GARE1_HUMAN
ID GARE1_HUMAN Reviewed; 876 AA.
AC Q9H706; Q0VAG3; Q0VAG4; Q8ND03; Q9BSF5;
DT 06-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 06-FEB-2007, sequence version 2.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=GRB2-associated and regulator of MAPK protein 1;
DE AltName: Full=GRB2-associated and regulator of MAPK1;
GN Name=GAREM1; Synonyms=C18orf11, FAM59A, GAREM;
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 [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Colon;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Lung;
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 [4]
RP FUNCTION, INTERACTION WITH EGFR; GRB2 AND PTPN11, ALTERNATIVE SPLICING
RP (ISOFORMS 1 AND 2), PHOSPHORYLATION AT TYR-453 AND TYR-105, MUTAGENESIS OF
RP TYR-105 AND TYR-453, AND TISSUE SPECIFICITY.
RX PubMed=19509291; DOI=10.1074/jbc.m109.021139;
RA Tashiro K., Tsunematsu T., Okubo H., Ohta T., Sano E., Yamauchi E.,
RA Taniguchi H., Konishi H.;
RT "GAREM, a novel adaptor protein for growth factor receptor-bound protein 2,
RT contributes to cellular transformation through the activation of
RT extracellular signal-regulated kinase signaling.";
RL J. Biol. Chem. 284:20206-20214(2009).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-610 AND SER-614, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
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 [6]
RP STRUCTURE BY NMR OF 2-165.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the SAM_PNT-domain of the hypothetical protein
RT LOC64762.";
RL Submitted (OCT-2006) to the PDB data bank.
CC -!- FUNCTION: [Isoform 1]: Acts as an adapter protein that plays a role in
CC intracellular signaling cascades triggered either by the cell surface
CC activated epidermal growth factor receptor and/or cytoplasmic protein
CC tyrosine kinases. Promotes activation of the MAPK/ERK signaling
CC pathway. Plays a role in the regulation of cell proliferation.
CC {ECO:0000269|PubMed:19509291}.
CC -!- SUBUNIT: Isoform 1 interacts with EGFR. Isoform 1 interacts (via
CC proline-rich domain and phosphorylated at Tyr-105 and Tyr-453) with
CC GRB2 (via SH3 domains); the interaction occurs upon EGF stimulation.
CC Isoform 1 interacts (phosphorylated at Tyr-453) with PTPN11; the
CC interaction increases MAPK/ERK activity and does not affect the
CC GRB2/SOS complex formation. Isoform 2 does not interact with GRB2.
CC {ECO:0000269|PubMed:19509291}.
CC -!- INTERACTION:
CC Q9H706; P46108: CRK; NbExp=4; IntAct=EBI-3440103, EBI-886;
CC Q9H706; O75791: GRAP2; NbExp=4; IntAct=EBI-3440103, EBI-740418;
CC Q9H706; P62993: GRB2; NbExp=11; IntAct=EBI-3440103, EBI-401755;
CC Q9H706; O43639: NCK2; NbExp=3; IntAct=EBI-3440103, EBI-713635;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9H706-1; Sequence=Displayed;
CC Name=2; Synonyms=GAREM(S);
CC IsoId=Q9H706-2; Sequence=VSP_023047;
CC Name=3;
CC IsoId=Q9H706-3; Sequence=VSP_023048;
CC -!- TISSUE SPECIFICITY: Isoform 1 is ubiquitously expressed.
CC {ECO:0000269|PubMed:19509291}.
CC -!- PTM: On EGF stimulation, phosphorylated on Tyr-105 and Tyr-453.
CC {ECO:0000269|PubMed:19509291}.
CC -!- SIMILARITY: Belongs to the GAREM family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAD39149.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK025263; BAB15094.1; -; mRNA.
DR EMBL; AL834491; CAD39149.1; ALT_INIT; mRNA.
DR EMBL; BC005074; AAH05074.1; -; mRNA.
DR EMBL; BC121067; AAI21068.1; -; mRNA.
DR EMBL; BC121068; AAI21069.1; -; mRNA.
DR CCDS; CCDS11905.1; -. [Q9H706-3]
DR CCDS; CCDS56057.1; -. [Q9H706-1]
DR RefSeq; NP_001229338.1; NM_001242409.1. [Q9H706-1]
DR RefSeq; NP_073588.1; NM_022751.2. [Q9H706-3]
DR PDB; 2DKZ; NMR; -; A=801-871.
DR PDBsum; 2DKZ; -.
DR AlphaFoldDB; Q9H706; -.
DR SMR; Q9H706; -.
DR BioGRID; 122275; 25.
DR IntAct; Q9H706; 24.
DR STRING; 9606.ENSP00000269209; -.
DR iPTMnet; Q9H706; -.
DR PhosphoSitePlus; Q9H706; -.
DR BioMuta; GAREM1; -.
DR DMDM; 125991851; -.
DR EPD; Q9H706; -.
DR jPOST; Q9H706; -.
DR MassIVE; Q9H706; -.
DR MaxQB; Q9H706; -.
DR PaxDb; Q9H706; -.
DR PeptideAtlas; Q9H706; -.
DR PRIDE; Q9H706; -.
