_Q9H706; -.
 OpenTargets; ENSG00000141441; -.
 PharmGKB; PA134888032; -.
 eggNOG; ENOG410II0U; Eukaryota.
 eggNOG; ENOG410XSPW; LUCA.
 GeneTree; ENSGT00530000063834; -.
 HOGENOM; CLU_014784_0_0_1; -.
 InParanoid; Q9H706; -.
 OMA; HMAMPRF; -.
 OrthoDB; 288834at2759; -.
 PhylomeDB; Q9H706; -.
 TreeFam; TF329726; -.
 BioGRID-ORCS; 64762; 16 hits in 781 CRISPR screens.
 ChiTaRS; GAREM1; human.
 EvolutionaryTrace; Q9H706; -.
 GenomeRNAi; 64762; -.
 Pharos; Q9H706; Tbio.
 PRO; PR:Q9H706; -.
 Proteomes; UP000005640; Chromosome 18.
 RNAct; Q9H706; protein.
 Bgee; ENSG00000141441; Expressed in frontal cortex and 217 other tissues.
 ExpressionAtlas; Q9H706; baseline and differential.
 Genevisible; Q9H706; HS.
 GO; GO:0005886; C:plasma membrane; NAS:UniProtKB.
 GO; GO:0070064; F:proline-rich region binding; IDA:UniProtKB.
 GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IDA:UniProtKB.
 GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:UniProtKB.
 GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
 GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:UniProtKB.
 GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
 Gene3D; 1.10.150.50; -; 1.
 InterPro; IPR025946; CABIT_dom.
 InterPro; IPR013761; SAM/pointed_sf.
 Pfam; PF12736; CABIT; 1.
 SUPFAM; SSF47769; SSF47769; 1.
 1: Evidence at protein level;
 3D-structure; Alternative splicing; Mitogen; Phosphoprotein; Polymorphism;
 Reference proteome.
 CHAIN           1..876
                 /note="GRB2-associated and regulator of MAPK protein 1"
                 /id="PRO_0000277647"
 DOMAIN          811..876
                 /note="SAM"
 REGION          12..320
                 /note="CABIT"
 REGION          498..550
                 /note="Necessary for interaction with GRB2"
                 /evidence="ECO:0000269|PubMed:19509291"
 COMPBIAS        512..566
                 /note="Pro-rich"
 MOD_RES         105
                 /note="Phosphotyrosine"
                 /evidence="ECO:0000269|PubMed:19509291"
 MOD_RES         453
                 /note="Phosphotyrosine"
                 /evidence="ECO:0000269|PubMed:19509291"
 MOD_RES         610
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:23186163"
 MOD_RES         614
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:23186163"
 VAR_SEQ         495..563
                 /note="Missing (in isoform 2)"
                 /evidence="ECO:0000303|PubMed:15489334"
                 /id="VSP_023047"
 VAR_SEQ         579
                 /note="Missing (in isoform 3)"
                 /evidence="ECO:0000303|PubMed:14702039"
                 /id="VSP_023048"
 VARIANT         243
                 /note="T -> N (in dbSNP:rs671138)"
                 /id="VAR_030580"
 VARIANT         291
                 /note="K -> R (in dbSNP:rs3744921)"
                 /id="VAR_030581"
 VARIANT         490
                 /note="A -> V (in dbSNP:rs16962974)"
                 /id="VAR_030582"
 VARIANT         580
                 /note="V -> I (in dbSNP:rs3891458)"
                 /id="VAR_030583"
 VARIANT         720
                 /note="T -> M (in dbSNP:rs2276374)"
                 /id="VAR_030584"
 MUTAGEN         105
                 /note="Y->F: Does not abolish phosphorylation upon EGF
                 stimulation. Reduces interaction with GRB2. Abolishes
                 phosphorylation, interaction with GRB2 and ERK activation
                 upon EGF stimulation; when associated with F-453."
                 /evidence="ECO:0000269|PubMed:19509291"
 MUTAGEN         453
                 /note="Y->F: Does not abolish phosphorylation upon EGF
                 stimulation. Abolishes interaction with PTPN11. Abolishes
                 phosphorylation upon EGF stimulation; when associated with
                 F-105."
                 /evidence="ECO:0000269|PubMed:19509291"
 HELIX           813..819
                 /evidence="ECO:0000244|PDB:2DKZ"
 HELIX           820..822
                 /evidence="ECO:0000244|PDB:2DKZ"
 HELIX           827..834
                 /evidence="ECO:0000244|PDB:2DKZ"
 TURN            835..837
                 /evidence="ECO:0000244|PDB:2DKZ"
 HELIX           840..845
                 /evidence="ECO:0000244|PDB:2DKZ"
 HELIX           848..853
                 /evidence="ECO:0000244|PDB:2DKZ"
 HELIX           859..870
                 /evidence="ECO:0000244|PDB:2DKZ"
 SEQUENCE   876 AA;  97186 MW;  668EBABC9CDE4CDF CRC64;
 MDPAPSLGCS LKDVKWSSVA VPLDLLVSTY RLPQIARLDN GECVEGLREN DYLLIHSCRQ
 WTTITAHSLE EGHYVIGPKI EIPVHYAGQF KLLEQDRDIK EPVQYFNSVE EVAKAFPERV
 YVMEDITFNV KVASGECNED TEVYNITLCT GDELTLMGQA EILYAKTFKE KSRLNTIFKK
 IGKLNSISKL GKGKMPCLIC MNHRTNESIS LPFQCKGRFS TRSPLELQMQ EGEHTIRNIV
 EKTRLPVNVT VPSPPPRNPY DLHFIREGHR YKFVNIQTKT VVVCCVLRNN KILPMHFPLH
 LTVPKFSLPE HLVKGESWPE TLVHHWLGIC QEQFDIDEYS RAVRDVKTDW NEECKSPKKG
 RCSGHNHVPN SLSYARDELT QSFHRLSVCV YGNNLHGNSE VNLHGCRDLG GDWAPFPHDI
 LPYQDSGDSG SDYLFPEASE ESAGIPGKSE LPYEELWLEE GKPSHQPLTR SLSEKNRCDQ
 FRGSVRSKCA TSPLPIPGTL GAAVKSSDTA LPPPPVPPKS EAVREECRLL NAPPVPPRSA
 KPLSTSPSIP PRTVKPARQQ TRSPSPTLSY YSSGLHNISV TKTDTNPSES TPVSCYPCNR
 VKTDSVDLKS PFGSPSAEAV SSRLSWPNHY SGASESQTRS DFLLDPSRSY SYPRQKTPGT
 PKRNCPAPFD FDGCELLASP TSPVTAEFSS SVSGCPKSAS YSLESTDVKS LAAGVTKQST
 SCPALPPRAP KLVEEKVASE TSPLPLKIDG AEEDPKSGSP DLSEDQYFVK KGMQDIFSAS
 YPFSSPLHLQ LAPRSCGDGS PWQPPADLSG LSIEEVSKSL RFIGLSEDVI SFFVTEKIDG
 NLLVQLTEEI LSEDFKLSKL QVKKIMQFIN GWRPKI

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