RPGF2_HUMAN
ID RPGF2_HUMAN Reviewed; 1499 AA.
AC Q9Y4G8; D3DP27;
DT 29-AUG-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 184.
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; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain {ECO:0000269|PubMed:9205841};
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. The
RT complete sequences of 100 new cDNA clones from brain which can code for
RT 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., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., 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., Mizoguchi A.,
RA Takai Y.;
RT "nRap GEP: a novel neural GDP/GTP exchange protein for rap1 small G protein
RT 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 humans.";
RL J. Biol. Chem. 274:37815-37820(1999).
RN [5] {ECO:0000305}
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 response
RT 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 (MAGI)-
RT 1/brain angiogenesis inhibitor 1-associated protein (BAP1) as a scaffolding
RT molecule for Rap small G protein GDP/GTP exchange protein at tight
RT junctions.";
RL Genes Cells 5:1009-1016(2000).
RN [8] {ECO:0000305}
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 Rap1
RT 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 MUTAGENESIS OF
RP 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 by
RT translocation induced by association with Rap1*GTP and enhances Rap1-
RT dependent B-Raf activation.";
RL J. Biol. Chem. 276:28478-28483(2001).
RN [10]
RP INTERACTION WITH HRAS AND NEDD4, UBIQUITINATION BY NEDD4, AND MUTAGENESIS
RP 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-nucleotide
RT 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., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT 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 melanogenesis
RT 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, AND
RP SUBCELLULAR LOCATION.
RX PubMed=17724123; DOI=10.1083/jcb.200610073;
RA Hisata S., Sakisaka T., Baba T., Yamada T., Aoki K., Matsuda M., Takai Y.;
RT "Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late endosomes,
RT leading to sustained activation of Rap1 and ERK and neurite 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, Hurov K.E.,
RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y.,
RA 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 IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [20]
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., Linnemann J.R.,
RA Spanjaard E., Brouwer P.M., van der Meer A.J., Zwartkruis F.J., Rehmann H.,
RA 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 [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1022; SER-1080; SER-1089;
RP SER-1095 AND SER-1159, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
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 [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 Neuronal
RT and Endocrine Cells.";
RL Sci. Signal. 6:RA51-RA51(2013).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [24]
RP INVOLVEMENT IN FAME7, AND TISSUE SPECIFICITY.
RX PubMed=29507423; DOI=10.1038/s41588-018-0067-2;
RA Ishiura H., Doi K., Mitsui J., Yoshimura J., Matsukawa M.K., Fujiyama A.,
RA Toyoshima Y., Kakita A., Takahashi H., Suzuki Y., Sugano S., Qu W.,
RA Ichikawa K., Yurino H., Higasa K., Shibata S., Mitsue A., Tanaka M.,
RA Ichikawa Y., Takahashi Y., Date H., Matsukawa T., Kanda J., Nakamoto F.K.,
RA Higashihara M., Abe K., Koike R., Sasagawa M., Kuroha Y., Hasegawa N.,
RA Kanesawa N., Kondo T., Hitomi T., Tada M., Takano H., Saito Y., Sanpei K.,
RA Onodera O., Nishizawa M., Nakamura M., Yasuda T., Sakiyama Y., Otsuka M.,
RA Ueki A., Kaida K.I., Shimizu J., Hanajima R., Hayashi T., Terao Y.,
RA Inomata-Terada S., Hamada M., Shirota Y., Kubota A., Ugawa Y., Koh K.,
RA Takiyama Y., Ohsawa-Yoshida N., Ishiura S., Yamasaki R., Tamaoka A.,
RA Akiyama H., Otsuki T., Sano A., Ikeda A., Goto J., Morishita S., Tsuji S.;
RT "Expansions of intronic TTTCA and TTTTA repeats in benign adult familial
RT myoclonic epilepsy.";
RL Nat. Genet. 50:581-590(2018).
