ID RPGF3_HUMAN Reviewed; 923 AA. AC O95398; A8K2G5; E7EQC8; O95634; Q8WVN0; DT 20-JUN-2003, integrated into UniProtKB/Swiss-Prot. DT 11-JAN-2011, sequence version 6. DT 24-JAN-2024, entry version 200. DE RecName: Full=Rap guanine nucleotide exchange factor 3; DE AltName: Full=Exchange factor directly activated by cAMP 1; DE AltName: Full=Exchange protein directly activated by cAMP 1; DE Short=EPAC 1; DE AltName: Full=Rap1 guanine-nucleotide-exchange factor directly activated by cAMP; DE AltName: Full=cAMP-regulated guanine nucleotide exchange factor I; DE Short=cAMP-GEFI; GN Name=RAPGEF3; Synonyms=CGEF1, EPAC, EPAC1; 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] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, RP MUTAGENESIS OF ARG-321, AND VARIANT GLY-193. RX PubMed=9856955; DOI=10.1126/science.282.5397.2275; RA Kawasaki H., Springett G.M., Mochizuki N., Toki S., Nakaya M., Matsuda M., RA Housman D.E., Graybiel A.M.; RT "A family of cAMP-binding proteins that directly activate rap1."; RL Science 282:2275-2279(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT GLY-193. RC TISSUE=Thalamus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT GLY-193. 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS PRO-16 AND RP GLY-193. RC TISSUE=Kidney; 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 43-923 (ISOFORM 1), FUNCTION, AND VARIANT RP GLY-193. RC TISSUE=Muscle; RX PubMed=9853756; DOI=10.1038/24884; RA de Rooij J., Zwartkruis F.J.T., Verheijen M.H., Cool R.H., Nijman S.M., RA Wittinghofer A., Bos J.L.; RT "Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by RT cyclic AMP."; RL Nature 396:474-477(1998). RN [7] RP FUNCTION, DOMAIN DEP, AND SUBCELLULAR LOCATION. RX PubMed=10777494; DOI=10.1074/jbc.m001113200; RA de Rooij J., Rehmann H., van Triest M., Cool R.H., Wittinghofer A., RA Bos J.L.; RT "Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs."; RL J. Biol. Chem. 275:20829-20836(2000). RN [8] RP MUTAGENESIS OF LEU-315 AND PHE-342. RX PubMed=12469113; DOI=10.1038/nsb878; RA Rehmann H., Prakash B., Wolf E., Rueppel A., De Rooij J., Bos J.L., RA Wittinghofer A.; RT "Structure and regulation of the cAMP-binding domains of Epac2."; RL Nat. Struct. Biol. 10:26-32(2003). RN [9] 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 [10] RP INTERACTION WITH PDE3B AND PIK3R6, AND MUTAGENESIS OF ASP-412; GLU-415; RP PHE-417; ASP-420 AND PHE-421. RX PubMed=21393242; DOI=10.1074/jbc.m110.217026; RA Wilson L.S., Baillie G.S., Pritchard L.M., Umana B., Terrin A., Zaccolo M., RA Houslay M.D., Maurice D.H.; RT "A phosphodiesterase 3B-based signaling complex integrates exchange protein RT activated by cAMP 1 and phosphatidylinositol 3-kinase signals in human RT arterial endothelial cells."; RL J. Biol. Chem. 286:16285-16296(2011). RN [11] {ECO:0007744|PDB:6H7E} RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 92-360 IN COMPLEX WITH CAMP. RA Ferrandez Y., Cherfils J., Peurois F.; RT "GEF regulatory domain."; RL Submitted (JUL-2018) to the PDB data bank. CC -!- FUNCTION: Guanine nucleotide exchange factor (GEF) for RAP1A and RAP2A CC small GTPases that is activated by binding cAMP. Through simultaneous CC binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling CC complex in which it activates the PI3K gamma complex and which is CC involved in angiogenesis. Plays a role in the modulation of the cAMP- CC induced dynamic control of endothelial barrier function through a CC pathway that is independent on Rho-mediated signaling. Required for the CC actin rearrangement at cell-cell junctions, such as stress fibers and CC junctional actin. {ECO:0000269|PubMed:10777494, CC ECO:0000269|PubMed:21840392, ECO:0000269|PubMed:9853756}. CC -!