Full text data of RAPGEF2
RAPGEF2
(KIAA0313, NRAPGEP, PDZGEF1)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Rap guanine nucleotide exchange factor 2 (Cyclic nucleotide ras GEF; CNrasGEF; Neural RAP guanine nucleotide exchange protein; nRap GEP; PDZ domain-containing guanine nucleotide exchange factor 1; PDZ-GEF1; RA-GEF-1; Ras/Rap1-associating GEF-1)
Rap guanine nucleotide exchange factor 2 (Cyclic nucleotide ras GEF; CNrasGEF; Neural RAP guanine nucleotide exchange protein; nRap GEP; PDZ domain-containing guanine nucleotide exchange factor 1; PDZ-GEF1; RA-GEF-1; Ras/Rap1-associating GEF-1)
UniProt
Q9Y4G8
ID RPGF2_HUMAN Reviewed; 1499 AA.
AC Q9Y4G8; D3DP27;
DT 29-AUG-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1999, sequence version 1.
DT 22-JAN-2014, entry version 117.
DE RecName: Full=Rap guanine nucleotide exchange factor 2;
DE AltName: Full=Cyclic nucleotide ras GEF;
DE Short=CNrasGEF;
DE AltName: Full=Neural RAP guanine nucleotide exchange protein;
DE Short=nRap GEP;
DE AltName: Full=PDZ domain-containing guanine nucleotide exchange factor 1;
DE Short=PDZ-GEF1;
DE AltName: Full=RA-GEF-1;
DE AltName: Full=Ras/Rap1-associating GEF-1;
GN Name=RAPGEF2; Synonyms=KIAA0313, NRAPGEP, PDZGEF1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=9205841; DOI=10.1093/dnares/4.2.141;
RA Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. VII.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 4:141-150(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION, AND INTERACTION WITH MAGI2.
RX PubMed=10548487; DOI=10.1006/bbrc.1999.1619;
RA Ohtsuka T., Hata Y., Ide N., Yasuda T., Inoue E., Inoue T.,
RA Mizoguchi A., Takai Y.;
RT "nRap GEP: a novel neural GDP/GTP exchange protein for rap1 small G
RT protein that interacts with synaptic scaffolding molecule (S-SCAM).";
RL Biochem. Biophys. Res. Commun. 265:38-44(1999).
RN [4]
RP FUNCTION, AND INTERACTION WITH HRAS AND RAP1A.
RX PubMed=10608844; DOI=10.1074/jbc.274.53.37815;
RA Liao Y., Kariya K., Hu C.-D., Shibatohge M., Goshima M., Okada T.,
RA Watari Y., Gao X., Jin T.-G., Yamawaki-Kataoka Y., Kataoka T.;
RT "RA-GEF, a novel Rap1A guanine nucleotide exchange factor containing a
RT Ras/Rap1A-associating domain, is conserved between nematode and
RT humans.";
RL J. Biol. Chem. 274:37815-37820(1999).
RN [5]
RP FUNCTION.
RX PubMed=10608883; DOI=10.1074/jbc.274.53.38125;
RA de Rooij J., Boenink N.M., van Triest M., Cool R.H., Wittinghofer A.,
RA Bos J.L.;
RT "PDZ-GEF1, a guanine nucleotide exchange factor specific for Rap1 and
RT Rap2.";
RL J. Biol. Chem. 274:38125-38130(1999).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-211; ARG-215;
RP 396-PRO--PHE-399 AND 1497-SER-VAL-1499.
RX PubMed=10801446; DOI=10.1016/S0960-9822(00)00473-5;
RA Pham N., Cheglakov I., Koch C.A., de Hoog C.L., Moran M.F., Rotin D.;
RT "The guanine nucleotide exchange factor CNrasGEF activates ras in
RT response to cAMP and cGMP.";
RL Curr. Biol. 10:555-558(2000).
RN [7]
RP INTERACTION WITH MAGI1, AND TISSUE SPECIFICITY.
RX PubMed=11168587; DOI=10.1046/j.1365-2443.2000.00385.x;
RA Mino A., Ohtsuka T., Inoue E., Takai Y.;
RT "Membrane-associated guanylate kinase with inverted orientation
RT (MAGI)-1/brain angiogenesis inhibitor 1-associated protein (BAP1) as a
RT scaffolding molecule for Rap small G protein GDP/GTP exchange protein
RT at tight junctions.";
RL Genes Cells 5:1009-1016(2000).
RN [8]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=10934204; DOI=10.1074/jbc.M005327200;
RA Rebhun J.F., Castro A.F., Quilliam L.A.;
RT "Identification of guanine nucleotide exchange factors (GEFs) for the
RT Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction.";
RL J. Biol. Chem. 275:34901-34908(2000).
RN [9]
RP FUNCTION, INTERACTION WITH RAP1A, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF 606-PRO--LYS-626.
RX PubMed=11359771; DOI=10.1074/jbc.M101737200;
RA Liao Y., Satoh T., Gao X., Jin T.G., Hu C.D., Kataoka T.;
RT "RA-GEF-1, a guanine nucleotide exchange factor for Rap1, is activated
RT by translocation induced by association with Rap1*GTP and enhances
RT Rap1-dependent B-Raf activation.";
RL J. Biol. Chem. 276:28478-28483(2001).
RN [10]
RP INTERACTION WITH HRAS AND NEDD4, UBIQUITINATION BY NEDD4, AND
RP MUTAGENESIS OF ARG-898; TYR-1406 AND TYR-1428.
RX PubMed=11598133; DOI=10.1074/jbc.M108373200;
RA Pham N., Rotin D.;
RT "Nedd4 regulates ubiquitination and stability of the guanine-
RT nucleotide exchange factor CNrasGEF.";
RL J. Biol. Chem. 276:46995-47003(2001).
RN [11]
RP FUNCTION, AND INTERACTION WITH ADRB1.
RX PubMed=12391161; DOI=10.1128/MCB.22.22.7942-7952.2002;
RA Pak Y., Pham N., Rotin D.;
RT "Direct binding of the beta1 adrenergic receptor to the cyclic AMP-
RT dependent guanine nucleotide exchange factor CNrasGEF leads to Ras
RT activation.";
RL Mol. Cell. Biol. 22:7942-7952(2002).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [13]
RP FUNCTION.
RX PubMed=16272156; DOI=10.1074/jbc.M507595200;
RA Amsen E.M., Pham N., Pak Y., Rotin D.;
RT "The guanine nucleotide exchange factor CNrasGEF regulates
RT melanogenesis and cell survival in melanoma cells.";
RL J. Biol. Chem. 281:121-128(2006).
RN [14]
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH KIDINS220; MAGI2 AND NTRK1,
RP AND SUBCELLULAR LOCATION.
RX PubMed=17724123; DOI=10.1083/jcb.200610073;
RA Hisata S., Sakisaka T., Baba T., Yamada T., Aoki K., Matsuda M.,
RA Takai Y.;
RT "Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late
RT endosomes, leading to sustained activation of Rap1 and ERK and neurite
RT outgrowth.";
RL J. Cell Biol. 178:843-860(2007).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1022, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [21]
RP FUNCTION.
RX PubMed=21840392; DOI=10.1016/j.cellsig.2011.07.022;
RA Pannekoek W.J., van Dijk J.J., Chan O.Y., Huveneers S.,
RA Linnemann J.R., Spanjaard E., Brouwer P.M., van der Meer A.J.,
RA Zwartkruis F.J., Rehmann H., de Rooij J., Bos J.L.;
RT "Epac1 and PDZ-GEF cooperate in Rap1 mediated endothelial junction
RT control.";
RL Cell. Signal. 23:2056-2064(2011).
RN [22]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=23800469; DOI=10.1126/scisignal.2003993;
RA Emery A.C., Eiden M.V., Mustafa T., Eiden L.E.;
RT "Rapgef2 Connects GPCR-Mediated cAMP Signals to ERK Activation in
RT Neuronal and Endocrine Cells.";
RL Sci. Signal. 6:RA51-RA51(2013).
