Full text data of RAP1A
RAP1A
(KREV1)
[Confidence: high (present in two of the MS resources)]
Ras-related protein Rap-1A (C21KG; G-22K; GTP-binding protein smg p21A; Ras-related protein Krev-1; Flags: Precursor)
Ras-related protein Rap-1A (C21KG; G-22K; GTP-binding protein smg p21A; Ras-related protein Krev-1; Flags: Precursor)
hRBCD
IPI00019345
IPI00019345 Ras-related protein Rap-1A Ras-related protein Rap-1A membrane n/a 5 3 n/a 4 n/a n/a n/a n/a n/a 3 n/a n/a 3 2 n/a 3 n/a n/a n/a Attached to the membrane by a lipid anchor. n/a found at its expected molecular weight found at molecular weight
IPI00019345 Ras-related protein Rap-1A Ras-related protein Rap-1A membrane n/a 5 3 n/a 4 n/a n/a n/a n/a n/a 3 n/a n/a 3 2 n/a 3 n/a n/a n/a Attached to the membrane by a lipid anchor. n/a found at its expected molecular weight found at molecular weight
UniProt
P62834
ID RAP1A_HUMAN Reviewed; 184 AA.
AC P62834; P10113;
DT 16-AUG-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-AUG-2004, sequence version 1.
DT 22-JAN-2014, entry version 116.
DE RecName: Full=Ras-related protein Rap-1A;
DE AltName: Full=C21KG;
DE AltName: Full=G-22K;
DE AltName: Full=GTP-binding protein smg p21A;
DE AltName: Full=Ras-related protein Krev-1;
DE Flags: Precursor;
GN Name=RAP1A; Synonyms=KREV1;
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 [MRNA].
RX PubMed=3045729;
RA Pizon V., Chardin P., Lerosey I., Olofsson B., Tavitian A.;
RT "Human cDNAs rap1 and rap2 homologous to the Drosophila gene Dras3
RT encode proteins closely related to ras in the 'effector' region.";
RL Oncogene 3:201-204(1988).
RN [2]
RP SEQUENCE REVISION TO 3.
RA Pizon V.;
RL Submitted (FEB-1989) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Platelet;
RX PubMed=2507536;
RA Nagata K., Itoh H., Katada T., Takenaka K., Ui M., Kaziro Y.,
RA Nozawa Y.;
RT "Purification, identification, and characterization of two GTP-binding
RT proteins with molecular weights of 25,000 and 21,000 in human platelet
RT cytosol. One is the rap1/smg21/Krev-1 protein and the other is a novel
RT GTP-binding protein.";
RL J. Biol. Chem. 264:17000-17005(1989).
RN [7]
RP PROTEIN SEQUENCE OF 1-35.
RX PubMed=3141412;
RA Bokoch G.M., Parkos C.A., Mumby S.M.;
RT "Purification and characterization of the 22,000-dalton GTP-binding
RT protein substrate for ADP-ribosylation by botulinum toxin, G22K.";
RL J. Biol. Chem. 263:16744-16749(1988).
RN [8]
RP PROTEIN SEQUENCE OF 1-5; 17-24; 32-42 AND 152-168.
RX PubMed=3144274; DOI=10.1016/S0006-291X(88)80302-4;
RA Ohmori T., Kikuchi A., Yamamoto K., Kawata M., Kondo J., Takai Y.;
RT "Identification of a platelet Mr 22,000 GTP-binding protein as the
RT novel smg-21 gene product having the same putative effector domain as
RT the ras gene products.";
RL Biochem. Biophys. Res. Commun. 157:670-676(1988).
RN [9]
RP ISOPRENYLATION AT CYS-181, AND METHYLATION AT CYS-181.
RX PubMed=1899909;
RA Buss J.E., Quilliam L.A., Kato K., Casey P.J., Solski P.A., Wong G.,
RA Clark R., McCormick F., Bokoch G.M., Der C.J.;
RT "The COOH-terminal domain of the Rap1A (Krev-1) protein is
RT isoprenylated and supports transformation by an H-Ras:Rap1A chimeric
RT protein.";
RL Mol. Cell. Biol. 11:1523-1530(1991).
RN [10]
RP INTERACTION WITH RAPGEF2.
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 [11]
RP INTERACTION WITH PLCE1.
RX PubMed=11022048; DOI=10.1074/jbc.M008324200;
RA Song C., Hu C.-D., Masago M., Kariya K., Yamawaki-Kataoka Y.,
RA Shibatohge M., Wu D., Satoh T., Kataoka T.;
RT "Regulation of a novel human phospholipase C, PLCepsilon, through
RT membrane targeting by Ras.";
RL J. Biol. Chem. 276:2752-2757(2001).
RN [12]
RP INTERACTION WITH RAPGEF2, AND SUBCELLULAR LOCATION.
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 [13]
RP INTERACTION WITH PLCE1.
RX PubMed=12444546; DOI=10.1038/sj.onc.1206003;
RA Song C., Satoh T., Edamatsu H., Wu D., Tadano M., Gao X., Kataoka T.;
RT "Differential roles of Ras and Rap1 in growth factor-dependent
RT activation of phospholipase C epsilon.";
RL Oncogene 21:8105-8113(2002).
RN [14]
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH ITGB1BP1 AND KRIT1, AND
RP INTERACTION WITH KRIT1.
RX PubMed=17916086; DOI=10.1111/j.1742-4658.2007.06068.x;
RA Beraud-Dufour S., Gautier R., Albiges-Rizo C., Chardin P.,
RA Faurobert E.;
RT "Krit 1 interactions with microtubules and membranes are regulated by
RT Rap1 and integrin cytoplasmic domain associated protein-1.";
RL FEBS J. 274:5518-5532(2007).
RN [15]
RP INTERACTION WITH RADIL.
RX PubMed=17704304; DOI=10.1101/gad.1561507;
RA Smolen G.A., Schott B.J., Stewart R.A., Diederichs S., Muir B.,
RA Provencher H.L., Look A.T., Sgroi D.C., Peterson R.T., Haber D.A.;
RT "A Rap GTPase interactor, RADIL, mediates migration of neural crest
RT precursors.";
RL Genes Dev. 21:2131-2136(2007).
RN [16]
RP INTERACTION WITH SGSM1; SGSM2 AND SGSM3.