- SUBUNIT: Interacts with PDE3B and PIK3R6; form a signaling complex that CC regulates phosphatidylinositol 3-kinase gamma in angiogenesis. CC {ECO:0000269|PubMed:21393242}. CC -!- INTERACTION: CC O95398; Q13370: PDE3B; NbExp=8; IntAct=EBI-6172806, EBI-6172856; CC -!- SUBCELLULAR LOCATION: Endomembrane system CC {ECO:0000269|PubMed:10777494}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=O95398-1; Sequence=Displayed; CC Name=2; CC IsoId=O95398-2; Sequence=VSP_007608, VSP_007609; CC Name=3; CC IsoId=O95398-3; Sequence=VSP_047007; CC -!- TISSUE SPECIFICITY: Widely expressed with highest levels in adult CC kidney, heart, thyroid and brain, and fetal kidney. CC {ECO:0000269|PubMed:9856955}. CC -!- DOMAIN: The DEP domain is involved in membrane localization independent CC from regulation by cAMP. {ECO:0000269|PubMed:10777494}. CC -!- CAUTION: It is uncertain whether Met-1 or Met-43 is the initiator. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAD02890.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAD12740.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U78168; AAD12740.1; ALT_INIT; mRNA. DR EMBL; U78169; AAD02890.1; ALT_INIT; mRNA. DR EMBL; AK290230; BAF82919.1; -; mRNA. DR EMBL; AC004241; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC137054; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471111; EAW57944.1; -; Genomic_DNA. DR EMBL; BC017728; AAH17728.2; -; mRNA. DR EMBL; AF103905; AAC83381.1; -; mRNA. DR CCDS; CCDS31784.1; -. [O95398-3] DR CCDS; CCDS41775.1; -. [O95398-1] DR RefSeq; NP_001092002.1; NM_001098532.2. DR RefSeq; NP_006096.2; NM_006105.5. DR PDB; 6H7E; X-ray; 2.30 A; A/B=92-360. DR PDBsum; 6H7E; -. DR AlphaFoldDB; O95398; -. DR SASBDB; O95398; -. DR SMR; O95398; -. DR BioGRID; 115682; 19. DR IntAct; O95398; 5. DR MINT; O95398; -. DR STRING; 9606.ENSP00000395708; -. DR BindingDB; O95398; -. DR ChEMBL; CHEMBL2029197; -. DR GuidetoPHARMACOLOGY; 1292; -. DR GlyGen; O95398; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O95398; -. DR PhosphoSitePlus; O95398; -. DR BioMuta; RAPGEF3; -. DR MassIVE; O95398; -. DR MaxQB; O95398; -. DR PaxDb; 9606-ENSP00000395708; -. DR PeptideAtlas; O95398; -. DR ProteomicsDB; 17545; -. DR ProteomicsDB; 50849; -. [O95398-1] DR ProteomicsDB; 50850; -. [O95398-2] DR Antibodypedia; 3824; 303 antibodies from 38 providers. DR DNASU; 10411; -. DR Ensembl; ENST00000389212.7; ENSP00000373864.3; ENSG00000079337.16. [O95398-1] DR Ensembl; ENST00000395358.7; ENSP00000378764.3; ENSG00000079337.16. [O95398-2] DR Ensembl; ENST00000405493.6; ENSP00000384521.2; ENSG00000079337.16. [O95398-3] DR Ensembl; ENST00000449771.7; ENSP00000395708.2; ENSG00000079337.16. [O95398-1] DR Ensembl; ENST00000549151.5; ENSP00000448619.1; ENSG00000079337.16. [O95398-3] DR GeneID; 10411; -. DR KEGG; hsa:10411; -. DR MANE-Select; ENST00000449771.7; ENSP00000395708.2; NM_001098531.4; NP_001092001.2. DR UCSC; uc001rpz.5; human. [O95398-1] DR AGR; HGNC:16629; -. DR CTD; 10411; -. DR DisGeNET; 10411; -. DR GeneCards; RAPGEF3; -. DR HGNC; HGNC:16629; RAPGEF3. DR HPA; ENSG00000079337; Low tissue specificity. DR MIM; 606057; gene. DR neXtProt; NX_O95398; -. DR OpenTargets; ENSG00000079337; -. DR PharmGKB; PA134910959; -. DR VEuPathDB; HostDB:ENSG00000079337; -. DR eggNOG; KOG2378; Eukaryota. DR GeneTree; ENSGT00940000159931; -. DR HOGENOM; CLU_006829_0_0_1; -. DR