CC -!- FUNCTION: Functions as a guanine nucleotide exchange factor (GEF),
CC which activates Rap and Ras family of small GTPases by exchanging
CC bound GDP for free GTP in a cAMP-dependent manner. Serves as a
CC link between cell surface receptors and Rap/Ras GTPases in
CC intracellular signaling cascades. Acts also as an effector for
CC Rap1 by direct association with Rap1-GTP thereby leading to the
CC amplification of Rap1-mediated signaling. Shows weak activity on
CC HRAS. It is controversial whether RAPGEF2 binds cAMP and cGMP
CC (PubMed:23800469, PubMed:10801446) or not (PubMed:10608844,
CC PubMed:10548487, PubMed:11359771). Its binding to ligand-activated
CC beta-1 adrenergic receptor ADRB1 leads to the Ras activation
CC through the G(s)-alpha signaling pathway. Involved in the cAMP-
CC induced Ras and Erk1/2 signaling pathway that leads to sustained
CC inhibition of long term melanogenesis by reducing dendrite
CC extension and melanin synthesis. Provides also inhibitory signals
CC for cell proliferation of melanoma cells and promotes their
CC apoptosis in a cAMP-independent nanner. Regulates cAMP-induced
CC neuritogenesis by mediating the Rap1/B-Raf/ERK signaling through a
CC pathway that is independent on both PKA and RAPGEF3/RAPGEF4.
CC Involved in neuron migration and in the formation of the major
CC forebrain fiber connections forming the corpus callosum, the
CC anterior commissure and the hippocampal commissure during brain
CC development. Involved in neuronal growth factor (NGF)-induced
CC sustained activation of Rap1 at late endosomes and in brain-
CC derived neurotrophic factor (BDNF)-induced axon outgrowth of
CC hippocampal neurons. Plays a role in the regulation of embryonic
CC blood vessel formation and in the establishment of basal junction
CC integrity and endothelial barrier function. May be involved in the
CC regulation of the vascular endothelial growth factor receptor KDR
CC and cadherin CDH5 expression at allantois endothelial cell-cell
CC junctions.
CC -!- SUBUNIT: Interacts with CDH1, CTNNB1 and TJP1 (By similarity).
CC Interacts (via C-terminus domain) with MAGI2 (via PDZ and WW
CC domains); the interaction occurs before or after NGF stimulation.
CC Interacts with KIDINS220 and NTRK1; the interactions occur after
CC NGF stimulation (By similarity). Found in a complex, at least
CC composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is
CC mainly formed at late endosomes in a neuronal growth factor (NGF)-
CC dependent manner. Interacts (via C-terminus domain) with NEDD4
CC (via WW domains); this interaction leads to ubiquitination and
CC degradation via the proteasome pathway in a cAMP-independent
CC manner. Interacts with MAGI1 isoform 3 (via PDZ domain). Interacts
CC with ADRB1 (via C-terminus PDZ motif); the interaction is direct.
CC Interacts (via Ras-associating domain) with RAP1A (via GTP-bound
CC active form). Interacts weakly with HRAS (via GDP- and GTP-bound
CC forms). Interacts (via C-terminus domain) with MAGI2 (via PDZ and
CC WW domains).
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, perinuclear region.
CC Cell membrane. Late endosome. Cell junction (By similarity).
CC Note=Associated with the synaptic plasma membrane. Colocalizes
CC with ADRB1 at the plasma membrane. Synaptosome. Enriched in
CC synaptic plasma membrane and neuronal cell body. Colocalized with
CC CTNNB1 at cell-cell contacts (By similarity). Localized diffusely
CC in the cytoplasm before neuronal growth factor (NGF) stimulation.
CC Recruited to late endosomes after NGF stimulation. Colocalized
CC with the high affinity nerve growth factor receptor NTRK1 at late
CC endosomes. Translocated to the perinuclear region in a RAP1A-
CC dependent manner. Translocated to the cell membrane.
CC -!- TISSUE SPECIFICITY: Expressed in primary neuronal and endocrine
CC cells (at protein level). Highest expression levels in brain.
CC Lower expression levels in heart, kidney, lung, placenta and blood
CC leukocytes.
CC -!- DOMAIN: The Ras-associating domain is necessary for the Rap
CC guanine nucleotide exchange activity. The N-terminus region is
CC necessary for cAMP-binding. The PDZ domain is necessary for its
CC targeting to the cell membrane.
CC -!- PTM: Ubiquitinated by NEDD4, leading to proteasomal degradation.
CC -!- PTM: Phosphorylation by PLK2 promotes its activity (By
CC similarity).
CC -!- SIMILARITY: Belongs to the RAPGEF2 family.
CC -!- SIMILARITY: Contains 1 cyclic nucleotide-binding domain.
CC -!- SIMILARITY: Contains 1 N-terminal Ras-GEF domain.
CC -!- SIMILARITY: Contains 1 PDZ (DHR) domain.
CC -!- SIMILARITY: Contains 1 Ras-associating domain.
CC -!- SIMILARITY: Contains 1 Ras-GEF domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA20772.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; AB002311; BAA20772.2; ALT_INIT; mRNA.
DR EMBL; CH471056; EAX04847.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04848.1; -; Genomic_DNA.
DR RefSeq; NP_055062.1; NM_014247.2.
DR UniGene; Hs.744884; -.
DR ProteinModelPortal; Q9Y4G8; -.
DR SMR; Q9Y4G8; 107-366, 397-464, 716-907.
DR IntAct; Q9Y4G8; 13.
DR MINT; MINT-109918; -.
DR STRING; 9606.ENSP00000264431; -.
DR PhosphoSite; Q9Y4G8; -.
DR DMDM; 34395737; -.
DR PaxDb; Q9Y4G8; -.
DR PRIDE; Q9Y4G8; -.
DR Ensembl; ENST00000264431; ENSP00000264431; ENSG00000109756.
DR GeneID; 9693; -.
DR KEGG; hsa:9693; -.
DR UCSC; uc003iqg.4; human.
DR CTD; 9693; -.
DR GeneCards; GC04P160025; -.
DR HGNC; HGNC:16854; RAPGEF2.
DR MIM; 609530; gene.
DR neXtProt; NX_Q9Y4G8; -.
DR PharmGKB; PA130413152; -.
DR eggNOG; NOG307777; -.
DR HOGENOM; HOG000247009; -.
DR HOVERGEN; HBG056658; -.
DR InParanoid; Q9Y4G8; -.
DR KO; K08018; -.
DR OMA; RILDFNT; -.
DR OrthoDB; EOG71VSRT; -.
DR PhylomeDB; Q9Y4G8; -.
DR GeneWiki; RAPGEF2; -.
DR GenomeRNAi; 9693; -.
DR NextBio; 36405; -.
DR PRO; PR:Q9Y4G8; -.
DR ArrayExpress; Q9Y4G8; -.
DR Bgee; Q9Y4G8; -.
DR CleanEx; HS_RAPGEF2; -.
DR Genevestigator; Q9Y4G8; -.
DR GO; GO:0005911; C:cell-cell junction; ISS:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; NAS:UniProtKB.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0043005; C:neuron projection; ISS:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; ISS:UniProtKB.
DR GO; GO:0031697; F:beta-1 adrenergic receptor binding; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; NAS:UniProtKB.
DR GO; GO:0030552; F:cAMP binding; IDA:UniProtKB.
DR GO; GO:0019992; F:diacylglycerol binding; NAS:UniProtKB.
DR GO; GO:0030165; F:PDZ domain binding; IDA:UniProtKB.
DR GO; GO:0046582; F:Rap GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0017034; F:Rap guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0004871; F:signal transducer activity; TAS:UniProtKB.
DR GO; GO:0050699; F:WW domain binding; IDA:UniProtKB.
DR GO; GO:0071880; P:adenylate cyclase-activating adrenergic receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0001568; P:blood vessel development; ISS:UniProtKB.
DR GO; GO:0031547; P:brain-derived neurotrophic factor receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0019933; P:cAMP-mediated signaling; IDA:UniProtKB.
DR GO; GO:0071320; P:cellular response to cAMP; IDA:UniProtKB.