RX PubMed=17509819; DOI=10.1016/j.ygeno.2007.03.013;
RA Yang H., Sasaki T., Minoshima S., Shimizu N.;
RT "Identification of three novel proteins (SGSM1, 2, 3) which modulate
RT small G protein (RAP and RAB)-mediated signaling pathway.";
RL Genomics 90:249-260(2007).
RN [17]
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 [18]
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 [19]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-167.
RX PubMed=7791872; DOI=10.1038/375554a0;
RA Nassar N., Horn G., Herrmann C., Scherer A., McCormick F.,
RA Wittinghofer A.;
RT "The 2.2 A crystal structure of the Ras-binding domain of the
RT serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP
RT analogue.";
RL Nature 375:554-560(1995).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-167.
RX PubMed=8756332; DOI=10.1038/nsb0896-723;
RA Nassar N., Horn G., Herrmann C., Block C., Janknecht R.,
RA Wittinghofer A.;
RT "Ras/Rap effector specificity determined by charge reversal.";
RL Nat. Struct. Biol. 3:723-729(1996).
CC -!- FUNCTION: Induces morphological reversion of a cell line
CC transformed by a Ras oncogene. Counteracts the mitogenic function
CC of Ras, at least partly because it can interact with Ras GAPs and
CC RAF in a competitive manner. Together with ITGB1BP1, regulates
CC KRIT1 localization to microtubules and membranes. Plays a role in
CC nerve growth factor (NGF)-induced neurite outgrowth. Plays a role
CC in the regulation of embryonic blood vessel formation. Involved in
CC the establishment of basal endothelial barrier function. May be
CC involved in the regulation of the vascular endothelial growth
CC factor receptor KDR expression at endothelial cell-cell junctions.
CC -!- ENZYME REGULATION: Activated by guanine nucleotide-exchange
CC factors (GEF) EPAC and EPAC2 in a cAMP-dependent manner, and GFR.
CC -!- SUBUNIT: Found in a complex, at least composed of ITGB1BP1, KRIT1
CC and RAP1A. Interacts (active GTP-bound form preferentially) with
CC KRIT1 (via C-terminus FERM domain); the interaction does not
CC induce the opening conformation of KRIT1. In its GTP-bound form
CC interacts with PLCE1 and RADIL. Interacts with SGSM1, SGSM2 and
CC SGSM3. Interacts (via GTP-bound active form) with RAPGEF2 (via
CC Ras-associating domain).
CC -!- INTERACTION:
CC P04049:RAF1; NbExp=2; IntAct=EBI-491414, EBI-365996;
CC Q8WWW0-2:RASSF5; NbExp=3; IntAct=EBI-491414, EBI-960502;
CC Q5EBH1:Rassf5 (xeno); NbExp=2; IntAct=EBI-491414, EBI-960530;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor. Cytoplasm.
CC Cytoplasm, perinuclear region. Cell junction (By similarity).
CC Early endosome (By similarity). Note=Recruited from early endosome
CC to late endosome compartment after nerve growth factor (NGF)
CC stimulation. Localized with RAPGEF2 at cell-cell junctions (By
CC similarity). Colocalized with RAPGEF2 in the perinuclear region.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Ras family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAB55685.2; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/RAP1AID272.html";
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DR EMBL; X12533; CAA31051.1; -; mRNA.
DR EMBL; M22995; AAA36150.1; -; mRNA.
DR EMBL; AF493912; AAM12626.1; -; mRNA.
DR EMBL; AL049557; CAB55685.2; ALT_SEQ; Genomic_DNA.
DR EMBL; BC014086; AAH14086.1; -; mRNA.
DR PIR; A32342; A32342.
DR RefSeq; NP_001010935.1; NM_001010935.1.
DR RefSeq; NP_002875.1; NM_002884.2.
DR UniGene; Hs.190334; -.
DR PDB; 1C1Y; X-ray; 1.90 A; A=1-167.
DR PDB; 1GUA; X-ray; 2.00 A; A=1-167.
DR PDB; 3KUC; X-ray; 1.92 A; A=1-167.
DR PDBsum; 1C1Y; -.
DR PDBsum; 1GUA; -.
DR PDBsum; 3KUC; -.
DR ProteinModelPortal; P62834; -.
DR SMR; P62834; 1-167.
DR DIP; DIP-29106N; -.
DR IntAct; P62834; 8.
DR MINT; MINT-1509313; -.
DR STRING; 9606.ENSP00000348786; -.
DR BindingDB; P62834; -.
DR ChEMBL; CHEMBL1255139; -.
DR PhosphoSite; P62834; -.
DR DMDM; 51338607; -.
DR OGP; P62834; -.
DR PaxDb; P62834; -.
DR PRIDE; P62834; -.
DR DNASU; 5906; -.
DR Ensembl; ENST00000356415; ENSP00000348786; ENSG00000116473.
DR Ensembl; ENST00000369709; ENSP00000358723; ENSG00000116473.
DR Ensembl; ENST00000436150; ENSP00000394318; ENSG00000116473.
DR Ensembl; ENST00000545460; ENSP00000443009; ENSG00000116473.
DR GeneID; 5906; -.
DR KEGG; hsa:5906; -.
DR UCSC; uc001ebi.3; human.
DR CTD; 5906; -.
DR GeneCards; GC01P112084; -.
DR HGNC; HGNC:9855; RAP1A.
DR HPA; CAB018335; -.
DR MIM; 179520; gene.
DR neXtProt; NX_P62834; -.
DR PharmGKB; PA34217; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233973; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P62834; -.
DR KO; K04353; -.
DR OMA; KPKKSLC; -.
DR OrthoDB; EOG7QVM41; -.
DR PhylomeDB; P62834; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P62834; -.
DR ChiTaRS; RAP1A; human.
DR EvolutionaryTrace; P62834; -.
DR GeneWiki; RAP1A; -.
DR GenomeRNAi; 5906; -.
DR NextBio; 22972; -.
DR PRO; PR:P62834; -.
DR ArrayExpress; P62834; -.
DR Bgee; P62834; -.
DR CleanEx; HS_RAP1A; -.
DR Genevestigator; P62834; -.
DR GO; GO:0030054; C:cell junction; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR GO; GO:0032045; C:guanyl-nucleotide exchange factor complex; IEA:Ensembl.
DR GO; GO:0005770; C:late endosome; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; TAS:ProtInc.
DR GO; GO:0032403; F:protein complex binding; IDA:UniProtKB.
DR GO; GO:0008565; F:protein transporter activity; IDA:UniProtKB.