CC -!- FUNCTION: Functions as a guanine nucleotide exchange factor (GEF),
CC which activates Rap and Ras family of small GTPases by exchanging bound
CC GDP for free GTP in a cAMP-dependent manner. Serves as a link between
CC cell surface receptors and Rap/Ras GTPases in intracellular signaling
CC cascades. Acts also as an effector for Rap1 by direct association with
CC Rap1-GTP thereby leading to the amplification of Rap1-mediated
CC signaling. Shows weak activity on HRAS. It is controversial whether
CC RAPGEF2 binds cAMP and cGMP (PubMed:23800469, PubMed:10801446) or not
CC (PubMed:10608844, PubMed:10548487, PubMed:11359771). Its binding to
CC ligand-activated beta-1 adrenergic receptor ADRB1 leads to the Ras
CC activation through the G(s)-alpha signaling pathway. Involved in the
CC cAMP-induced Ras and Erk1/2 signaling pathway that leads to sustained
CC inhibition of long term melanogenesis by reducing dendrite extension
CC and melanin synthesis. Provides also inhibitory signals for cell
CC proliferation of melanoma cells and promotes their apoptosis in a cAMP-
CC independent nanner. Regulates cAMP-induced neuritogenesis by mediating
CC the Rap1/B-Raf/ERK signaling through a pathway that is independent on
CC both PKA and RAPGEF3/RAPGEF4. Involved in neuron migration and in the
CC formation of the major forebrain fiber connections forming the corpus
CC callosum, the anterior commissure and the hippocampal commissure during
CC brain development. Involved in neuronal growth factor (NGF)-induced
CC sustained activation of Rap1 at late endosomes and in brain-derived
CC neurotrophic factor (BDNF)-induced axon outgrowth of hippocampal
CC neurons. Plays a role in the regulation of embryonic blood vessel
CC formation and in the establishment of basal junction integrity and
CC endothelial barrier function. May be involved in the regulation of the
CC vascular endothelial growth factor receptor KDR and cadherin CDH5
CC expression at allantois endothelial cell-cell junctions.
CC {ECO:0000269|PubMed:10548487, ECO:0000269|PubMed:10608844,
CC ECO:0000269|PubMed:10608883, ECO:0000269|PubMed:10801446,
CC ECO:0000269|PubMed:10934204, ECO:0000269|PubMed:11359771,
CC ECO:0000269|PubMed:12391161, ECO:0000269|PubMed:16272156,
CC ECO:0000269|PubMed:17724123, ECO:0000269|PubMed:21840392,
CC ECO:0000269|PubMed:23800469}.
CC -!- SUBUNIT: Interacts with CDH1, CTNNB1 and TJP1 (By similarity).
CC Interacts (via C-terminal domain) with MAGI2 (via PDZ and WW domains);
CC the interaction occurs before or after NGF stimulation. Interacts with
CC KIDINS220 and NTRK1; the interactions occur after NGF stimulation (By
CC similarity). Found in a complex, at least composed of KIDINS220, MAGI2,
CC NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a
CC neuronal growth factor (NGF)-dependent manner. Interacts (via C-
CC terminal domain) with NEDD4 (via WW domains); this interaction leads to
CC ubiquitination and degradation via the proteasome pathway in a cAMP-
CC independent manner. Interacts with MAGI1 isoform 3 (via PDZ domain).
CC Interacts with ADRB1 (via C-terminal PDZ motif); the interaction is
CC direct. Interacts (via Ras-associating domain) with RAP1A (via GTP-
CC bound active form). Interacts weakly with HRAS (via GDP- and GTP-bound
CC forms). Interacts (via C-terminal domain) with MAGI2 (via PDZ and WW
CC domains). {ECO:0000250, ECO:0000269|PubMed:10548487,
CC ECO:0000269|PubMed:10608844, ECO:0000269|PubMed:11168587,
CC ECO:0000269|PubMed:11359771, ECO:0000269|PubMed:11598133,
CC ECO:0000269|PubMed:12391161, ECO:0000269|PubMed:17724123}.