DR GO; GO:0071321; P:cellular response to cGMP; IDA:UniProtKB.
DR GO; GO:0061028; P:establishment of endothelial barrier; IMP:UniProtKB.
DR GO; GO:0021884; P:forebrain neuron development; ISS:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; NAS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:UniProtKB.
DR GO; GO:0050774; P:negative regulation of dendrite morphogenesis; IDA:UniProtKB.
DR GO; GO:0048022; P:negative regulation of melanin biosynthetic process; ISS:UniProtKB.
DR GO; GO:0038180; P:nerve growth factor signaling pathway; ISS:UniProtKB.
DR GO; GO:0001764; P:neuron migration; ISS:UniProtKB.
DR GO; GO:0031175; P:neuron projection development; IDA:UniProtKB.
DR GO; GO:0007218; P:neuropeptide signaling pathway; IDA:UniProtKB.
DR GO; GO:2000481; P:positive regulation of cAMP-dependent protein kinase activity; IDA:UniProtKB.
DR GO; GO:0043950; P:positive regulation of cAMP-mediated signaling; IDA:UniProtKB.
DR GO; GO:2000670; P:positive regulation of dendritic cell apoptotic process; IDA:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
DR GO; GO:2001224; P:positive regulation of neuron migration; ISS:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISS:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; ISS:UniProtKB.
DR GO; GO:2001214; P:positive regulation of vasculogenesis; ISS:UniProtKB.
DR GO; GO:0032486; P:Rap protein signal transduction; IMP:UniProtKB.
DR GO; GO:1901888; P:regulation of cell junction assembly; IMP:UniProtKB.
DR GO; GO:0048167; P:regulation of synaptic plasticity; ISS:UniProtKB.
DR GO; GO:0021591; P:ventricular system development; ISS:UniProtKB.
DR Gene3D; 1.10.840.10; -; 1.
DR Gene3D; 2.60.120.10; -; 1.
DR InterPro; IPR018490; cNMP-bd-like.
DR InterPro; IPR000595; cNMP-bd_dom.
DR InterPro; IPR001478; PDZ.
DR InterPro; IPR000159; Ras-assoc.
DR InterPro; IPR000651; Ras-like_Gua-exchang_fac_N.
DR InterPro; IPR008937; Ras_GEF.
DR InterPro; IPR023578; Ras_GEF_dom.
DR InterPro; IPR001895; RasGRF_CDC25.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR PANTHER; PTHR23113; PTHR23113; 1.
DR Pfam; PF00027; cNMP_binding; 1.
DR Pfam; PF00595; PDZ; 1.
DR Pfam; PF00788; RA; 1.
DR Pfam; PF00617; RasGEF; 1.
DR Pfam; PF00618; RasGEF_N; 1.
DR SMART; SM00100; cNMP; 1.
DR SMART; SM00228; PDZ; 1.
DR SMART; SM00314; RA; 1.
DR SMART; SM00147; RasGEF; 1.
DR SMART; SM00229; RasGEFN; 1.
DR SUPFAM; SSF48366; SSF48366; 3.
DR SUPFAM; SSF50156; SSF50156; 1.
DR SUPFAM; SSF51206; SSF51206; 1.
DR PROSITE; PS00888; CNMP_BINDING_1; FALSE_NEG.
DR PROSITE; PS00889; CNMP_BINDING_2; FALSE_NEG.
DR PROSITE; PS50042; CNMP_BINDING_3; 1.
DR PROSITE; PS50106; PDZ; 1.
DR PROSITE; PS50200; RA; 1.
DR PROSITE; PS00720; RASGEF; FALSE_NEG.
DR PROSITE; PS50009; RASGEF_CAT; 1.
DR PROSITE; PS50212; RASGEF_NTER; 1.
PE 1: Evidence at protein level;
KW Cell junction; Cell membrane; Complete proteome; Cytoplasm;
KW Developmental protein; Differentiation; Endosome; GTPase activation;
KW Guanine-nucleotide releasing factor; Membrane; Neurogenesis;
KW Phosphoprotein; Reference proteome; Ubl conjugation.
FT CHAIN 1 1499 Rap guanine nucleotide exchange factor 2.
FT /FTId=PRO_0000068865.
FT DOMAIN 267 380 N-terminal Ras-GEF.
FT DOMAIN 385 470 PDZ.
FT DOMAIN 606 692 Ras-associating.
FT DOMAIN 717 944 Ras-GEF.
FT NP_BIND 135 254 cNMP.
FT COMPBIAS 1108 1166 Ser-rich.
FT MOD_RES 644 644 Phosphothreonine; by PLK2 (By
FT similarity).
FT MOD_RES 806 806 Phosphoserine; by PLK2 (By similarity).
FT MOD_RES 933 933 Phosphoserine; by PLK2 (By similarity).
FT MOD_RES 1022 1022 Phosphoserine.
FT MOD_RES 1176 1176 Phosphoserine; by PLK2 (By similarity).
FT MUTAGEN 211 211 K->R: Abolishes cAMP-binding.
FT MUTAGEN 215 215 R->D: Does not abolishe cAMP-binding.
FT MUTAGEN 396 399 PLPF->AAA: Loss of cell membrane
FT targeting.
FT MUTAGEN 606 626 Missing: Abolishes interaction with RAP1A
FT GTP-bound form and translocation from the
FT cytoplasm to the perinuclear region. Does
FT not abolish GEF activity on RAP1A.
FT MUTAGEN 898 898 R->D: Does not inhibit interaction with
FT NEDD4. Does not interact with HRAS.
FT Reduces ubiquitination.
FT MUTAGEN 1406 1406 Y->A: Abolishes interaction with NEDD4
FT and NEDD4-induced ubiquitination and
FT degradation; when associated with A-1428.
FT MUTAGEN 1428 1428 Y->A: Abolishes interaction with NEDD4
FT and NEDD4-induced ubiquitination and
FT degradation; when associated with A-1406.
FT MUTAGEN 1497 1499 SAV->AAA: No loss of cell membrane
FT targeting.
SQ SEQUENCE 1499 AA; 167417 MW; 1909E8A12637E001 CRC64;
MKPLAIPANH GVMGQQEKHS LPADFTKLHL TDSLHPQVTH VSSSHSGCSI TSDSGSSSLS
DIYQATESEA GDMDLSGLPE TAVDSEDDDD EEDIERASDP LMSRDIVRDC LEKDPIDRTD
DDIEQLLEFM HQLPAFANMT MSVRRELCAV MVFAVVERAG TIVLNDGEEL DSWSVILNGS
VEVTYPDGKA EILCMGNSFG VSPTMDKEYM KGVMRTKVDD CQFVCIAQQD YCRILNQVEK
NMQKVEEEGE IVMVKEHREL DRTGTRKGHI VIKGTSERLT MHLVEEHSVV DPTFIEDFLL
TYRTFLSSPM EVGKKLLEWF NDPSLRDKVT RVVLLWVNNH FNDFEGDPAM TRFLEEFENN
LEREKMGGHL RLLNIACAAK AKRRLMTLTK PSREAPLPFI LLGGSEKGFG IFVDSVDSGS
KATEAGLKRG DQILEVNGQN FENIQLSKAM EILRNNTHLS ITVKTNLFVF KELLTRLSEE
KRNGAPHLPK IGDIKKASRY SIPDLAVDVE QVIGLEKVNK KSKANTVGGR NKLKKILDKT
RISILPQKPY NDIGIGQSQD DSIVGLRQTK HIPTALPVSG TLSSSNPDLL QSHHRILDFS
ATPDLPDQVL RVFKADQQSR YIMISKDTTA KEVVIQAIRE FAVTATPDQY SLCEVSVTPE
GVIKQRRLPD QLSKLADRIQ LSGRYYLKNN METETLCSDE DAQELLRESQ ISLLQLSTVE
VATQLSMRNF ELFRNIEPTE YIDDLFKLRS KTSCANLKRF EEVINQETFW VASEILRETN
QLKRMKIIKH FIKIALHCRE CKNFNSMFAI ISGLNLAPVA RLRTTWEKLP NKYEKLFQDL
QDLFDPSRNM AKYRNVLNSQ NLQPPIIPLF PVIKKDLTFL HEGNDSKVDG LVNFEKLRMI
AKEIRHVGRM ASVNMDPALM FRTRKKKWRS LGSLSQGSTN ATVLDVAQTG GHKKRVRRSS
FLNAKKLYED AQMARKVKQY LSNLELEMDE ESLQTLSLQC EPATNTLPKN PGDKKPVKSE
TSPVAPRAGS QQKAQSLPQP QQQPPPAHKI NQGLQVPAVS LYPSRKKVPV KDLPPFGINS
PQALKKILSL SEEGSLERHK KQAEDTISNA SSQLSSPPTS PQSSPRKGYT LAPSGTVDNF
SDSGHSEISS RSSIVSNSSF DSVPVSLHDE RRQRHSVSIV ETNLGMGRME RRTMIEPDQY
SLGSYAPMSE GRGLYATATV ISSPSTEELS QDQGDRASLD AADSGRGSWT SCSSGSHDNI
QTIQHQRSWE TLPFGHTHFD YSGDPAGLWA SSSHMDQIMF SDHSTKYNRQ NQSRESLEQA
QSRASWASST GYWGEDSEGD TGTIKRRGGK DVSIEAESSS LTSVTTEETK PVPMPAHIAV
ASSTTKGLIA RKEGRYREPP PTPPGYIGIP ITDFPEGHSH PARKPPDYNV ALQRSRMVAR
SSDTAGPSSV QQPHGHPTSS RPVNKPQWHK PNESDPRLAP YQSQGFSTEE DEDEQVSAV
//
ID RPGF2_HUMAN Reviewed; 1499 AA.