DR GO; GO:0017034; F:Rap guanyl-nucleotide exchange factor activity; ISS:UniProtKB.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0071320; P:cellular response to cAMP; IDA:UniProtKB.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0061028; P:establishment of endothelial barrier; IMP:UniProtKB.
DR GO; GO:0038180; P:nerve growth factor signaling pathway; ISS:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISS:UniProtKB.
DR GO; GO:0032854; P:positive regulation of Rap GTPase activity; 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:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR020849; Small_GTPase_Ras.
DR PANTHER; PTHR24070; PTHR24070; 1.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00173; RAS; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51421; RAS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell junction; Cell membrane; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Endosome; GTP-binding;
KW Lipoprotein; Membrane; Methylation; Neurogenesis; Nucleotide-binding;
KW Prenylation; Reference proteome; Tumor suppressor.
FT CHAIN 1 181 Ras-related protein Rap-1A.
FT /FTId=PRO_0000030199.
FT PROPEP 182 184 Removed in mature form.
FT /FTId=PRO_0000030200.
FT NP_BIND 10 17 GTP (By similarity).
FT NP_BIND 57 61 GTP (By similarity).
FT NP_BIND 116 119 GTP (By similarity).
FT MOTIF 32 40 Effector region (Probable).
FT MOD_RES 181 181 Cysteine methyl ester.
FT LIPID 181 181 S-geranylgeranyl cysteine.
FT STRAND 3 9
FT HELIX 16 25
FT STRAND 36 48
FT STRAND 50 58
FT HELIX 67 74
FT STRAND 76 83
FT HELIX 87 91
FT HELIX 93 104
FT STRAND 111 116
FT HELIX 121 123
FT HELIX 128 137
FT TURN 138 140
FT STRAND 142 145
FT TURN 148 151
FT HELIX 154 165
SQ SEQUENCE 184 AA; 20987 MW; 42C39290C98E0A92 CRC64;
MREYKLVVLG SGGVGKSALT VQFVQGIFVE KYDPTIEDSY RKQVEVDCQQ CMLEILDTAG
TEQFTAMRDL YMKNGQGFAL VYSITAQSTF NDLQDLREQI LRVKDTEDVP MILVGNKCDL
EDERVVGKEQ GQNLARQWCN CAFLESSAKS KINVNEIFYD LVRQINRKTP VEKKKPKKKS
CLLL
//
ID RAP1A_HUMAN Reviewed; 184 AA.
AC P62834; P10113;
DT 16-AUG-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-AUG-2004, sequence version 1.
DT 22-JAN-2014, entry version 116.
DE RecName: Full=Ras-related protein Rap-1A;
DE AltName: Full=C21KG;
DE AltName: Full=G-22K;
DE AltName: Full=GTP-binding protein smg p21A;
DE AltName: Full=Ras-related protein Krev-1;
DE Flags: Precursor;
GN Name=RAP1A; Synonyms=KREV1;
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 [MRNA].
RX PubMed=3045729;
RA Pizon V., Chardin P., Lerosey I., Olofsson B., Tavitian A.;
RT "Human cDNAs rap1 and rap2 homologous to the Drosophila gene Dras3
RT encode proteins closely related to ras in the 'effector' region.";
RL Oncogene 3:201-204(1988).
RN [2]
RP SEQUENCE REVISION TO 3.
RA Pizon V.;
RL Submitted (FEB-1989) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Platelet;
RX PubMed=2507536;
RA Nagata K., Itoh H., Katada T., Takenaka K., Ui M., Kaziro Y.,
RA Nozawa Y.;
RT "Purification, identification, and characterization of two GTP-binding
RT proteins with molecular weights of 25,000 and 21,000 in human platelet
RT cytosol. One is the rap1/smg21/Krev-1 protein and the other is a novel
RT GTP-binding protein.";
RL J. Biol. Chem. 264:17000-17005(1989).
RN [7]
RP PROTEIN SEQUENCE OF 1-35.
RX PubMed=3141412;
RA Bokoch G.M., Parkos C.A., Mumby S.M.;
RT "Purification and characterization of the 22,000-dalton GTP-binding
RT protein substrate for ADP-ribosylation by botulinum toxin, G22K.";
RL J. Biol. Chem. 263:16744-16749(1988).
RN [8]
RP PROTEIN SEQUENCE OF 1-5; 17-24; 32-42 AND 152-168.
RX PubMed=3144274; DOI=10.1016/S0006-291X(88)80302-4;
RA Ohmori T., Kikuchi A., Yamamoto K., Kawata M., Kondo J., Takai Y.;
RT "Identification of a platelet Mr 22,000 GTP-binding protein as the
RT novel smg-21 gene product having the same putative effector domain as
RT the ras gene products.";
RL Biochem. Biophys. Res. Commun. 157:670-676(1988).
RN [9]
RP ISOPRENYLATION AT CYS-181, AND METHYLATION AT CYS-181.
RX PubMed=1899909;
RA Buss J.E., Quilliam L.A., Kato K., Casey P.J., Solski P.A., Wong G.,
RA Clark R., McCormick F., Bokoch G.M., Der C.J.;
RT "The COOH-terminal domain of the Rap1A (Krev-1) protein is
RT isoprenylated and supports transformation by an H-Ras:Rap1A chimeric
RT protein.";
RL Mol. Cell. Biol. 11:1523-1530(1991).
RN [10]
RP INTERACTION WITH RAPGEF2.
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 [11]
RP INTERACTION WITH PLCE1.
RX PubMed=11022048; DOI=10.1074/jbc.M008324200;
RA Song C., Hu C.-D., Masago M., Kariya K., Yamawaki-Kataoka Y.,
RA Shibatohge M., Wu D., Satoh T., Kataoka T.;
RT "Regulation of a novel human phospholipase C, PLCepsilon, through
RT membrane targeting by Ras.";
RL J. Biol. Chem. 276:2752-2757(2001).
RN [12]
RP INTERACTION WITH RAPGEF2, AND SUBCELLULAR LOCATION.
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 [13]
RP INTERACTION WITH PLCE1.
RX PubMed=12444546; DOI=10.1038/sj.onc.1206003;
RA Song C., Satoh T., Edamatsu H., Wu D., Tadano M., Gao X., Kataoka T.;
RT "Differential roles of Ras and Rap1 in growth factor-dependent
RT activation of phospholipase C epsilon.";
RL Oncogene 21:8105-8113(2002).