CC -!- INTERACTION:
CC Q9Y4G8; Q96QZ7-3: MAGI1; NbExp=2; IntAct=EBI-307079, EBI-8769674;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, perinuclear region. Cell
CC membrane. Late endosome. Cell junction {ECO:0000250}. Note=Associated
CC with the synaptic plasma membrane. Colocalizes with ADRB1 at the plasma
CC membrane. Synaptosome. Enriched in synaptic plasma membrane and
CC neuronal cell body. Colocalized with CTNNB1 at cell-cell contacts (By
CC similarity). Localized diffusely in the cytoplasm before neuronal
CC growth factor (NGF) stimulation. Recruited to late endosomes after NGF
CC stimulation. Colocalized with the high affinity nerve growth factor
CC receptor NTRK1 at late endosomes. Translocated to the perinuclear
CC region in a RAP1A-dependent manner. Translocated to the cell membrane.
CC {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Expressed in primary neuronal and endocrine cells
CC (at protein level). Highest expression levels in brain. Lower
CC expression levels in heart, kidney, lung, placenta and blood
CC leukocytes. {ECO:0000269|PubMed:10934204, ECO:0000269|PubMed:11168587,
CC ECO:0000269|PubMed:23800469, ECO:0000269|PubMed:29507423}.
CC -!- DOMAIN: The Ras-associating domain is necessary for the Rap guanine
CC nucleotide exchange activity. The N-terminal regionis necessary for
CC cAMP-binding. The PDZ domain is necessary for its targeting to the cell
CC membrane.
CC -!- PTM: Ubiquitinated by NEDD4, leading to proteasomal degradation.
CC {ECO:0000269|PubMed:11598133}.
CC -!- PTM: Phosphorylation by PLK2 promotes its activity. {ECO:0000250}.
CC -!- DISEASE: Epilepsy, familial adult myoclonic, 7 (FAME7) [MIM:618075]: A
CC form of familial myoclonic epilepsy, a neurologic disorder
CC characterized by cortical hand tremors, myoclonic jerks and occasional
CC generalized or focal seizures with a non-progressive or very slowly
CC progressive disease course. Usually, myoclonic tremor is the presenting
CC symptom, characterized by tremulous finger movements and myoclonic
CC jerks of the limbs increased by action and posture. In a minority of
CC patients, seizures are the presenting symptom. Some patients exhibit
CC mild cognitive impairment. FAME7 inheritance is autosomal dominant.
CC {ECO:0000269|PubMed:29507423}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the RAPGEF2 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA20772.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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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 CCDS; CCDS43277.1; -.
DR RefSeq; NP_055062.1; NM_014247.2.
DR PDB; 6QDT; X-ray; 1.70 A; B=747-757.
DR PDBsum; 6QDT; -.
DR AlphaFoldDB; Q9Y4G8; -.
DR SMR; Q9Y4G8; -.
DR BioGRID; 115045; 73.
DR IntAct; Q9Y4G8; 40.
DR MINT; Q9Y4G8; -.
DR STRING; 9606.ENSP00000264431; -.
DR GlyGen; Q9Y4G8; 3 sites, 1 O-linked glycan (3 sites).
DR iPTMnet; Q9Y4G8; -.
DR PhosphoSitePlus; Q9Y4G8; -.
DR BioMuta; RAPGEF2; -.
DR DMDM; 34395737; -.
DR EPD; Q9Y4G8; -.
DR jPOST; Q9Y4G8; -.
DR MassIVE; Q9Y4G8; -.
DR MaxQB; Q9Y4G8; -.
DR PaxDb; Q9Y4G8; -.
DR PeptideAtlas; Q9Y4G8; -.
DR PRIDE; Q9Y4G8; -.
DR ProteomicsDB; 86204; -.
DR Antibodypedia; 28211; 135 antibodies from 22 providers.
DR DNASU; 9693; -.
DR Ensembl; ENST00000264431.8; ENSP00000264431.4; ENSG00000109756.10.
DR GeneID; 9693; -.
DR KEGG; hsa:9693; -.
DR UCSC; uc003iqg.5; human.
DR CTD; 9693; -.
DR DisGeNET; 9693; -.