DR ProteomicsDB; 81068; -. [Q9H706-1]
DR ProteomicsDB; 81069; -. [Q9H706-2]
DR ProteomicsDB; 81070; -. [Q9H706-3]
DR Antibodypedia; 41891; 116 antibodies from 23 providers.
DR DNASU; 64762; -.
DR Ensembl; ENST00000269209.7; ENSP00000269209.6; ENSG00000141441.16. [Q9H706-1]
DR Ensembl; ENST00000399218.8; ENSP00000382165.3; ENSG00000141441.16. [Q9H706-3]
DR GeneID; 64762; -.
DR KEGG; hsa:64762; -.
DR MANE-Select; ENST00000269209.7; ENSP00000269209.6; NM_001242409.2; NP_001229338.1.
DR UCSC; uc002kxk.3; human. [Q9H706-1]
DR CTD; 64762; -.
DR DisGeNET; 64762; -.
DR GeneCards; GAREM1; -.
DR HGNC; HGNC:26136; GAREM1.
DR HPA; ENSG00000141441; Tissue enhanced (pancreas).
DR MIM; 617998; gene.
DR neXtProt; NX_Q9H706; -.
DR OpenTargets; ENSG00000141441; -.
DR PharmGKB; PA134888032; -.
DR VEuPathDB; HostDB:ENSG00000141441; -.
DR eggNOG; ENOG502QRDN; Eukaryota.
DR GeneTree; ENSGT00530000063834; -.
DR HOGENOM; CLU_014784_0_0_1; -.
DR InParanoid; Q9H706; -.
DR OMA; HNISGAC; -.
DR OrthoDB; 288834at2759; -.
DR PhylomeDB; Q9H706; -.
DR TreeFam; TF329726; -.
DR PathwayCommons; Q9H706; -.
DR SignaLink; Q9H706; -.
DR BioGRID-ORCS; 64762; 25 hits in 1062 CRISPR screens.
DR ChiTaRS; GAREM1; human.
DR EvolutionaryTrace; Q9H706; -.
DR GenomeRNAi; 64762; -.
DR Pharos; Q9H706; Tbio.
DR PRO; PR:Q9H706; -.
DR Proteomes; UP000005640; Chromosome 18.
DR RNAct; Q9H706; protein.
DR Bgee; ENSG00000141441; Expressed in cortical plate and 199 other tissues.
DR ExpressionAtlas; Q9H706; baseline and differential.
DR Genevisible; Q9H706; HS.
DR GO; GO:0005886; C:plasma membrane; NAS:UniProtKB.
DR GO; GO:0070064; F:proline-rich region binding; IDA:UniProtKB.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IDA:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
DR Gene3D; 1.10.150.50; -; 1.
DR InterPro; IPR025946; CABIT_dom.
DR InterPro; IPR013761; SAM/pointed_sf.
DR Pfam; PF12736; CABIT; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Mitogen; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..876
FT /note="GRB2-associated and regulator of MAPK protein 1"
FT /id="PRO_0000277647"
FT DOMAIN 811..876
FT /note="SAM"
FT REGION 12..320
FT /note="CABIT"
FT REGION 496..572
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 498..550
FT /note="Necessary for interaction with GRB2"
FT /evidence="ECO:0000269|PubMed:19509291"
FT REGION 626..664
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 738..763
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 545..572
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 626..658
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 105
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:19509291"
FT MOD_RES 453
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:19509291"
FT MOD_RES 610
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 614
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 495..563
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_023047"
FT VAR_SEQ 579
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_023048"
FT VARIANT 243
FT /note="T -> N (in dbSNP:rs671138)"
FT /id="VAR_030580"
FT VARIANT 291
FT /note="K -> R (in dbSNP:rs3744921)"
FT /id="VAR_030581"
FT VARIANT 490
FT /note="A -> V (in dbSNP:rs16962974)"
FT /id="VAR_030582"
FT VARIANT 580
FT /note="V -> I (in dbSNP:rs3891458)"
FT /id="VAR_030583"
FT VARIANT 720
FT /note="T -> M (in dbSNP:rs2276374)"
FT /id="VAR_030584"
FT MUTAGEN 105
FT /note="Y->F: Does not abolish phosphorylation upon EGF
FT stimulation. Reduces interaction with GRB2. Abolishes
FT phosphorylation, interaction with GRB2 and ERK activation
FT upon EGF stimulation; when associated with F-453."
FT /evidence="ECO:0000269|PubMed:19509291"
FT MUTAGEN 453
FT /note="Y->F: Does not abolish phosphorylation upon EGF
FT stimulation. Abolishes interaction with PTPN11. Abolishes
FT phosphorylation upon EGF stimulation; when associated with
FT F-105."
FT /evidence="ECO:0000269|PubMed:19509291"
FT HELIX 813..819
FT /evidence="ECO:0007829|PDB:2DKZ"
FT HELIX 820..822
FT /evidence="ECO:0007829|PDB:2DKZ"
FT HELIX 827..834
FT /evidence="ECO:0007829|PDB:2DKZ"
FT TURN 835..837
FT /evidence="ECO:0007829|PDB:2DKZ"
FT HELIX 840..845
FT /evidence="ECO:0007829|PDB:2DKZ"
FT HELIX 848..853
FT /evidence="ECO:0007829|PDB:2DKZ"
FT HELIX 859..870
FT /evidence="ECO:0007829|PDB:2DKZ"
SQ 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