RN [14]
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH ITGB1BP1 AND KRIT1, AND
RP INTERACTION WITH KRIT1.
RX PubMed=17916086; DOI=10.1111/j.1742-4658.2007.06068.x;
RA Beraud-Dufour S., Gautier R., Albiges-Rizo C., Chardin P.,
RA Faurobert E.;
RT "Krit 1 interactions with microtubules and membranes are regulated by
RT Rap1 and integrin cytoplasmic domain associated protein-1.";
RL FEBS J. 274:5518-5532(2007).
RN [15]
RP INTERACTION WITH RADIL.
RX PubMed=17704304; DOI=10.1101/gad.1561507;
RA Smolen G.A., Schott B.J., Stewart R.A., Diederichs S., Muir B.,
RA Provencher H.L., Look A.T., Sgroi D.C., Peterson R.T., Haber D.A.;
RT "A Rap GTPase interactor, RADIL, mediates migration of neural crest
RT precursors.";
RL Genes Dev. 21:2131-2136(2007).
RN [16]
RP INTERACTION WITH SGSM1; SGSM2 AND SGSM3.
RX PubMed=17509819; DOI=10.1016/j.ygeno.2007.03.013;
RA Yang H., Sasaki T., Minoshima S., Shimizu N.;
RT "Identification of three novel proteins (SGSM1, 2, 3) which modulate
RT small G protein (RAP and RAB)-mediated signaling pathway.";
RL Genomics 90:249-260(2007).
RN [17]
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 [18]
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 [19]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-167.
RX PubMed=7791872; DOI=10.1038/375554a0;
RA Nassar N., Horn G., Herrmann C., Scherer A., McCormick F.,
RA Wittinghofer A.;
RT "The 2.2 A crystal structure of the Ras-binding domain of the
RT serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP
RT analogue.";
RL Nature 375:554-560(1995).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-167.
RX PubMed=8756332; DOI=10.1038/nsb0896-723;
RA Nassar N., Horn G., Herrmann C., Block C., Janknecht R.,
RA Wittinghofer A.;
RT "Ras/Rap effector specificity determined by charge reversal.";
RL Nat. Struct. Biol. 3:723-729(1996).
CC -!- FUNCTION: Induces morphological reversion of a cell line
CC transformed by a Ras oncogene. Counteracts the mitogenic function
CC of Ras, at least partly because it can interact with Ras GAPs and
CC RAF in a competitive manner. Together with ITGB1BP1, regulates
CC KRIT1 localization to microtubules and membranes. Plays a role in
CC nerve growth factor (NGF)-induced neurite outgrowth. Plays a role
CC in the regulation of embryonic blood vessel formation. Involved in
CC the establishment of basal endothelial barrier function. May be
CC involved in the regulation of the vascular endothelial growth
CC factor receptor KDR expression at endothelial cell-cell junctions.
CC -!- ENZYME REGULATION: Activated by guanine nucleotide-exchange
CC factors (GEF) EPAC and EPAC2 in a cAMP-dependent manner, and GFR.
CC -!- SUBUNIT: Found in a complex, at least composed of ITGB1BP1, KRIT1
CC and RAP1A. Interacts (active GTP-bound form preferentially) with
CC KRIT1 (via C-terminus FERM domain); the interaction does not
CC induce the opening conformation of KRIT1. In its GTP-bound form
CC interacts with PLCE1 and RADIL. Interacts with SGSM1, SGSM2 and
CC SGSM3. Interacts (via GTP-bound active form) with RAPGEF2 (via
CC Ras-associating domain).
CC -!- INTERACTION:
CC P04049:RAF1; NbExp=2; IntAct=EBI-491414, EBI-365996;
CC Q8WWW0-2:RASSF5; NbExp=3; IntAct=EBI-491414, EBI-960502;
CC Q5EBH1:Rassf5 (xeno); NbExp=2; IntAct=EBI-491414, EBI-960530;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor. Cytoplasm.
CC Cytoplasm, perinuclear region. Cell junction (By similarity).
CC Early endosome (By similarity). Note=Recruited from early endosome
CC to late endosome compartment after nerve growth factor (NGF)
CC stimulation. Localized with RAPGEF2 at cell-cell junctions (By
CC similarity). Colocalized with RAPGEF2 in the perinuclear region.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Ras family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAB55685.2; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/RAP1AID272.html";
CC -----------------------------------------------------------------------
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DR EMBL; X12533; CAA31051.1; -; mRNA.
DR EMBL; M22995; AAA36150.1; -; mRNA.
DR EMBL; AF493912; AAM12626.1; -; mRNA.
DR EMBL; AL049557; CAB55685.2; ALT_SEQ; Genomic_DNA.
DR EMBL; BC014086; AAH14086.1; -; mRNA.
DR PIR; A32342; A32342.
DR RefSeq; NP_001010935.1; NM_001010935.1.
DR RefSeq; NP_002875.1; NM_002884.2.
DR UniGene; Hs.190334; -.
DR PDB; 1C1Y; X-ray; 1.90 A; A=1-167.
DR PDB; 1GUA; X-ray; 2.00 A; A=1-167.
DR PDB; 3KUC; X-ray; 1.92 A; A=1-167.
DR PDBsum; 1C1Y; -.
DR PDBsum; 1GUA; -.
DR PDBsum; 3KUC; -.
DR ProteinModelPortal; P62834; -.
DR SMR; P62834; 1-167.
DR DIP; DIP-29106N; -.
DR IntAct; P62834; 8.
DR MINT; MINT-1509313; -.
DR STRING; 9606.ENSP00000348786; -.
DR BindingDB; P62834; -.
DR ChEMBL; CHEMBL1255139; -.
DR PhosphoSite; P62834; -.
DR DMDM; 51338607; -.
DR OGP; P62834; -.
DR PaxDb; P62834; -.
DR PRIDE; P62834; -.
DR DNASU; 5906; -.
DR Ensembl; ENST00000356415; ENSP00000348786; ENSG00000116473.
DR Ensembl; ENST00000369709; ENSP00000358723; ENSG00000116473.
DR Ensembl; ENST00000436150; ENSP00000394318; ENSG00000116473.
DR Ensembl; ENST00000545460; ENSP00000443009; ENSG00000116473.
DR GeneID; 5906; -.
DR KEGG; hsa:5906; -.
DR UCSC; uc001ebi.3; human.
DR CTD; 5906; -.