AC Q9Y4G8; D3DP27;
DT 29-AUG-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1999, sequence version 1.
DT 22-JAN-2014, entry version 117.
DE RecName: Full=Rap guanine nucleotide exchange factor 2;
DE AltName: Full=Cyclic nucleotide ras GEF;
DE Short=CNrasGEF;
DE AltName: Full=Neural RAP guanine nucleotide exchange protein;
DE Short=nRap GEP;
DE AltName: Full=PDZ domain-containing guanine nucleotide exchange factor 1;
DE Short=PDZ-GEF1;
DE AltName: Full=RA-GEF-1;
DE AltName: Full=Ras/Rap1-associating GEF-1;
GN Name=RAPGEF2; Synonyms=KIAA0313, NRAPGEP, PDZGEF1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=9205841; DOI=10.1093/dnares/4.2.141;
RA Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. VII.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 4:141-150(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION, AND INTERACTION WITH MAGI2.
RX PubMed=10548487; DOI=10.1006/bbrc.1999.1619;
RA Ohtsuka T., Hata Y., Ide N., Yasuda T., Inoue E., Inoue T.,
RA Mizoguchi A., Takai Y.;
RT "nRap GEP: a novel neural GDP/GTP exchange protein for rap1 small G
RT protein that interacts with synaptic scaffolding molecule (S-SCAM).";
RL Biochem. Biophys. Res. Commun. 265:38-44(1999).
RN [4]
RP FUNCTION, AND INTERACTION WITH HRAS AND RAP1A.
RX PubMed=10608844; DOI=10.1074/jbc.274.53.37815;
RA Liao Y., Kariya K., Hu C.-D., Shibatohge M., Goshima M., Okada T.,
RA Watari Y., Gao X., Jin T.-G., Yamawaki-Kataoka Y., Kataoka T.;
RT "RA-GEF, a novel Rap1A guanine nucleotide exchange factor containing a
RT Ras/Rap1A-associating domain, is conserved between nematode and
RT humans.";
RL J. Biol. Chem. 274:37815-37820(1999).
RN [5]
RP FUNCTION.
RX PubMed=10608883; DOI=10.1074/jbc.274.53.38125;
RA de Rooij J., Boenink N.M., van Triest M., Cool R.H., Wittinghofer A.,
RA Bos J.L.;
RT "PDZ-GEF1, a guanine nucleotide exchange factor specific for Rap1 and
RT Rap2.";
RL J. Biol. Chem. 274:38125-38130(1999).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-211; ARG-215;
RP 396-PRO--PHE-399 AND 1497-SER-VAL-1499.
RX PubMed=10801446; DOI=10.1016/S0960-9822(00)00473-5;
RA Pham N., Cheglakov I., Koch C.A., de Hoog C.L., Moran M.F., Rotin D.;
RT "The guanine nucleotide exchange factor CNrasGEF activates ras in
RT response to cAMP and cGMP.";
RL Curr. Biol. 10:555-558(2000).
RN [7]
RP INTERACTION WITH MAGI1, AND TISSUE SPECIFICITY.
RX PubMed=11168587; DOI=10.1046/j.1365-2443.2000.00385.x;
RA Mino A., Ohtsuka T., Inoue E., Takai Y.;
RT "Membrane-associated guanylate kinase with inverted orientation
RT (MAGI)-1/brain angiogenesis inhibitor 1-associated protein (BAP1) as a
RT scaffolding molecule for Rap small G protein GDP/GTP exchange protein
RT at tight junctions.";
RL Genes Cells 5:1009-1016(2000).
RN [8]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=10934204; DOI=10.1074/jbc.M005327200;
RA Rebhun J.F., Castro A.F., Quilliam L.A.;
RT "Identification of guanine nucleotide exchange factors (GEFs) for the
RT Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction.";
RL J. Biol. Chem. 275:34901-34908(2000).
RN [9]
RP FUNCTION, INTERACTION WITH RAP1A, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF 606-PRO--LYS-626.
RX PubMed=11359771; DOI=10.1074/jbc.M101737200;
RA Liao Y., Satoh T., Gao X., Jin T.G., Hu C.D., Kataoka T.;
RT "RA-GEF-1, a guanine nucleotide exchange factor for Rap1, is activated
RT by translocation induced by association with Rap1*GTP and enhances
RT Rap1-dependent B-Raf activation.";
RL J. Biol. Chem. 276:28478-28483(2001).
RN [10]
RP INTERACTION WITH HRAS AND NEDD4, UBIQUITINATION BY NEDD4, AND
RP MUTAGENESIS OF ARG-898; TYR-1406 AND TYR-1428.
RX PubMed=11598133; DOI=10.1074/jbc.M108373200;
RA Pham N., Rotin D.;
RT "Nedd4 regulates ubiquitination and stability of the guanine-
RT nucleotide exchange factor CNrasGEF.";
RL J. Biol. Chem. 276:46995-47003(2001).
RN [11]
RP FUNCTION, AND INTERACTION WITH ADRB1.
RX PubMed=12391161; DOI=10.1128/MCB.22.22.7942-7952.2002;
RA Pak Y., Pham N., Rotin D.;
RT "Direct binding of the beta1 adrenergic receptor to the cyclic AMP-
RT dependent guanine nucleotide exchange factor CNrasGEF leads to Ras
RT activation.";
RL Mol. Cell. Biol. 22:7942-7952(2002).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [13]
RP FUNCTION.
RX PubMed=16272156; DOI=10.1074/jbc.M507595200;
RA Amsen E.M., Pham N., Pak Y., Rotin D.;
RT "The guanine nucleotide exchange factor CNrasGEF regulates
RT melanogenesis and cell survival in melanoma cells.";
RL J. Biol. Chem. 281:121-128(2006).
RN [14]
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH KIDINS220; MAGI2 AND NTRK1,
RP AND SUBCELLULAR LOCATION.
RX PubMed=17724123; DOI=10.1083/jcb.200610073;
RA Hisata S., Sakisaka T., Baba T., Yamada T., Aoki K., Matsuda M.,
RA Takai Y.;
RT "Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late
RT endosomes, leading to sustained activation of Rap1 and ERK and neurite
RT outgrowth.";
RL J. Cell Biol. 178:843-860(2007).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1022, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [21]
RP FUNCTION.
