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.
 16-OCT-2019, entry version 138.
 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:
     O75791:GRAP2; NbExp=3; IntAct=EBI-3440103, EBI-740418;
     P62993:GRB2; NbExp=8; IntAct=EBI-3440103, EBI-401755;
 -!- 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; 10.
 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]
 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; -.
 GeneCards; GAREM1; -.
 HGNC; HGNC:26136; GAREM1.
 HPA; HPA040709; -.
 HPA; HPA042046; -.
 MIM; 617998; gene.
 neXtProt; NX_Q9H706; -.
 OpenTargets; ENSG00000141441; -.
 PharmGKB; PA134888032; -.
 eggNOG; ENOG410II0U; Eukaryota.
 eggNOG; ENOG410XSPW; LUCA.
 GeneTree; ENSGT00530000063834; -.
 HOGENOM; HOG000074085; -.
 InParanoid; Q9H706; -.
 OMA; HMAMPRF; -.
 OrthoDB; 288834at2759; -.
 PhylomeDB; Q9H706; -.
 TreeFam; TF329726; -.
 ChiTaRS; GAREM1; human.
 EvolutionaryTrace; Q9H706; -.
 GenomeRNAi; 64762; -.
 Pharos; Q9H706; -.
 PRO; PR:Q9H706; -.
 Proteomes; UP000005640; Chromosome 18.
 Bgee; ENSG00000141441; Expressed in 218 organ(s), highest expression level in frontal cortex.
 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; Complete proteome; Mitogen;
 Phosphoprotein; Polymorphism; Reference proteome.
 CHAIN         1    876       GRB2-associated and regulator of MAPK
                              protein 1.
                              /FTId=PRO_0000277647.
 DOMAIN      811    876       SAM.
 REGION       12    320       CABIT.
 REGION      498    550       Necessary for interaction with GRB2.
                              {ECO:0000269|PubMed:19509291}.
 COMPBIAS    512    566       Pro-rich.
 MOD_RES     105    105       Phosphotyrosine.
                              {ECO:0000269|PubMed:19509291}.
 MOD_RES     453    453       Phosphotyrosine.
                              {ECO:0000269|PubMed:19509291}.
 MOD_RES     610    610       Phosphoserine.
                              {ECO:0000244|PubMed:23186163}.
 MOD_RES     614    614       Phosphoserine.
                              {ECO:0000244|PubMed:23186163}.
 VAR_SEQ     495    563       Missing (in isoform 2).
                              {ECO:0000303|PubMed:15489334}.
                              /FTId=VSP_023047.
 VAR_SEQ     579    579       Missing (in isoform 3).
                              {ECO:0000303|PubMed:14702039}.
                              /FTId=VSP_023048.
 VARIANT     243    243       T -> N (in dbSNP:rs671138).
                              /FTId=VAR_030580.
 VARIANT     291    291       K -> R (in dbSNP:rs3744921).
                              /FTId=VAR_030581.
 VARIANT     490    490       A -> V (in dbSNP:rs16962974).
                              /FTId=VAR_030582.
 VARIANT     580    580       V -> I (in dbSNP:rs3891458).
                              /FTId=VAR_030583.
 VARIANT     720    720       T -> M (in dbSNP:rs2276374).
                              /FTId=VAR_030584.
 MUTAGEN     105    105       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.
                              {ECO:0000269|PubMed:19509291}.
 MUTAGEN     453    453       Y->F: Does not abolish phosphorylation
                              upon EGF stimulation. Abolishes
                              interaction with PTPN11. Abolishes
                              phosphorylation upon EGF stimulation;
                              when associated with F-105.
                              {ECO:0000269|PubMed:19509291}.
 HELIX       813    819       {ECO:0000244|PDB:2DKZ}.
 HELIX       820    822       {ECO:0000244|PDB:2DKZ}.
 HELIX       827    834       {ECO:0000244|PDB:2DKZ}.
 TURN        835    837       {ECO:0000244|PDB:2DKZ}.
 HELIX       840    845       {ECO:0000244|PDB:2DKZ}.
 HELIX       848    853       {ECO:0000244|PDB:2DKZ}.
 HELIX       859    870       {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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