DR GeneCards; GC01P112084; -.
DR HGNC; HGNC:9855; RAP1A.
DR HPA; CAB018335; -.
DR MIM; 179520; gene.
DR neXtProt; NX_P62834; -.
DR PharmGKB; PA34217; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233973; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P62834; -.
DR KO; K04353; -.
DR OMA; KPKKSLC; -.
DR OrthoDB; EOG7QVM41; -.
DR PhylomeDB; P62834; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P62834; -.
DR ChiTaRS; RAP1A; human.
DR EvolutionaryTrace; P62834; -.
DR GeneWiki; RAP1A; -.
DR GenomeRNAi; 5906; -.
DR NextBio; 22972; -.
DR PRO; PR:P62834; -.
DR ArrayExpress; P62834; -.
DR Bgee; P62834; -.
DR CleanEx; HS_RAP1A; -.
DR Genevestigator; P62834; -.
DR GO; GO:0030054; C:cell junction; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR GO; GO:0032045; C:guanyl-nucleotide exchange factor complex; IEA:Ensembl.
DR GO; GO:0005770; C:late endosome; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; TAS:ProtInc.
DR GO; GO:0032403; F:protein complex binding; IDA:UniProtKB.
DR GO; GO:0008565; F:protein transporter activity; IDA:UniProtKB.
DR GO; GO:0017034; F:Rap guanyl-nucleotide exchange factor activity; ISS:UniProtKB.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0071320; P:cellular response to cAMP; IDA:UniProtKB.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0061028; P:establishment of endothelial barrier; IMP:UniProtKB.
DR GO; GO:0038180; P:nerve growth factor signaling pathway; ISS:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISS:UniProtKB.
DR GO; GO:0032854; P:positive regulation of Rap GTPase activity; 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:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR020849; Small_GTPase_Ras.
DR PANTHER; PTHR24070; PTHR24070; 1.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00173; RAS; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51421; RAS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell junction; Cell membrane; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Endosome; GTP-binding;
KW Lipoprotein; Membrane; Methylation; Neurogenesis; Nucleotide-binding;
KW Prenylation; Reference proteome; Tumor suppressor.
FT CHAIN 1 181 Ras-related protein Rap-1A.
FT /FTId=PRO_0000030199.
FT PROPEP 182 184 Removed in mature form.
FT /FTId=PRO_0000030200.
FT NP_BIND 10 17 GTP (By similarity).
FT NP_BIND 57 61 GTP (By similarity).
FT NP_BIND 116 119 GTP (By similarity).
FT MOTIF 32 40 Effector region (Probable).
FT MOD_RES 181 181 Cysteine methyl ester.
FT LIPID 181 181 S-geranylgeranyl cysteine.
FT STRAND 3 9
FT HELIX 16 25
FT STRAND 36 48
FT STRAND 50 58
FT HELIX 67 74
FT STRAND 76 83
FT HELIX 87 91
FT HELIX 93 104
FT STRAND 111 116
FT HELIX 121 123
FT HELIX 128 137
FT TURN 138 140
FT STRAND 142 145
FT TURN 148 151
FT HELIX 154 165
SQ SEQUENCE 184 AA; 20987 MW; 42C39290C98E0A92 CRC64;
MREYKLVVLG SGGVGKSALT VQFVQGIFVE KYDPTIEDSY RKQVEVDCQQ CMLEILDTAG
TEQFTAMRDL YMKNGQGFAL VYSITAQSTF NDLQDLREQI LRVKDTEDVP MILVGNKCDL
EDERVVGKEQ GQNLARQWCN CAFLESSAKS KINVNEIFYD LVRQINRKTP VEKKKPKKKS
CLLL
//
MIM
179520
*RECORD*
*FIELD* NO
179520
*FIELD* TI
*179520 RAS-RELATED PROTEIN 1A; RAP1A
KREV1
*FIELD* TX
CLONING
Rousseau-Merck et al. (1990) stated that 3 human cDNAs encoding 'new'
read moreRAS-related proteins, designated RAP1A, RAP1B (179530), and RAP2
(179540), were isolated by Pizon et al. (1988) and Pizon et al. (1988).
These proteins share approximately 50% amino acid identity with the
classical RAS proteins and have numerous structural features in common.
The most striking difference between the RAP and RAS proteins resides in
their 61st amino acid: glutamine in RAS is replaced by threonine in RAP
proteins.
Kitayama et al. (1989) isolated a human cDNA termed Krev1 that can
suppress the transformed phenotype of a Kirsten transformed cell line.
The predicted amino acid sequence of the Krev1 protein is identical to
that of RAP1A.
GENE FUNCTION
Boussiotis et al. (1997) noted that C3G (600303) catalyzes GTP exchange
of Rap1. Immunoblot analysis showed that in anergic T cells, CBL
(165360) is constitutively phosphorylated, CRKL (602007)-C3G complexes
are recruited, and Rap1, an antagonist of Ras function and a negative
regulator of IL2 transcription, is activated. Boussiotis et al. (1997)
suggested that the key determinant of the functional outcome of T cell
receptor-initiated signals may be the ratio of Ras-GTP to RAP1-GTP, with
the predominance of the former enhancing, and the of the latter
blocking, IL2 transcription.
Asha et al. (1999) demonstrated that RAS1-mediated signaling pathways in
Drosophila are not influenced by RAP1 levels, suggesting that RAS1 and
RAP1 function via distinct pathways. Moreover, a mutation that abolishes
the putative cAMP-dependent kinase phosphorylation site of Drosophila
RAP1 can still rescue the RAP1 mutant phenotype. Asha et al. (1999)
demonstrated that RAP1 is not needed for cell proliferation and
cell-fate specification but has a critical function in regulating normal
morphogenesis in the eye disc, the ovary, and the embryo. RAP1 mutations
also disrupt cell migrations and cause abnormalities in cell shape.
These findings indicate a role for RAP proteins as regulators of
morphogenesis in vivo.