InParanoid; O95398; -. DR OMA; QVFPDRC; -. DR OrthoDB; 5473909at2759; -. DR PhylomeDB; O95398; -. DR TreeFam; TF313184; -. DR PathwayCommons; O95398; -. DR Reactome; R-HSA-354192; Integrin signaling. DR Reactome; R-HSA-381676; Glucagon-like Peptide-1 (GLP1) regulates insulin secretion. DR Reactome; R-HSA-392517; Rap1 signalling. DR Reactome; R-HSA-422356; Regulation of insulin secretion. DR SignaLink; O95398; -. DR SIGNOR; O95398; -. DR BioGRID-ORCS; 10411; 15 hits in 1149 CRISPR screens. DR ChiTaRS; RAPGEF3; human. DR GeneWiki; RAPGEF3; -. DR GenomeRNAi; 10411; -. DR Pharos; O95398; Tchem. DR PRO; PR:O95398; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; O95398; Protein. DR Bgee; ENSG00000079337; Expressed in metanephros cortex and 175 other cell types or tissues. DR ExpressionAtlas; O95398; baseline and differential. DR GO; GO:0012505; C:endomembrane system; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0030175; C:filopodium; IDA:UniProtKB. DR GO; GO:0030027; C:lamellipodium; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; TAS:ProtInc. DR GO; GO:0005902; C:microvillus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0030552; F:cAMP binding; IEA:UniProtKB-KW. DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IMP:UniProtKB. DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB. DR GO; GO:0002250; P:adaptive immune response; TAS:Reactome. DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW. DR GO; GO:0008306; P:associative learning; IEA:Ensembl. DR GO; GO:0019933; P:cAMP-mediated signaling; NAS:BHF-UCL. DR GO; GO:0071320; P:cellular response to cAMP; IDA:UniProtKB. DR GO; GO:0061028; P:establishment of endothelial barrier; IMP:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IMP:UniProtKB. DR GO; GO:0034242; P:negative regulation of syncytium formation by plasma membrane fusion; IMP:UniProtKB. DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:UniProtKB. DR GO; GO:0043547; P:positive regulation of GTPase activity; IMP:UniProtKB. DR GO; GO:0046827; P:positive regulation of protein export from nucleus; IDA:UniProtKB. DR GO; GO:0051496; P:positive regulation of stress fiber assembly; IMP:UniProtKB. DR GO; GO:0060143; P:positive regulation of syncytium formation by plasma membrane fusion; 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:0032956; P:regulation of actin cytoskeleton organization; IMP:UniProtKB. DR GO; GO:0045765; P:regulation of angiogenesis; IMP:UniProt. DR GO; GO:0051896; P:regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IMP:UniProt. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR CDD; cd00038; CAP_ED; 1. DR CDD; cd04437; DEP_Epac; 1. DR CDD; cd00155; RasGEF; 1. DR CDD; cd06224; REM; 1. DR Gene3D; 1.10.8.1240; -; 1. DR Gene3D; 2.60.120.10; Jelly Rolls; 1. DR Gene3D; 1.10.840.10; Ras guanine-nucleotide exchange factors catalytic domain; 1. DR Gene3D; 1.20.870.10; Son of sevenless (SoS) protein Chain: S domain 1; 1. DR Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 1. DR InterPro; IPR000595; cNMP-bd_dom. DR InterPro; IPR018490; cNMP-bd_dom_sf. DR InterPro; IPR000591; DEP_dom. DR InterPro; IPR008937; Ras-like_GEF. DR InterPro; IPR000651; Ras-like_Gua-exchang_fac_N. DR InterPro; IPR019804; Ras_G-nucl-exch_fac_CS. 