RX PubMed=21840392; DOI=10.1016/j.cellsig.2011.07.022;
RA Pannekoek W.J., van Dijk J.J., Chan O.Y., Huveneers S.,
RA Linnemann J.R., Spanjaard E., Brouwer P.M., van der Meer A.J.,
RA Zwartkruis F.J., Rehmann H., de Rooij J., Bos J.L.;
RT "Epac1 and PDZ-GEF cooperate in Rap1 mediated endothelial junction
RT control.";
RL Cell. Signal. 23:2056-2064(2011).
RN [22]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=23800469; DOI=10.1126/scisignal.2003993;
RA Emery A.C., Eiden M.V., Mustafa T., Eiden L.E.;
RT "Rapgef2 Connects GPCR-Mediated cAMP Signals to ERK Activation in
RT Neuronal and Endocrine Cells.";
RL Sci. Signal. 6:RA51-RA51(2013).
CC -!- FUNCTION: Functions as a guanine nucleotide exchange factor (GEF),
CC which activates Rap and Ras family of small GTPases by exchanging
CC bound GDP for free GTP in a cAMP-dependent manner. Serves as a
CC link between cell surface receptors and Rap/Ras GTPases in
CC intracellular signaling cascades. Acts also as an effector for
CC Rap1 by direct association with Rap1-GTP thereby leading to the
CC amplification of Rap1-mediated signaling. Shows weak activity on
CC HRAS. It is controversial whether RAPGEF2 binds cAMP and cGMP
CC (PubMed:23800469, PubMed:10801446) or not (PubMed:10608844,
CC PubMed:10548487, PubMed:11359771). Its binding to ligand-activated
CC beta-1 adrenergic receptor ADRB1 leads to the Ras activation
CC through the G(s)-alpha signaling pathway. Involved in the cAMP-
CC induced Ras and Erk1/2 signaling pathway that leads to sustained
CC inhibition of long term melanogenesis by reducing dendrite
CC extension and melanin synthesis. Provides also inhibitory signals
CC for cell proliferation of melanoma cells and promotes their
CC apoptosis in a cAMP-independent nanner. Regulates cAMP-induced
CC neuritogenesis by mediating the Rap1/B-Raf/ERK signaling through a
CC pathway that is independent on both PKA and RAPGEF3/RAPGEF4.
CC Involved in neuron migration and in the formation of the major
CC forebrain fiber connections forming the corpus callosum, the
CC anterior commissure and the hippocampal commissure during brain
CC development. Involved in neuronal growth factor (NGF)-induced
CC sustained activation of Rap1 at late endosomes and in brain-
CC derived neurotrophic factor (BDNF)-induced axon outgrowth of
CC hippocampal neurons. Plays a role in the regulation of embryonic
CC blood vessel formation and in the establishment of basal junction
CC integrity and endothelial barrier function. May be involved in the
CC regulation of the vascular endothelial growth factor receptor KDR
CC and cadherin CDH5 expression at allantois endothelial cell-cell
CC junctions.
CC -!- SUBUNIT: Interacts with CDH1, CTNNB1 and TJP1 (By similarity).
CC Interacts (via C-terminus domain) with MAGI2 (via PDZ and WW
CC domains); the interaction occurs before or after NGF stimulation.
CC Interacts with KIDINS220 and NTRK1; the interactions occur after
CC NGF stimulation (By similarity). Found in a complex, at least
CC composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is
CC mainly formed at late endosomes in a neuronal growth factor (NGF)-
CC dependent manner. Interacts (via C-terminus domain) with NEDD4
CC (via WW domains); this interaction leads to ubiquitination and
CC degradation via the proteasome pathway in a cAMP-independent
CC manner. Interacts with MAGI1 isoform 3 (via PDZ domain). Interacts
CC with ADRB1 (via C-terminus PDZ motif); the interaction is direct.
CC Interacts (via Ras-associating domain) with RAP1A (via GTP-bound
CC active form). Interacts weakly with HRAS (via GDP- and GTP-bound
CC forms). Interacts (via C-terminus domain) with MAGI2 (via PDZ and
CC WW domains).
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, perinuclear region.
CC Cell membrane. Late endosome. Cell junction (By similarity).
CC Note=Associated with the synaptic plasma membrane. Colocalizes
CC with ADRB1 at the plasma membrane. Synaptosome. Enriched in
CC synaptic plasma membrane and neuronal cell body. Colocalized with
CC CTNNB1 at cell-cell contacts (By similarity). Localized diffusely
CC in the cytoplasm before neuronal growth factor (NGF) stimulation.
CC Recruited to late endosomes after NGF stimulation. Colocalized
CC with the high affinity nerve growth factor receptor NTRK1 at late
CC endosomes. Translocated to the perinuclear region in a RAP1A-
CC dependent manner. Translocated to the cell membrane.
CC -!- TISSUE SPECIFICITY: Expressed in primary neuronal and endocrine
CC cells (at protein level). Highest expression levels in brain.
CC Lower expression levels in heart, kidney, lung, placenta and blood
CC leukocytes.
CC -!- DOMAIN: The Ras-associating domain is necessary for the Rap
CC guanine nucleotide exchange activity. The N-terminus region is
CC necessary for cAMP-binding. The PDZ domain is necessary for its
CC targeting to the cell membrane.
CC -!- PTM: Ubiquitinated by NEDD4, leading to proteasomal degradation.
CC -!- PTM: Phosphorylation by PLK2 promotes its activity (By
CC similarity).
CC -!- SIMILARITY: Belongs to the RAPGEF2 family.
CC -!- SIMILARITY: Contains 1 cyclic nucleotide-binding domain.
CC -!- SIMILARITY: Contains 1 N-terminal Ras-GEF domain.
CC -!- SIMILARITY: Contains 1 PDZ (DHR) domain.
CC -!- SIMILARITY: Contains 1 Ras-associating domain.
CC -!- SIMILARITY: Contains 1 Ras-GEF domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA20772.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; AB002311; BAA20772.2; ALT_INIT; mRNA.
DR EMBL; CH471056; EAX04847.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04848.1; -; Genomic_DNA.
DR RefSeq; NP_055062.1; NM_014247.2.
DR UniGene; Hs.744884; -.
DR ProteinModelPortal; Q9Y4G8; -.
DR SMR; Q9Y4G8; 107-366, 397-464, 716-907.
DR IntAct; Q9Y4G8; 13.
DR MINT; MINT-109918; -.
DR STRING; 9606.ENSP00000264431; -.
DR PhosphoSite; Q9Y4G8; -.
DR DMDM; 34395737; -.
DR PaxDb; Q9Y4G8; -.
DR PRIDE; Q9Y4G8; -.
DR Ensembl; ENST00000264431; ENSP00000264431; ENSG00000109756.
DR GeneID; 9693; -.
DR KEGG; hsa:9693; -.
DR UCSC; uc003iqg.4; human.
DR CTD; 9693; -.
DR GeneCards; GC04P160025; -.
DR HGNC; HGNC:16854; RAPGEF2.
DR MIM; 609530; gene.
DR neXtProt; NX_Q9Y4G8; -.
DR PharmGKB; PA130413152; -.
DR eggNOG; NOG307777; -.
DR HOGENOM; HOG000247009; -.
DR HOVERGEN; HBG056658; -.
DR InParanoid; Q9Y4G8; -.
DR KO; K08018; -.
DR OMA; RILDFNT; -.
DR OrthoDB; EOG71VSRT; -.
DR PhylomeDB; Q9Y4G8; -.
DR GeneWiki; RAPGEF2; -.
DR GenomeRNAi; 9693; -.
DR NextBio; 36405; -.
DR PRO; PR:Q9Y4G8; -.
DR ArrayExpress; Q9Y4G8; -.
DR Bgee; Q9Y4G8; -.
DR CleanEx; HS_RAPGEF2; -.
DR Genevestigator; Q9Y4G8; -.
DR GO; GO:0005911; C:cell-cell junction; ISS:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; NAS:UniProtKB.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0043005; C:neuron projection; ISS:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; ISS:UniProtKB.
DR GO; GO:0031697; F:beta-1 adrenergic receptor binding; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; NAS:UniProtKB.