Mochizuki et al. (2001) used fluorescent resonance energy transfer
(FRET)-based sensors to evaluate the spatiotemporal images of growth
factor-induced activation of RAS and RAP1. Epidermal growth factor
(131530) activated RAS at the peripheral plasma membrane and RAP1 at the
intracellular perinuclear region of COS-1 cells. In PC12 cells, nerve
growth factor (see 162030)-induced activation of RAS was initiated at
the plasma membrane and transmitted to the whole cell body. After 3
hours, high RAS activity was observed at the extending neurites. By
using the FRAP (fluorescence recovery after photobleaching) technique,
Mochizuki et al. (2001) found that RAS at the neurites turned over
rapidly; therefore, the sustained RAS activity at neurites was due to
high GTP/GDP exchange rate and/or low GTPase activity, but not to the
retention of the active RAS. While previous biochemical analyses rarely
detected more than 40% activation of RAS upon growth factor stimulation,
Mochizuki et al. (2001) concluded that their data show that growth
factor stimulation strongly activates RAS/RAP1 in a very restricted area
within cells, and that a large population of RAS or RAP1 remains
inactive, causing an apparent low-level response in biochemical assays.
Zhu et al. (2002) examined the small GTPases RAS and RAP in the
postsynaptic signaling underlying synaptic plasticity. They showed that
RAS relays the NMDA receptor (see 138252) and
calcium/calmodulin-dependent protein kinase II (see 114078) signaling
that drives synaptic delivery of AMPA receptors (see 138248) during
long-term potentiation. In contrast, RAP was found to mediate the NMDA
receptor-dependent removal of synaptic AMPA receptors that occurs during
long-term depression. The authors determined that RAS and RAP exert
their effects on AMPA receptors that contain different subunit
composition. Thus, RAS and RAP, whose activities can be controlled by
postsynaptic enzymes, serve as independent regulators for potentiating
and depressing central synapses.
Knox and Brown (2002) found that even distribution of adherens junctions
is an active process that requires RAP1. Cells mutant for RAP1 condensed
their adherens junctions to 1 side of the cell. This disrupted normal
epithelial cell behavior and mutant cell clones dispersed into the
surrounding wildtype tissue. RAP1 is enriched at adherens junctions,
particularly between newly divided sister cells where it may reseal the
adherens junction ring.
MAPPING
Rousseau-Merck et al. (1990) used cDNA probes to assign the RAP genes by
in situ hybridization; RAP1A, RAP1B, and RAP2A were assigned to
1p13-p12, 12q14, and 13q34, respectively, without cross-hybridization or
any secondary signal. By fluorescence in situ hybridization, Takai et
al. (1993) narrowed the assignment of the KREV1 gene to 1p13.3 and
mapped its pseudogene (KREV1P) to 14q24.3.
ANIMAL MODEL
Using mice transgenic for constitutive expression of Rap1a within the
T-cell lineage, Sebzda et al. (2002) found that instead of anergy, these
T cells showed enhanced T-cell receptor-mediated responses, both in
thymocytes and in mature T cells. In addition, Rap1a activation induced
strong activation of beta-1 (135630) and beta-2 (600065) integrins. The
authors concluded that Rap1a positively influences T cells by augmenting
their responses and directing integrin activation.
Li et al. (2007) generated mice lacking Rap1a. Although loss of Rap1a
did not initially affect mouse size or viability, upon backcross into
C57BL/6J mice some Rap1a -/- embryos died in utero. Rap1a -/- mice
showed no defects in development of T, B, or myeloid cells. However,
Rap1a -/- macrophages exhibited increased random movement, or
haptotaxis, on fibronectin (FN1; 135600) and vitronectin (VTN; 193190)
matrices that correlated with decreased adhesion. The chemotactic
responses of Rap1a -/- lymphoid and myeloid cells to Cxcl12 (600835) and
Ccl21 (602737) were significantly reduced, but FcR (see 146790)-mediated
phagocytosis increased. Neutrophils from Rap1a -/- mice had reduced
superoxide production when stimulated with the synthetic chemotactic
peptide FMLP. Li et al. (2007) concluded that, in spite of 95% sequence
identity, similar intracellular distribution, and broad tissue
distribution, Rap1a and Rap1b are not functionally redundant and,
instead, differentially regulate some cellular events.
*FIELD* RF
1. Asha, H.; de Ruiter, N. D.; Wang, M.-G.; Hariharan, I. K.: The
Rap1 GTPase functions as a regulator of morphogenesis in vivo. EMBO
J. 18: 605-615, 1999.
2. Boussiotis, V. A.; Freeman, G. J.; Berezovskaya, A.; Barber, D.
L.; Nadler, L. M.: Maintenance of human T cell anergy: blocking of
IL-2 gene transcription by activated Rap1. Science 278: 124-128,
1997.
3. Kitayama, H.; Sugimoto, Y.; Matsuzaki, T.; Ikawa, Y.; Noda, M.
: A ras-related gene with transformation suppressor activity. Cell 56:
77-84, 1989.
4. Knox, A. L.; Brown, N. H.: Rap1 GTPase regulation of adherens
junction positioning and cell adhesion. Science 295: 1285-1288,
2002.
5. Li, Y.; Yan, J.; De, P.; Chang, H.-C.; Yamauchi, A.; Christopherson,
K. W., II; Paranavitana, N. C.; Peng, X.; Kim, C.; Munugalavadla,
V.; Kapur, R.; Chen, H.; Shou, W.; Stone, J. C.; Kaplan, M. H.; Dinauer,
M. C.; Durden, D. L.; Quilliam, L. A.: Rap1a null mice have altered
myeloid cell functions suggesting distinct roles for the closely related
Rap1a and 1b proteins. J. Immun. 179: 8322-8331, 2007. Note: Erratum:
J. Immun. 180: 3612 only, 2008.
6. Mochizuki, N.; Yamashita, S.; Kurokawa, K.; Ohba, Y.; Nagai, T.;
Miyawaki, A.; Matsuda, M.: Spatio-temporal images of growth-factor-induced
activation of Ras and Rap1. Nature 411: 1065-1068, 2001.
7. Pizon, V.; Chardin, P.; Lerosey, I.; Olofsson, B.; Tavitian, A.
: Human cDNAs RAP1 and RAP2 homologous to the Drosophila gene Dras3
encode proteins closely related to ras in the 'effector' region. Oncogene 3:
201-204, 1988.
8. Pizon, V.; Lerosey, I.; Chardin, P.; Tavitian, A.: Nucleotide
sequence of a human cDNA encoding ras-related protein (rap1B). Nucleic
Acids Res. 16: 7719 only, 1988.
9. Rousseau-Merck, M. F.; Pizon, V.; Tavitian, A.; Berger, R.: Chromosome
mapping of the human RAS-related RAP1A, RAP1B, and RAP2 genes to chromosomes
1p12-p13, 12q14, and 13q34, respectively. Cytogenet. Cell Genet. 53:
2-4, 1990.