DR GeneCards; RAPGEF2; -.
DR HGNC; HGNC:16854; RAPGEF2.
DR HPA; ENSG00000109756; Low tissue specificity.
DR MalaCards; RAPGEF2; -.
DR MIM; 609530; gene.
DR MIM; 618075; phenotype.
DR neXtProt; NX_Q9Y4G8; -.
DR OpenTargets; ENSG00000109756; -.
DR PharmGKB; PA130413152; -.
DR VEuPathDB; HostDB:ENSG00000109756; -.
DR eggNOG; KOG3542; Eukaryota.
DR GeneTree; ENSGT00940000156418; -.
DR HOGENOM; CLU_002782_0_1_1; -.
DR InParanoid; Q9Y4G8; -.
DR OrthoDB; 31139at2759; -.
DR PhylomeDB; Q9Y4G8; -.
DR TreeFam; TF313184; -.
DR PathwayCommons; Q9Y4G8; -.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR SignaLink; Q9Y4G8; -.
DR SIGNOR; Q9Y4G8; -.
DR BioGRID-ORCS; 9693; 9 hits in 1078 CRISPR screens.
DR ChiTaRS; RAPGEF2; human.
DR GeneWiki; RAPGEF2; -.
DR GenomeRNAi; 9693; -.
DR Pharos; Q9Y4G8; Tbio.
DR PRO; PR:Q9Y4G8; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q9Y4G8; protein.
DR Bgee; ENSG00000109756; Expressed in Brodmann (1909) area 23 and 213 other tissues.
DR ExpressionAtlas; Q9Y4G8; baseline and differential.
DR Genevisible; Q9Y4G8; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0005923; C:bicellular tight junction; IDA:UniProtKB.
DR GO; GO:0005911; C:cell-cell junction; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0030139; C:endocytic vesicle; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; NAS:UniProtKB.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; 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:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0032991; C:protein-containing 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:0005096; F:GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0030165; F:PDZ domain binding; IDA:UniProtKB.
DR GO; GO:0070300; F:phosphatidic acid binding; IDA: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:1990090; P:cellular response to nerve growth factor stimulus; ISS:UniProtKB.
DR GO; GO:0061028; P:establishment of endothelial barrier; IMP:UniProtKB.
DR GO; GO:0090557; P:establishment of endothelial intestinal barrier; IMP:UniProtKB.
DR GO; GO:0021884; P:forebrain neuron development; ISS:UniProtKB.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; TAS:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; NAS:UniProtKB.
DR GO; GO:0030033; P:microvillus assembly; IGI:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population 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:0043547; P:positive regulation of GTPase activity; 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:0045860; P:positive regulation of protein kinase activity; IDA:UniProtKB.
DR GO; GO:2001214; P:positive regulation of vasculogenesis; ISS:UniProtKB.
DR GO; GO:0072659; P:protein localization to plasma membrane; IMP:UniProtKB.
DR GO; GO:0032486; P:Rap protein signal transduction; IMP:UniProtKB.
DR GO; GO:0007265; P:Ras protein signal transduction; IBA:GO_Central.
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:0007264; P:small GTPase mediated signal transduction; TAS:UniProtKB.
DR GO; GO:0021591; P:ventricular system development; ISS:UniProtKB.
DR CDD; cd00038; CAP_ED; 1.
DR CDD; cd00155; RasGEF; 1.
DR CDD; cd06224; REM; 1.
DR Gene3D; 1.10.840.10; -; 1.
DR Gene3D; 2.30.42.10; -; 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; IPR036034; PDZ_sf.
DR InterPro; IPR000159; RA_dom.
DR InterPro; IPR030739; RapGEF2.
DR InterPro; IPR008937; Ras-like_GEF.
DR InterPro; IPR000651; Ras-like_Gua-exchang_fac_N.
DR InterPro; IPR023578; Ras_GEF_dom_sf.
DR InterPro; IPR001895; RASGEF_cat_dom.
DR InterPro; IPR036964; RASGEF_cat_dom_sf.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR InterPro; IPR029071; Ubiquitin-like_domsf.