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 InterPro; IPR036388; WH-like_DNA-bd_sf. DR InterPro; IPR036390; WH_DNA-bd_sf. DR PANTHER; PTHR23113; GUANINE NUCLEOTIDE EXCHANGE FACTOR; 1. DR PANTHER; PTHR23113:SF24; RAP GUANINE NUCLEOTIDE EXCHANGE FACTOR 3; 1. DR Pfam; PF00027; cNMP_binding; 1. DR Pfam; PF00610; DEP; 1. DR Pfam; PF00617; RasGEF; 1. DR Pfam; PF00618; RasGEF_N; 1. DR PRINTS; PR00103; CAMPKINASE. DR SMART; SM00100; cNMP; 1. DR SMART; SM00049; DEP; 1. DR SMART; SM00147; RasGEF; 1. DR SMART; SM00229; RasGEFN; 1. DR SUPFAM; SSF51206; cAMP-binding domain-like; 1. DR SUPFAM; SSF48366; Ras GEF; 1. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR SUPFAM; SSF46785; Winged helix' DNA-binding domain; 1. DR PROSITE; PS50042; CNMP_BINDING_3; 1. DR PROSITE; PS50186; DEP; 1. DR PROSITE; PS00720; RASGEF; 1. DR PROSITE; PS50009; RASGEF_CAT; 1. DR PROSITE; PS50212; RASGEF_NTER; 1. DR Genevisible; O95398; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Angiogenesis; cAMP; cAMP-binding; KW Guanine-nucleotide releasing factor; Membrane; Nucleotide-binding; KW Phosphoprotein; Reference proteome. FT CHAIN 1..923 FT /note="Rap guanine nucleotide exchange factor 3" FT /id="PRO_0000068867" FT DOMAIN 110..186 FT /note="DEP" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00066" FT DOMAIN 384..518 FT /note="N-terminal Ras-GEF" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00135" FT DOMAIN 662..889 FT /note="Ras-GEF" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00168" FT REGION 218..242 FT /note="Interaction with PDE3B" FT /evidence="ECO:0000269|PubMed:21393242" FT REGION 398..422 FT /note="Interaction with PDE3B" FT /evidence="ECO:0000269|PubMed:21393242" FT BINDING 311..314 FT /ligand="3',5'-cyclic AMP" FT /ligand_id="ChEBI:CHEBI:58165" FT /evidence="ECO:0007744|PDB:6H7E" FT BINDING 321..322 FT /ligand="3',5'-cyclic AMP" FT /ligand_id="ChEBI:CHEBI:58165" FT /evidence="ECO:0007744|PDB:6H7E" FT MOD_RES 79 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8VCC8" FT MOD_RES 528 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8VCC8" FT MOD_RES 864 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8VCC8" FT VAR_SEQ 1..42 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_047007" FT VAR_SEQ 533..598 FT /note="ARNLPVWLPNQDEPLPGSSCAIQVGDKVPYDICRPDHSVLTLQLPVTASVRE FT VMAALAQEDGWTKG -> VSAWPQFLSSAPPGLQAPPSPPDPEGLCGRGKLSSHRHTLG FT SLIGVHGALAACGALGQAVPGGAEA (in isoform 2)" FT /evidence="ECO:0000303|PubMed:9856955" FT /id="VSP_007608" FT VAR_SEQ 599..923 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:9856955" FT /id="VSP_007609" FT VARIANT 16 FT /note="A -> P (in dbSNP:rs11168230)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_047924" FT VARIANT 193 FT /note="R -> G (in dbSNP:rs2016123)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:9853756, FT ECO:0000269|PubMed:9856955, ECO:0000269|Ref.4" FT /id="VAR_047925" FT VARIANT 374 FT /note="G -> S (in dbSNP:rs12422983)" FT /id="VAR_047926" FT VARIANT 517 FT /note="C -> Y (in dbSNP:rs61709815)" FT /id="VAR_061784" FT MUTAGEN 315 FT /note="L->W: Abolishes activation of RAP1A." FT /evidence="ECO:0000269|PubMed:12469113" FT MUTAGEN 321 FT /note="R->K: Reduces activation of RAP1A." FT /evidence="ECO:0000269|PubMed:9856955" FT MUTAGEN 342 FT /note="F->A,T: Diminishes GEF activity dependence on cAMP FT concentration." FT /evidence="ECO:0000269|PubMed:12469113" FT MUTAGEN 412 FT /note="D->A: Abolishes interaction with PDE3B." FT /evidence="ECO:0000269|PubMed:21393242" FT MUTAGEN 415 FT /note="E->A: Abolishes interaction with PDE3B." FT /evidence="ECO:0000269|PubMed:21393242" FT MUTAGEN 417 FT /note="F->A: Abolishes interaction with PDE3B." FT /evidence="ECO:0000269|PubMed:21393242" FT MUTAGEN 420 FT /note="D->A: Abolishes interaction with PDE3B." FT /evidence="ECO:0000269|PubMed:21393242" FT