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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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Related Genes :
[GAREM1 C18orf11 FAM59A GAREM] GRB2-associated and regulator of MAPK protein 1 (GRB2-associated and regulator of MAPK1)
[GRB2 ASH] Growth factor receptor-bound protein 2 (Adapter protein GRB2) (Protein Ash) (SH2/SH3 adapter GRB2)
[Garem1 Fam59a Garem Gm944 Kiaa4238] GRB2-associated and regulator of MAPK protein (GRB2-associated and regulator of MAPK1)
[Grb2] Growth factor receptor-bound protein 2 (Adapter protein GRB2) (SH2/SH3 adapter GRB2)
[Grb2 Ash] Growth factor receptor-bound protein 2 (Adapter protein GRB2) (Protein Ash) (SH2/SH3 adapter GRB2)
[GRB2] Growth factor receptor-bound protein 2 (Adapter protein GRB2) (SH2/SH3 adapter GRB2)
[Mapk1 Erk2 Mapk Prkm1] Mitogen-activated protein kinase 1 (MAP kinase 1) (MAPK 1) (EC 2.7.11.24) (ERT1) (Extracellular signal-regulated kinase 2) (ERK-2) (MAP kinase isoform p42) (p42-MAPK) (Mitogen-activated protein kinase 2) (MAP kinase 2) (MAPK 2)
[GAB1] GRB2-associated-binding protein 1 (GRB2-associated binder 1) (Growth factor receptor bound protein 2-associated protein 1)
[MED28 EG1 FKSG20] Mediator of RNA polymerase II transcription subunit 28 (Endothelial-derived protein 1) (Mediator complex subunit 28) (Merlin and Grb2-interacting cytoskeletal protein) (Magicin) (Tumor angiogenesis marker EG-1)
[Themis] Protein THEMIS (Grb2-associating protein) (Gasp) (Protein thylex) (Thymocyte-expressed molecule involved in selection)
[SGIP1] SH3-containing GRB2-like protein 3-interacting protein 1 (Endophilin-3-interacting protein)
[SH3GL2 CNSA2 SH3D2A] Endophilin-A1 (EEN-B1) (Endophilin-1) (SH3 domain protein 2A) (SH3 domain-containing GRB2-like protein 2)
[Sgip1] SH3-containing GRB2-like protein 3-interacting protein 1 (Endophilin-3-interacting protein)
[Sgip1] SH3-containing GRB2-like protein 3-interacting protein 1 (Endophilin-3-interacting protein)
[Sh3gl2 Sh3d2a Sh3p4] Endophilin-A1 (Endophilin-1) (SH3 domain protein 2A) (SH3 domain-containing GRB2-like protein 2) (SH3p4)
[Mapk1 Erk2 Mapk Prkm1] Mitogen-activated protein kinase 1 (MAP kinase 1) (MAPK 1) (EC 2.7.11.24) (ERT1) (Extracellular signal-regulated kinase 2) (ERK-2) (MAP kinase isoform p42) (p42-MAPK) (Mitogen-activated protein kinase 2) (MAP kinase 2) (MAPK 2)
[GRAP] GRB2-related adapter protein
[MAPK1 ERK2 PRKM1 PRKM2] Mitogen-activated protein kinase 1 (MAP kinase 1) (MAPK 1) (EC 2.7.11.24) (ERT1) (Extracellular signal-regulated kinase 2) (ERK-2) (MAP kinase isoform p42) (p42-MAPK) (Mitogen-activated protein kinase 2) (MAP kinase 2) (MAPK 2)
[MAPK1 ERK2 PRKM1] Mitogen-activated protein kinase 1 (MAP kinase 1) (MAPK 1) (EC 2.7.11.24) (ERT1) (Extracellular signal-regulated kinase 2) (ERK-2) (Mitogen-activated protein kinase 2) (MAP kinase 2) (MAPK 2)
[Mapk3 Erk1 Prkm3] Mitogen-activated protein kinase 3 (MAP kinase 3) (MAPK 3) (EC 2.7.11.24) (ERT2) (Extracellular signal-regulated kinase 1) (ERK-1) (Insulin-stimulated MAP2 kinase) (MAP kinase isoform p44) (p44-MAPK) (MNK1) (Microtubule-associated protein 2 kinase) (p44-ERK1)
[SGIP1] SH3-containing GRB2-like protein 3-interacting protein 1 (Endophilin-3-interacting protein)
[FLT4 VEGFR3] Vascular endothelial growth factor receptor 3 (VEGFR-3) (EC 2.7.10.1) (Fms-like tyrosine kinase 4) (FLT-4) (Tyrosine-protein kinase receptor FLT4)
[FLT1 FLT FRT VEGFR1] Vascular endothelial growth factor receptor 1 (VEGFR-1) (EC 2.7.10.1) (Fms-like tyrosine kinase 1) (FLT-1) (Tyrosine-protein kinase FRT) (Tyrosine-protein kinase receptor FLT) (FLT) (Vascular permeability factor receptor)
[Csf1r Csfmr Fms] Macrophage colony-stimulating factor 1 receptor (CSF-1 receptor) (CSF-1-R) (CSF-1R) (M-CSF-R) (EC 2.7.10.1) (Proto-oncogene c-Fms) (CD antigen CD115)
[Mertk Mer] Tyrosine-protein kinase Mer (EC 2.7.10.1) (Proto-oncogene c-Mer) (Receptor tyrosine kinase MerTK)
[Khdrbs1] KH domain-containing, RNA-binding, signal transduction-associated protein 1 (GAP-associated tyrosine phosphoprotein p62) (Src-associated in mitosis 68 kDa protein) (Sam68) (p21 Ras GTPase-activating protein-associated p62) (p68)
[PTPRJ DEP1] Receptor-type tyrosine-protein phosphatase eta (Protein-tyrosine phosphatase eta) (R-PTP-eta) (EC 3.1.3.48) (Density-enhanced phosphatase 1) (DEP-1) (HPTP eta) (Protein-tyrosine phosphatase receptor type J) (R-PTP-J) (CD antigen CD148)
[PTPN11 PTP2C SHPTP2] Tyrosine-protein phosphatase non-receptor type 11 (EC 3.1.3.48) (Protein-tyrosine phosphatase 1D) (PTP-1D) (Protein-tyrosine phosphatase 2C) (PTP-2C) (SH-PTP2) (SHP-2) (Shp2) (SH-PTP3)
[KDR FLK1 VEGFR2] Vascular endothelial growth factor receptor 2 (VEGFR-2) (EC 2.7.10.1) (Fetal liver kinase 1) (FLK-1) (Kinase insert domain receptor) (KDR) (Protein-tyrosine kinase receptor flk-1) (CD antigen CD309)
[Flt1 Emrk2 Flt Vegfr1] Vascular endothelial growth factor receptor 1 (VEGFR-1) (EC 2.7.10.1) (Embryonic receptor kinase 2) (Fms-like tyrosine kinase 1) (FLT-1) (Tyrosine-protein kinase receptor FLT)

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