DR PANTHER; PTHR23113; PTHR23113; 1.
DR PANTHER; PTHR23113:SF217; PTHR23113:SF217; 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; 1.
DR SUPFAM; SSF50156; SSF50156; 1.
DR SUPFAM; SSF51206; SSF51206; 1.
DR SUPFAM; SSF54236; SSF54236; 1.
DR PROSITE; PS50042; CNMP_BINDING_3; 1.
DR PROSITE; PS50106; PDZ; 1.
DR PROSITE; PS50200; RA; 1.
DR PROSITE; PS50009; RASGEF_CAT; 1.
DR PROSITE; PS50212; RASGEF_NTER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell junction; Cell membrane; Cytoplasm;
KW Developmental protein; Differentiation; Endosome; Epilepsy;
KW GTPase activation; Guanine-nucleotide releasing factor; Membrane;
KW Neurogenesis; Phosphoprotein; Reference proteome; Ubl conjugation.
FT CHAIN 1..1499
FT /note="Rap guanine nucleotide exchange factor 2"
FT /id="PRO_0000068865"
FT DOMAIN 267..380
FT /note="N-terminal Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00135"
FT DOMAIN 385..470
FT /note="PDZ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143,
FT ECO:0000305"
FT DOMAIN 606..692
FT /note="Ras-associating"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00166"
FT DOMAIN 717..944
FT /note="Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00168"
FT REGION 40..59
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 68..101
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1002..1050
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1095..1160
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1224..1256
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1305..1499
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 81..96
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1024..1038
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1106..1160
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1305..1336
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1339..1353
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1355..1369
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1435..1467
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 135..254
FT /ligand="a nucleoside 3',5'-cyclic phosphate"
FT /ligand_id="ChEBI:CHEBI:58464"
FT MOD_RES 501
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MOD_RES 644
FT /note="Phosphothreonine; by PLK2"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MOD_RES 806
FT /note="Phosphoserine; by PLK2"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MOD_RES 930
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MOD_RES 933
FT /note="Phosphoserine; by PLK2"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MOD_RES 1022
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1080
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1089
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1095
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1116
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8CHG7"
FT MOD_RES 1120
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8CHG7"
FT MOD_RES 1159
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1176
FT /note="Phosphoserine; by PLK2"
FT /evidence="ECO:0000250|UniProtKB:F1M386"
FT MUTAGEN 211
FT /note="K->R: Abolishes cAMP-binding."
FT /evidence="ECO:0000269|PubMed:10801446"
FT MUTAGEN 215
FT /note="R->D: Does not abolish cAMP-binding."
FT /evidence="ECO:0000269|PubMed:10801446"
FT MUTAGEN 396..399
FT /note="PLPF->AAA: Loss of cell membrane targeting."
FT /evidence="ECO:0000269|PubMed:10801446"
FT MUTAGEN 606..626
FT /note="Missing: Abolishes interaction with RAP1A GTP-bound
FT form and translocation from the cytoplasm to the
FT perinuclear region. Does not abolish GEF activity on
FT RAP1A."
FT /evidence="ECO:0000269|PubMed:11359771"
FT MUTAGEN 898
FT /note="R->D: Does not inhibit interaction with NEDD4. Does
FT not interact with HRAS. Reduces ubiquitination."
FT /evidence="ECO:0000269|PubMed:11598133"
FT MUTAGEN 1406
FT /note="Y->A: Abolishes interaction with NEDD4 and NEDD4-
FT induced ubiquitination and degradation; when associated
FT with A-1428."
FT /evidence="ECO:0000269|PubMed:11598133"
FT MUTAGEN 1428
FT /note="Y->A: Abolishes interaction with NEDD4 and NEDD4-
FT induced ubiquitination and degradation; when associated
FT with A-1406."
FT /evidence="ECO:0000269|PubMed:11598133"
FT MUTAGEN 1497..1499
FT /note="SAV->AAA: No loss of cell membrane targeting."
FT /evidence="ECO:0000269|PubMed:10801446"
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