MUTAGEN 421 FT /note="F->A: Abolishes interaction with PDE3B." FT /evidence="ECO:0000269|PubMed:21393242" FT CONFLICT 64 FT /note="R -> H (in Ref. 1; AAD12740/AAD02890)" FT /evidence="ECO:0000305" FT CONFLICT 106 FT /note="R -> Q (in Ref. 1; AAD12740/AAD02890)" FT /evidence="ECO:0000305" FT CONFLICT 116 FT /note="I -> T (in Ref. 6; AAC83381)" FT /evidence="ECO:0000305" FT CONFLICT 330 FT /note="D -> Y (in Ref. 1; AAD12740/AAD02890)" FT /evidence="ECO:0000305" FT CONFLICT 394 FT /note="E -> D (in Ref. 1; AAD12740/AAD02890)" FT /evidence="ECO:0000305" FT CONFLICT 406 FT /note="P -> L (in Ref. 1; AAD12740/AAD02890)" FT /evidence="ECO:0000305" FT CONFLICT 414 FT /note="T -> K (in Ref. 1; AAD12740/AAD02890)" FT /evidence="ECO:0000305" FT CONFLICT 491 FT /note="Q -> H (in Ref. 1; AAD12740)" FT /evidence="ECO:0000305" FT CONFLICT 638 FT /note="V -> A (in Ref. 6; AAC83381)" FT /evidence="ECO:0000305" FT CONFLICT 736 FT /note="R -> K (in Ref. 1; AAD12740)" FT /evidence="ECO:0000305" FT CONFLICT 751 FT /note="L -> V (in Ref. 1; AAD12740)" FT /evidence="ECO:0000305" FT CONFLICT 765 FT /note="A -> P (in Ref. 1; AAD12740)" FT /evidence="ECO:0000305" FT HELIX 94..111 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 115..121 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 124..131 FT /evidence="ECO:0007829|PDB:6H7E" FT HELIX 132..142 FT /evidence="ECO:0007829|PDB:6H7E" FT HELIX 149..161 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 164..167 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 177..179 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 181..183 FT /evidence="ECO:0007829|PDB:6H7E" FT HELIX 200..222 FT /evidence="ECO:0007829|PDB:6H7E" FT HELIX 230..240 FT /evidence="ECO:0007829|PDB:6H7E" FT HELIX 244..246 FT /evidence="ECO:0007829|PDB:6H7E" FT HELIX 251..260 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 262..265 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 272..274 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 282..295 FT /evidence="ECO:0007829|PDB:6H7E" FT TURN 296..298 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 299..305 FT /evidence="ECO:0007829|PDB:6H7E" FT HELIX 312..317 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 322..327 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 329..331 FT /evidence="ECO:0007829|PDB:6H7E" FT STRAND 333..338 FT /evidence="ECO:0007829|PDB:6H7E" FT HELIX 339..346 FT /evidence="ECO:0007829|PDB:6H7E" SQ SEQUENCE 923 AA; 103751 MW; 8B3A24341F20515F CRC64; MKVGWPGESC WQVGLAVEDS PALGAPRVGA LPDVVPEGTL LNMVLRRMHR PRSCSYQLLL EHQRPSCIQG LRWTPLTNSE ESLDFSESLE QASTERVLRA GRQLHRHLLA TCPNLIRDRK YHLRLYRQCC SGRELVDGIL ALGLGVHSRS QVVGICQVLL DEGALCHVKH DWAFQDRDAQ FYRFPGPEPE PVRTHEMEEE LAEAVALLSQ RGPDALLTVA LRKPPGQRTD EELDLIFEEL LHIKAVAHLS NSVKRELAAV LLFEPHSKAG TVLFSQGDKG TSWYIIWKGS VNVVTHGKGL VTTLHEGDDF GQLALVNDAP RAATIILRED NCHFLRVDKQ DFNRIIKDVE AKTMRLEEHG KVVLVLERAS QGAGPSRPPT PGRNRYTVMS GTPEKILELL LEAMGPDSSA HDPTETFLSD FLLTHRVFMP SAQLCAALLH HFHVEPAGGS EQERSTYVCN KRQQILRLVS QWVALYGSML HTDPVATSFL QKLSDLVGRD TRLSNLLREQ WPERRRCHRL ENGCGNASPQ MKARNLPVWL PNQDEPLPGS SCAIQVGDKV PYDICRPDHS VLTLQLPVTA SVREVMAALA QEDGWTKGQV LVKVNSAGDA IGLQPDARGV ATSLGLNERL FVVNPQEVHE LIPHPDQLGP TVGSAEGLDL VSAKDLAGQL TDHDWSLFNS IHQVELIHYV LGPQHLRDVT TANLERFMRR FNELQYWVAT ELCLCPVPGP RAQLLRKFIK LAAHLKEQKN LNSFFAVMFG LSNSAISRLA HTWERLPHKV RKLYSALERL LDPSWNHRVY RLALAKLSPP VIPFMPLLLK DMTFIHEGNH TLVENLINFE KMRMMARAAR MLHHCRSHNP VPLSPLRSRV SHLHEDSQVA RISTCSEQSL STRSPASTWA YVQQLKVIDN QRELSRLSRE LEP //