10. Sebzda, E.; Bracke, M.; Tugal, T.; Hogg, N.; Cantrell, D. A.:
Rap1a positively regulates T cells via integrin activation rather
than inhibiting lymphocyte signaling. Nature Immun. 3: 251-258,
2002.
11. Takai, S.; Nishino, N.; Kitayama, H.; Ikawa, Y.; Noda, M.: Mapping
of the KREV1 transformation suppressor gene and its pseudogene (KREV1P)
to human chromosome 1p13.3 and 14q24.3, respectively, by fluorescence
in situ hybridization. Cytogenet. Cell Genet. 63: 59-61, 1993.
12. Zhu, J. J.; Qin, Y.; Zhao, M.; Van Aelst, L.; Malinow, R.: Ras
and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110:
443-455, 2002.
*FIELD* CN
Paul J. Converse - updated: 1/22/2009
Stylianos E. Antonarakis - updated: 9/9/2002
Ada Hamosh - updated: 2/20/2002
Paul J. Converse - updated: 2/11/2002
*FIELD* CD
Victor A. McKusick: 9/6/1989
*FIELD* ED
terry: 06/06/2012
mgross: 1/26/2009
terry: 1/22/2009
carol: 10/13/2006
carol: 8/29/2005
mgross: 10/11/2004
terry: 7/19/2004
mgross: 9/9/2002
alopez: 3/12/2002
alopez: 2/22/2002
terry: 2/20/2002
alopez: 2/11/2002
mark: 2/17/1997
mark: 2/13/1997
terry: 2/13/1997
mark: 1/10/1997
carol: 5/26/1993
supermim: 3/16/1992
carol: 7/12/1990
supermim: 3/20/1990
carol: 12/12/1989
ddp: 10/27/1989
*RECORD*
*FIELD* NO
179520
*FIELD* TI
*179520 RAS-RELATED PROTEIN 1A; RAP1A
KREV1
*FIELD* TX
CLONING
Rousseau-Merck et al. (1990) stated that 3 human cDNAs encoding 'new'
read moreRAS-related proteins, designated RAP1A, RAP1B (179530), and RAP2
(179540), were isolated by Pizon et al. (1988) and Pizon et al. (1988).
These proteins share approximately 50% amino acid identity with the
classical RAS proteins and have numerous structural features in common.
The most striking difference between the RAP and RAS proteins resides in
their 61st amino acid: glutamine in RAS is replaced by threonine in RAP
proteins.
Kitayama et al. (1989) isolated a human cDNA termed Krev1 that can
suppress the transformed phenotype of a Kirsten transformed cell line.
The predicted amino acid sequence of the Krev1 protein is identical to
that of RAP1A.
GENE FUNCTION
Boussiotis et al. (1997) noted that C3G (600303) catalyzes GTP exchange
of Rap1. Immunoblot analysis showed that in anergic T cells, CBL
(165360) is constitutively phosphorylated, CRKL (602007)-C3G complexes
are recruited, and Rap1, an antagonist of Ras function and a negative
regulator of IL2 transcription, is activated. Boussiotis et al. (1997)
suggested that the key determinant of the functional outcome of T cell
receptor-initiated signals may be the ratio of Ras-GTP to RAP1-GTP, with
the predominance of the former enhancing, and the of the latter
blocking, IL2 transcription.
Asha et al. (1999) demonstrated that RAS1-mediated signaling pathways in
Drosophila are not influenced by RAP1 levels, suggesting that RAS1 and
RAP1 function via distinct pathways. Moreover, a mutation that abolishes
the putative cAMP-dependent kinase phosphorylation site of Drosophila
RAP1 can still rescue the RAP1 mutant phenotype. Asha et al. (1999)
demonstrated that RAP1 is not needed for cell proliferation and
cell-fate specification but has a critical function in regulating normal
morphogenesis in the eye disc, the ovary, and the embryo. RAP1 mutations
also disrupt cell migrations and cause abnormalities in cell shape.
These findings indicate a role for RAP proteins as regulators of
morphogenesis in vivo.
Mochizuki et al. (2001) used fluorescent resonance energy transfer
(FRET)-based sensors to evaluate the spatiotemporal images of growth
factor-induced activation of RAS and RAP1. Epidermal growth factor
(131530) activated RAS at the peripheral plasma membrane and RAP1 at the
intracellular perinuclear region of COS-1 cells. In PC12 cells, nerve
growth factor (see 162030)-induced activation of RAS was initiated at
the plasma membrane and transmitted to the whole cell body. After 3
hours, high RAS activity was observed at the extending neurites. By
using the FRAP (fluorescence recovery after photobleaching) technique,
Mochizuki et al. (2001) found that RAS at the neurites turned over
rapidly; therefore, the sustained RAS activity at neurites was due to
high GTP/GDP exchange rate and/or low GTPase activity, but not to the
retention of the active RAS. While previous biochemical analyses rarely
detected more than 40% activation of RAS upon growth factor stimulation,
Mochizuki et al. (2001) concluded that their data show that growth
factor stimulation strongly activates RAS/RAP1 in a very restricted area
within cells, and that a large population of RAS or RAP1 remains
inactive, causing an apparent low-level response in biochemical assays.
Zhu et al. (2002) examined the small GTPases RAS and RAP in the
postsynaptic signaling underlying synaptic plasticity. They showed that
RAS relays the NMDA receptor (see 138252) and
calcium/calmodulin-dependent protein kinase II (see 114078) signaling
that drives synaptic delivery of AMPA receptors (see 138248) during
long-term potentiation. In contrast, RAP was found to mediate the NMDA
receptor-dependent removal of synaptic AMPA receptors that occurs during
long-term depression. The authors determined that RAS and RAP exert
their effects on AMPA receptors that contain different subunit
composition. Thus, RAS and RAP, whose activities can be controlled by
postsynaptic enzymes, serve as independent regulators for potentiating
and depressing central synapses.
Knox and Brown (2002) found that even distribution of adherens junctions
is an active process that requires RAP1. Cells mutant for RAP1 condensed
their adherens junctions to 1 side of the cell. This disrupted normal
epithelial cell behavior and mutant cell clones dispersed into the
surrounding wildtype tissue. RAP1 is enriched at adherens junctions,
particularly between newly divided sister cells where it may reseal the
adherens junction ring.