DR GO; GO:0030552; F:cAMP binding; IDA:UniProtKB.
DR GO; GO:0019992; F:diacylglycerol binding; NAS:UniProtKB.
DR GO; GO:0030165; F:PDZ domain binding; IDA:UniProtKB.
DR GO; GO:0046582; F:Rap GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0017034; F:Rap guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0004871; F:signal transducer activity; TAS:UniProtKB.
DR GO; GO:0050699; F:WW domain binding; IDA:UniProtKB.
DR GO; GO:0071880; P:adenylate cyclase-activating adrenergic receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0001568; P:blood vessel development; ISS:UniProtKB.
DR GO; GO:0031547; P:brain-derived neurotrophic factor receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0019933; P:cAMP-mediated signaling; IDA:UniProtKB.
DR GO; GO:0071320; P:cellular response to cAMP; IDA:UniProtKB.
DR GO; GO:0071321; P:cellular response to cGMP; IDA:UniProtKB.
DR GO; GO:0061028; P:establishment of endothelial barrier; IMP:UniProtKB.
DR GO; GO:0021884; P:forebrain neuron development; ISS:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; NAS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:UniProtKB.
DR GO; GO:0050774; P:negative regulation of dendrite morphogenesis; IDA:UniProtKB.
DR GO; GO:0048022; P:negative regulation of melanin biosynthetic process; ISS:UniProtKB.
DR GO; GO:0038180; P:nerve growth factor signaling pathway; ISS:UniProtKB.
DR GO; GO:0001764; P:neuron migration; ISS:UniProtKB.
DR GO; GO:0031175; P:neuron projection development; IDA:UniProtKB.
DR GO; GO:0007218; P:neuropeptide signaling pathway; IDA:UniProtKB.
DR GO; GO:2000481; P:positive regulation of cAMP-dependent protein kinase activity; IDA:UniProtKB.
DR GO; GO:0043950; P:positive regulation of cAMP-mediated signaling; IDA:UniProtKB.
DR GO; GO:2000670; P:positive regulation of dendritic cell apoptotic process; IDA:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
DR GO; GO:2001224; P:positive regulation of neuron migration; ISS:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISS:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; ISS:UniProtKB.
DR GO; GO:2001214; P:positive regulation of vasculogenesis; ISS:UniProtKB.
DR GO; GO:0032486; P:Rap protein signal transduction; IMP:UniProtKB.
DR GO; GO:1901888; P:regulation of cell junction assembly; IMP:UniProtKB.
DR GO; GO:0048167; P:regulation of synaptic plasticity; ISS:UniProtKB.
DR GO; GO:0021591; P:ventricular system development; ISS:UniProtKB.
DR Gene3D; 1.10.840.10; -; 1.
DR Gene3D; 2.60.120.10; -; 1.
DR InterPro; IPR018490; cNMP-bd-like.
DR InterPro; IPR000595; cNMP-bd_dom.
DR InterPro; IPR001478; PDZ.
DR InterPro; IPR000159; Ras-assoc.
DR InterPro; IPR000651; Ras-like_Gua-exchang_fac_N.
DR InterPro; IPR008937; Ras_GEF.
DR InterPro; IPR023578; Ras_GEF_dom.
DR InterPro; IPR001895; RasGRF_CDC25.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR PANTHER; PTHR23113; PTHR23113; 1.
DR Pfam; PF00027; cNMP_binding; 1.
DR Pfam; PF00595; PDZ; 1.
DR Pfam; PF00788; RA; 1.
DR Pfam; PF00617; RasGEF; 1.
DR Pfam; PF00618; RasGEF_N; 1.
DR SMART; SM00100; cNMP; 1.
DR SMART; SM00228; PDZ; 1.
DR SMART; SM00314; RA; 1.
DR SMART; SM00147; RasGEF; 1.
DR SMART; SM00229; RasGEFN; 1.
DR SUPFAM; SSF48366; SSF48366; 3.
DR SUPFAM; SSF50156; SSF50156; 1.
DR SUPFAM; SSF51206; SSF51206; 1.
DR PROSITE; PS00888; CNMP_BINDING_1; FALSE_NEG.
DR PROSITE; PS00889; CNMP_BINDING_2; FALSE_NEG.
DR PROSITE; PS50042; CNMP_BINDING_3; 1.
DR PROSITE; PS50106; PDZ; 1.
DR PROSITE; PS50200; RA; 1.
DR PROSITE; PS00720; RASGEF; FALSE_NEG.
DR PROSITE; PS50009; RASGEF_CAT; 1.
DR PROSITE; PS50212; RASGEF_NTER; 1.
PE 1: Evidence at protein level;
KW Cell junction; Cell membrane; Complete proteome; Cytoplasm;
KW Developmental protein; Differentiation; Endosome; GTPase activation;
KW Guanine-nucleotide releasing factor; Membrane; Neurogenesis;
KW Phosphoprotein; Reference proteome; Ubl conjugation.
FT CHAIN 1 1499 Rap guanine nucleotide exchange factor 2.
FT /FTId=PRO_0000068865.
FT DOMAIN 267 380 N-terminal Ras-GEF.
FT DOMAIN 385 470 PDZ.
FT DOMAIN 606 692 Ras-associating.
FT DOMAIN 717 944 Ras-GEF.
FT NP_BIND 135 254 cNMP.
FT COMPBIAS 1108 1166 Ser-rich.
FT MOD_RES 644 644 Phosphothreonine; by PLK2 (By
FT similarity).
FT MOD_RES 806 806 Phosphoserine; by PLK2 (By similarity).
FT MOD_RES 933 933 Phosphoserine; by PLK2 (By similarity).
FT MOD_RES 1022 1022 Phosphoserine.
FT MOD_RES 1176 1176 Phosphoserine; by PLK2 (By similarity).
FT MUTAGEN 211 211 K->R: Abolishes cAMP-binding.
FT MUTAGEN 215 215 R->D: Does not abolishe cAMP-binding.
FT MUTAGEN 396 399 PLPF->AAA: Loss of cell membrane
FT targeting.
FT MUTAGEN 606 626 Missing: Abolishes interaction with RAP1A
FT GTP-bound form and translocation from the
FT cytoplasm to the perinuclear region. Does
FT not abolish GEF activity on RAP1A.
FT MUTAGEN 898 898 R->D: Does not inhibit interaction with
FT NEDD4. Does not interact with HRAS.
FT Reduces ubiquitination.
FT MUTAGEN 1406 1406 Y->A: Abolishes interaction with NEDD4
FT and NEDD4-induced ubiquitination and
FT degradation; when associated with A-1428.
FT MUTAGEN 1428 1428 Y->A: Abolishes interaction with NEDD4
FT and NEDD4-induced ubiquitination and
FT degradation; when associated with A-1406.
FT MUTAGEN 1497 1499 SAV->AAA: No loss of cell membrane
FT targeting.
