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GARE1_HUMAN Reviewed; 876 AA.
Q9H706; Q0VAG3; Q0VAG4; Q8ND03; Q9BSF5;
06-FEB-2007, integrated into UniProtKB/Swiss-Prot.
06-FEB-2007, sequence version 2.
02-DEC-2020, entry version 145.
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; 10.
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; ENOG502QRDN; Eukaryota.
GeneTree; ENSGT00530000063834; -.
HOGENOM; CLU_014784_0_0_1; -.
InParanoid; Q9H706; -.
OMA; HMAMPRF; -.
OrthoDB; 288834at2759; -.
PhylomeDB; Q9H706; -.
TreeFam; TF329726; -.
PathwayCommons; Q9H706; -.
BioGRID-ORCS; 64762; 17 hits in 837 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 231 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