MAPPING
Rousseau-Merck et al. (1990) used cDNA probes to assign the RAP genes by
in situ hybridization; RAP1A, RAP1B, and RAP2A were assigned to
1p13-p12, 12q14, and 13q34, respectively, without cross-hybridization or
any secondary signal. By fluorescence in situ hybridization, Takai et
al. (1993) narrowed the assignment of the KREV1 gene to 1p13.3 and
mapped its pseudogene (KREV1P) to 14q24.3.
ANIMAL MODEL
Using mice transgenic for constitutive expression of Rap1a within the
T-cell lineage, Sebzda et al. (2002) found that instead of anergy, these
T cells showed enhanced T-cell receptor-mediated responses, both in
thymocytes and in mature T cells. In addition, Rap1a activation induced
strong activation of beta-1 (135630) and beta-2 (600065) integrins. The
authors concluded that Rap1a positively influences T cells by augmenting
their responses and directing integrin activation.
Li et al. (2007) generated mice lacking Rap1a. Although loss of Rap1a
did not initially affect mouse size or viability, upon backcross into
C57BL/6J mice some Rap1a -/- embryos died in utero. Rap1a -/- mice
showed no defects in development of T, B, or myeloid cells. However,
Rap1a -/- macrophages exhibited increased random movement, or
haptotaxis, on fibronectin (FN1; 135600) and vitronectin (VTN; 193190)
matrices that correlated with decreased adhesion. The chemotactic
responses of Rap1a -/- lymphoid and myeloid cells to Cxcl12 (600835) and
Ccl21 (602737) were significantly reduced, but FcR (see 146790)-mediated
phagocytosis increased. Neutrophils from Rap1a -/- mice had reduced
superoxide production when stimulated with the synthetic chemotactic
peptide FMLP. Li et al. (2007) concluded that, in spite of 95% sequence
identity, similar intracellular distribution, and broad tissue
distribution, Rap1a and Rap1b are not functionally redundant and,
instead, differentially regulate some cellular events.
*FIELD* RF
1. Asha, H.; de Ruiter, N. D.; Wang, M.-G.; Hariharan, I. K.: The
Rap1 GTPase functions as a regulator of morphogenesis in vivo. EMBO
J. 18: 605-615, 1999.
2. Boussiotis, V. A.; Freeman, G. J.; Berezovskaya, A.; Barber, D.
L.; Nadler, L. M.: Maintenance of human T cell anergy: blocking of
IL-2 gene transcription by activated Rap1. Science 278: 124-128,
1997.
3. Kitayama, H.; Sugimoto, Y.; Matsuzaki, T.; Ikawa, Y.; Noda, M.
: A ras-related gene with transformation suppressor activity. Cell 56:
77-84, 1989.
4. Knox, A. L.; Brown, N. H.: Rap1 GTPase regulation of adherens
junction positioning and cell adhesion. Science 295: 1285-1288,
2002.
5. Li, Y.; Yan, J.; De, P.; Chang, H.-C.; Yamauchi, A.; Christopherson,
K. W., II; Paranavitana, N. C.; Peng, X.; Kim, C.; Munugalavadla,
V.; Kapur, R.; Chen, H.; Shou, W.; Stone, J. C.; Kaplan, M. H.; Dinauer,
M. C.; Durden, D. L.; Quilliam, L. A.: Rap1a null mice have altered
myeloid cell functions suggesting distinct roles for the closely related
Rap1a and 1b proteins. J. Immun. 179: 8322-8331, 2007. Note: Erratum:
J. Immun. 180: 3612 only, 2008.
6. Mochizuki, N.; Yamashita, S.; Kurokawa, K.; Ohba, Y.; Nagai, T.;
Miyawaki, A.; Matsuda, M.: Spatio-temporal images of growth-factor-induced
activation of Ras and Rap1. Nature 411: 1065-1068, 2001.
7. Pizon, V.; Chardin, P.; Lerosey, I.; Olofsson, B.; Tavitian, A.
: Human cDNAs RAP1 and RAP2 homologous to the Drosophila gene Dras3
encode proteins closely related to ras in the 'effector' region. Oncogene 3:
201-204, 1988.
8. Pizon, V.; Lerosey, I.; Chardin, P.; Tavitian, A.: Nucleotide
sequence of a human cDNA encoding ras-related protein (rap1B). Nucleic
Acids Res. 16: 7719 only, 1988.
9. Rousseau-Merck, M. F.; Pizon, V.; Tavitian, A.; Berger, R.: Chromosome
mapping of the human RAS-related RAP1A, RAP1B, and RAP2 genes to chromosomes
1p12-p13, 12q14, and 13q34, respectively. Cytogenet. Cell Genet. 53:
2-4, 1990.
10. Sebzda, E.; Bracke, M.; Tugal, T.; Hogg, N.; Cantrell, D. A.:
Rap1a positively regulates T cells via integrin activation rather
than inhibiting lymphocyte signaling. Nature Immun. 3: 251-258,
2002.
11. Takai, S.; Nishino, N.; Kitayama, H.; Ikawa, Y.; Noda, M.: Mapping
of the KREV1 transformation suppressor gene and its pseudogene (KREV1P)
to human chromosome 1p13.3 and 14q24.3, respectively, by fluorescence
in situ hybridization. Cytogenet. Cell Genet. 63: 59-61, 1993.
12. Zhu, J. J.; Qin, Y.; Zhao, M.; Van Aelst, L.; Malinow, R.: Ras
and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110:
443-455, 2002.
*FIELD* CN
Paul J. Converse - updated: 1/22/2009
Stylianos E. Antonarakis - updated: 9/9/2002
Ada Hamosh - updated: 2/20/2002
Paul J. Converse - updated: 2/11/2002
*FIELD* CD
Victor A. McKusick: 9/6/1989
*FIELD* ED
terry: 06/06/2012
mgross: 1/26/2009
terry: 1/22/2009
carol: 10/13/2006
carol: 8/29/2005
mgross: 10/11/2004
terry: 7/19/2004
mgross: 9/9/2002
alopez: 3/12/2002
alopez: 2/22/2002
terry: 2/20/2002
alopez: 2/11/2002
mark: 2/17/1997
mark: 2/13/1997
terry: 2/13/1997
mark: 1/10/1997
carol: 5/26/1993
supermim: 3/16/1992
carol: 7/12/1990
supermim: 3/20/1990
carol: 12/12/1989
ddp: 10/27/1989