SQ SEQUENCE 1499 AA; 167417 MW; 1909E8A12637E001 CRC64;
MKPLAIPANH GVMGQQEKHS LPADFTKLHL TDSLHPQVTH VSSSHSGCSI TSDSGSSSLS
DIYQATESEA GDMDLSGLPE TAVDSEDDDD EEDIERASDP LMSRDIVRDC LEKDPIDRTD
DDIEQLLEFM HQLPAFANMT MSVRRELCAV MVFAVVERAG TIVLNDGEEL DSWSVILNGS
VEVTYPDGKA EILCMGNSFG VSPTMDKEYM KGVMRTKVDD CQFVCIAQQD YCRILNQVEK
NMQKVEEEGE IVMVKEHREL DRTGTRKGHI VIKGTSERLT MHLVEEHSVV DPTFIEDFLL
TYRTFLSSPM EVGKKLLEWF NDPSLRDKVT RVVLLWVNNH FNDFEGDPAM TRFLEEFENN
LEREKMGGHL RLLNIACAAK AKRRLMTLTK PSREAPLPFI LLGGSEKGFG IFVDSVDSGS
KATEAGLKRG DQILEVNGQN FENIQLSKAM EILRNNTHLS ITVKTNLFVF KELLTRLSEE
KRNGAPHLPK IGDIKKASRY SIPDLAVDVE QVIGLEKVNK KSKANTVGGR NKLKKILDKT
RISILPQKPY NDIGIGQSQD DSIVGLRQTK HIPTALPVSG TLSSSNPDLL QSHHRILDFS
ATPDLPDQVL RVFKADQQSR YIMISKDTTA KEVVIQAIRE FAVTATPDQY SLCEVSVTPE
GVIKQRRLPD QLSKLADRIQ LSGRYYLKNN METETLCSDE DAQELLRESQ ISLLQLSTVE
VATQLSMRNF ELFRNIEPTE YIDDLFKLRS KTSCANLKRF EEVINQETFW VASEILRETN
QLKRMKIIKH FIKIALHCRE CKNFNSMFAI ISGLNLAPVA RLRTTWEKLP NKYEKLFQDL
QDLFDPSRNM AKYRNVLNSQ NLQPPIIPLF PVIKKDLTFL HEGNDSKVDG LVNFEKLRMI
AKEIRHVGRM ASVNMDPALM FRTRKKKWRS LGSLSQGSTN ATVLDVAQTG GHKKRVRRSS
FLNAKKLYED AQMARKVKQY LSNLELEMDE ESLQTLSLQC EPATNTLPKN PGDKKPVKSE
TSPVAPRAGS QQKAQSLPQP QQQPPPAHKI NQGLQVPAVS LYPSRKKVPV KDLPPFGINS
PQALKKILSL SEEGSLERHK KQAEDTISNA SSQLSSPPTS PQSSPRKGYT LAPSGTVDNF
SDSGHSEISS RSSIVSNSSF DSVPVSLHDE RRQRHSVSIV ETNLGMGRME RRTMIEPDQY
SLGSYAPMSE GRGLYATATV ISSPSTEELS QDQGDRASLD AADSGRGSWT SCSSGSHDNI
QTIQHQRSWE TLPFGHTHFD YSGDPAGLWA SSSHMDQIMF SDHSTKYNRQ NQSRESLEQA
QSRASWASST GYWGEDSEGD TGTIKRRGGK DVSIEAESSS LTSVTTEETK PVPMPAHIAV
ASSTTKGLIA RKEGRYREPP PTPPGYIGIP ITDFPEGHSH PARKPPDYNV ALQRSRMVAR
SSDTAGPSSV QQPHGHPTSS RPVNKPQWHK PNESDPRLAP YQSQGFSTEE DEDEQVSAV
//
MIM
609530
*RECORD*
*FIELD* NO
609530
*FIELD* TI
*609530 RAP GUANINE NUCLEOTIDE EXCHANGE FACTOR 2; RAPGEF2
;;NEURAL RAP GUANINE NUCLEOTIDE EXCHANGE PROTEIN; NRAPGEP;;
read moreRAS-ASSOCIATING GUANINE NUCLEOTIDE EXCHANGE FACTOR; RAGEF;;
PDZ DOMAIN-CONTAINING GUANINE NUCLEOTIDE EXCHANGE FACTOR 1; PDZGEF1;;
KIAA0313
*FIELD* TX
DESCRIPTION
Members of the RAS (see HRAS; 190020) subfamily of GTPases function in
signal transduction as GTP/GDP-regulated switches that cycle between
inactive GDP- and active GTP-bound states. Guanine nucleotide exchange
factors (GEFs), such as RAPGEF2, serve as RAS activators by promoting
acquisition of GTP to maintain the active GTP-bound state and are the
key link between cell surface receptors and RAS activation (Rebhun et
al., 2000).
CLONING
By sequencing clones obtained from a size-fractionated brain cDNA
library, Nagase et al. (1997) cloned RAPGEF2, which they designated
KIAA0313. The deduced 1,499-amino acid protein has an apparent molecular
mass of more than 100 kD, and it shares significant amino acid identity
with RAPGEF5 (609527). RT-PCR detected high RAPGEF2 expression in
kidney, placenta, and liver, intermediate expression in ovary, and low
expression in small intestine, brain, and lung. No expression was
detected in other tissues examined.
Ohtsuka et al. (1999) determined that RAPGEF2, which they called
NRAPGEP, contains an incomplete cAMP-binding region (RCBD), followed by
a PDZ domain, a RAS association domain, a RAS GDP/GTP exchange protein
domain, and a C-terminal consensus PDZ-binding motif.
Using Northern blot analysis, de Rooij et al. (1999) detected expression
of RAPGEF2, which they called PDZGEF1, in all tissues examined. Western
blot analysis detected PDZGEF1 protein at an apparent molecular mass of
200 kD in cell lines derived from several tissues and various species.
De Rooij et al. (1999) identified a RAS exchange motif (REM) between the
RCBD and PDZ domain in the N-terminal half of PDZGEF1.
GENE FUNCTION
Ohtsuka et al. (1999) found that recombinant RAPGEF2 stimulated
dissociation of GDP from RAP1B (179530) and binding of a nonhydrolyzable
GTP analog to RAP1B in dose- and time-dependent manners. RAPGEF2 did not
show GEP activity for other small G proteins tested, and its activity
was not affected by cAMP. Ohtsuka et al. (1999) found that mouse Rapgef2
interacted with a synaptic scaffold protein, Sscam (MAGI2; 606382), and
by blot overlay and coimmunoprecipitation assays, they found that human
RAPGEF2 also interacted with mouse Sscam. Mutation analysis indicated
that the second PDZ domain of Sscam bound to the C-terminal PDZ-binding
motif of RAPGEF2. Since rat Rapgef2 showed abundant expression in brain,
and the protein was enriched in synaptic plasma membrane vesicles,
Ohtsuka et al. (1999) hypothesized that RAPGEF2 may play a role at the
synapse.
De Rooij et al. (1999) showed that PDZGEF1 increased binding of GTP to
RAP1A (179520) and RAP1B following transfection in COS-7 cells, but it
did not increase the amount of GTP bound to other small G proteins. cAMP
and cGMP had no effect on the GEF activity of PDZGEF1. By assaying the
GEF activity of truncated proteins, de Rooij et al. (1999) determined
that RCBD is a GEF inhibitory domain.
Liao et al. (1999) found that RAGEF bound RAP1A in a GTP-dependent
manner through its RAS association domain, and it stimulated GDP/GTP
exchange of RAP1A in vitro and in vivo through its REM and GEF domains.
RAGEF failed to bind cAMP or cGMP.
Rebhun et al. (2000) showed that PDZGEF specifically bound RAP1A- and
RAP2B (179541)-GTP. They found that PDZGEF induced ELK1
(311040)-mediated reporter gene expression.
Kawajiri et al. (2000) found that human RAPGEF2 interacted with mouse
beta-catenin (CTNNB1; 116806). Coimmunoprecipitation assays indicated
that endogenous Rapgef2 and beta-catenin interacted in canine kidney
cells in culture. Immunolocalization showed that Rapgef2 colocalized
with beta-catenin and ZO1 (TJP1; 601009) at sites of cell-cell contact.
MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the RAPGEF2
gene to chromosome 4.
*FIELD* RF
1. de Rooij, J.; Boenink, N. M.; van Triest, M.; Cool, R. H.; Wittinghofer,
A.; Bos, J. L.: PDZ-GEF1, a guanine nucleotide exchange factor specific
for Rap1 and Rap2. J. Biol. Chem. 274: 38125-38130, 1999.
2. Kawajiri, A.; Itoh, N.; Fukata, M.; Nakagawa, M.; Yamaga, M.; Iwamatsu,
A.; Kaibuchi, K.: Identification of a novel beta-catenin-interacting
protein. Biochem. Biophys. Res. Commun. 273: 712-717, 2000.
3. Liao, Y.; Kariya, K.; Hu, C.-D.; Shibatohge, M.; Goshima, M.; Okada,
T.; Watari, Y.; Gao, X.; Jin, T.-G.; Yamawaki-Kataoka, Y.; Kataoka,
T.: RA-GEF, a novel Rap1A guanine nucleotide exchange factor containing
a Ras/Rap1A-associating domain, is conserved between nematode and
humans. J. Biol. Chem. 274: 37815-37820, 1999.
4. Nagase, T.; Ishikawa, K.; Nakajima, D.; Ohira, M.; Seki, N.; Miyajima,
N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.: Prediction of
the coding sequences of unidentified human genes. VII. The complete
sequences of 100 new cDNA clones from brain which can code for large
proteins in vitro. DNA Res. 4: 141-150, 1997.
5. Ohtsuka, T.; Hata, Y.; Ide, N.; Yasuda, T.; Inoue, E.; Inoue, T.;
Mizoguchi, A.; Takai, Y.: nRap GEP: a novel neural GDP/GTP exchange
protein for Rap1 small G protein that interacts with synaptic scaffolding
molecule (S-SCAM). Biochem. Biophys. Res. Commun. 265: 38-44, 1999.
6. Rebhun, J. F.; Castro, A. F.; Quilliam, L. A.: Identification
of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase:
regulation of MR-GEF by M-Ras-GTP interaction. J. Biol. Chem. 275:
34901-34908, 2000.
*FIELD* CD
Patricia A. Hartz: 8/9/2005
*FIELD* ED
mgross: 08/09/2005
*RECORD*
*FIELD* NO
609530
*FIELD* TI
*609530 RAP GUANINE NUCLEOTIDE EXCHANGE FACTOR 2; RAPGEF2
;;NEURAL RAP GUANINE NUCLEOTIDE EXCHANGE PROTEIN; NRAPGEP;;
read moreRAS-ASSOCIATING GUANINE NUCLEOTIDE EXCHANGE FACTOR; RAGEF;;
PDZ DOMAIN-CONTAINING GUANINE NUCLEOTIDE EXCHANGE FACTOR 1; PDZGEF1;;
KIAA0313
*FIELD* TX
DESCRIPTION
Members of the RAS (see HRAS; 190020) subfamily of GTPases function in
signal transduction as GTP/GDP-regulated switches that cycle between
inactive GDP- and active GTP-bound states. Guanine nucleotide exchange
factors (GEFs), such as RAPGEF2, serve as RAS activators by promoting
acquisition of GTP to maintain the active GTP-bound state and are the
key link between cell surface receptors and RAS activation (Rebhun et
al., 2000).
CLONING
By sequencing clones obtained from a size-fractionated brain cDNA
library, Nagase et al. (1997) cloned RAPGEF2, which they designated
KIAA0313. The deduced 1,499-amino acid protein has an apparent molecular
mass of more than 100 kD, and it shares significant amino acid identity
with RAPGEF5 (609527). RT-PCR detected high RAPGEF2 expression in
kidney, placenta, and liver, intermediate expression in ovary, and low
expression in small intestine, brain, and lung. No expression was
detected in other tissues examined.
Ohtsuka et al. (1999) determined that RAPGEF2, which they called
NRAPGEP, contains an incomplete cAMP-binding region (RCBD), followed by
a PDZ domain, a RAS association domain, a RAS GDP/GTP exchange protein
domain, and a C-terminal consensus PDZ-binding motif.
Using Northern blot analysis, de Rooij et al. (1999) detected expression
of RAPGEF2, which they called PDZGEF1, in all tissues examined. Western
blot analysis detected PDZGEF1 protein at an apparent molecular mass of
200 kD in cell lines derived from several tissues and various species.
De Rooij et al. (1999) identified a RAS exchange motif (REM) between the
RCBD and PDZ domain in the N-terminal half of PDZGEF1.
GENE FUNCTION
Ohtsuka et al. (1999) found that recombinant RAPGEF2 stimulated
dissociation of GDP from RAP1B (179530) and binding of a nonhydrolyzable
GTP analog to RAP1B in dose- and time-dependent manners. RAPGEF2 did not
show GEP activity for other small G proteins tested, and its activity
was not affected by cAMP. Ohtsuka et al. (1999) found that mouse Rapgef2
interacted with a synaptic scaffold protein, Sscam (MAGI2; 606382), and
by blot overlay and coimmunoprecipitation assays, they found that human
RAPGEF2 also interacted with mouse Sscam. Mutation analysis indicated
that the second PDZ domain of Sscam bound to the C-terminal PDZ-binding
motif of RAPGEF2. Since rat Rapgef2 showed abundant expression in brain,
and the protein was enriched in synaptic plasma membrane vesicles,
Ohtsuka et al. (1999) hypothesized that RAPGEF2 may play a role at the
synapse.
De Rooij et al. (1999) showed that PDZGEF1 increased binding of GTP to
RAP1A (179520) and RAP1B following transfection in COS-7 cells, but it
did not increase the amount of GTP bound to other small G proteins. cAMP
and cGMP had no effect on the GEF activity of PDZGEF1. By assaying the
GEF activity of truncated proteins, de Rooij et al. (1999) determined
that RCBD is a GEF inhibitory domain.
Liao et al. (1999) found that RAGEF bound RAP1A in a GTP-dependent
manner through its RAS association domain, and it stimulated GDP/GTP
exchange of RAP1A in vitro and in vivo through its REM and GEF domains.
RAGEF failed to bind cAMP or cGMP.
Rebhun et al. (2000) showed that PDZGEF specifically bound RAP1A- and
RAP2B (179541)-GTP. They found that PDZGEF induced ELK1
(311040)-mediated reporter gene expression.
Kawajiri et al. (2000) found that human RAPGEF2 interacted with mouse
beta-catenin (CTNNB1; 116806). Coimmunoprecipitation assays indicated
that endogenous Rapgef2 and beta-catenin interacted in canine kidney
cells in culture. Immunolocalization showed that Rapgef2 colocalized
with beta-catenin and ZO1 (TJP1; 601009) at sites of cell-cell contact.
MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the RAPGEF2
gene to chromosome 4.
*FIELD* RF
1. de Rooij, J.; Boenink, N. M.; van Triest, M.; Cool, R. H.; Wittinghofer,
A.; Bos, J. L.: PDZ-GEF1, a guanine nucleotide exchange factor specific
for Rap1 and Rap2. J. Biol. Chem. 274: 38125-38130, 1999.
2. Kawajiri, A.; Itoh, N.; Fukata, M.; Nakagawa, M.; Yamaga, M.; Iwamatsu,
A.; Kaibuchi, K.: Identification of a novel beta-catenin-interacting
protein. Biochem. Biophys. Res. Commun. 273: 712-717, 2000.
3. Liao, Y.; Kariya, K.; Hu, C.-D.; Shibatohge, M.; Goshima, M.; Okada,
T.; Watari, Y.; Gao, X.; Jin, T.-G.; Yamawaki-Kataoka, Y.; Kataoka,
T.: RA-GEF, a novel Rap1A guanine nucleotide exchange factor containing
a Ras/Rap1A-associating domain, is conserved between nematode and
humans. J. Biol. Chem. 274: 37815-37820, 1999.
4. Nagase, T.; Ishikawa, K.; Nakajima, D.; Ohira, M.; Seki, N.; Miyajima,
N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.: Prediction of
the coding sequences of unidentified human genes. VII. The complete
sequences of 100 new cDNA clones from brain which can code for large
proteins in vitro. DNA Res. 4: 141-150, 1997.
5. Ohtsuka, T.; Hata, Y.; Ide, N.; Yasuda, T.; Inoue, E.; Inoue, T.;
Mizoguchi, A.; Takai, Y.: nRap GEP: a novel neural GDP/GTP exchange
protein for Rap1 small G protein that interacts with synaptic scaffolding
molecule (S-SCAM). Biochem. Biophys. Res. Commun. 265: 38-44, 1999.
6. Rebhun, J. F.; Castro, A. F.; Quilliam, L. A.: Identification
of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase:
regulation of MR-GEF by M-Ras-GTP interaction. J. Biol. Chem. 275:
34901-34908, 2000.
*FIELD* CD
Patricia A. Hartz: 8/9/2005
*FIELD* ED
mgross: 08/09/2005