O95398 (RPGF3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Rap guanine nucleotide exchange factor 3

Alternative name(s):
Exchange factor directly activated by cAMP 1
Exchange protein directly activated by cAMP 1
Short name=EPAC 1
Rap1 guanine-nucleotide-exchange factor directly activated by cAMP
cAMP-regulated guanine nucleotide exchange factor I
Short name=cAMP-GEFI

Gene names

Name:	RAPGEF3
Synonyms:	CGEF1, EPAC, EPAC1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	923 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Guanine nucleotide exchange factor (GEF) for RAP1A and RAP2A small GTPases that is activated by binding cAMP. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which it activates the PI3K gamma complex and which is involved in angiogenesis. Ref.4 Ref.5
Subunit structure	Interacts with PDE3B. Ref.7
Subcellular location	Endomembrane system Ref.5.
Tissue specificity	Widely expressed with highest levels in adult kidney, heart, thyroid and brain, and fetal kidney. Ref.1
Domain	The DEP domain is involved in membrane localization independent from regulation by cAMP. Ref.5
Sequence similarities	Contains 1 cyclic nucleotide-binding domain. Contains 1 DEP domain. Contains 1 N-terminal Ras-GEF domain. Contains 1 Ras-GEF domain.
Caution	It is uncertain whether Met-1 or Met-43 is the initiator.
Sequence caution	The sequence AAD02890.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence AAD12740.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
Biological process	Angiogenesis
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	Nucleotide-binding cAMP cAMP-binding
Molecular function	Guanine-nucleotide releasing factor
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW cell proliferation Traceable author statement Ref.4. Source: ProtInc energy reserve metabolic process Traceable author statement. Source: Reactome platelet activation Traceable author statement. Source: Reactome positive regulation of angiogenesis Inferred from mutant phenotype Ref.7. Source: UniProtKB regulation of insulin secretion Traceable author statement. Source: Reactome regulation of small GTPase mediated signal transduction Inferred from electronic annotation. Source: InterPro signal transduction Traceable author statement Ref.4. Source: ProtInc small GTPase mediated signal transduction Inferred from electronic annotation. Source: InterPro small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	cAMP-dependent protein kinase complex Inferred from electronic annotation. Source: InterPro endomembrane system Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Traceable author statement. Source: Reactome
Molecular_function	cAMP binding Inferred from electronic annotation. Source: UniProtKB-KW cAMP-dependent protein kinase regulator activity Inferred from electronic annotation. Source: InterPro guanyl-nucleotide exchange factor activity Traceable author statement Ref.4. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
PDE3B	Q13370	8	EBI-6172806,EBI-6172856

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O95398-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O95398-2)

The sequence of this isoform differs from the canonical sequence as follows:
     533-598: ARNLPVWLPN...LAQEDGWTKG → VSAWPQFLSS...GQAVPGGAEA
     599-923: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 923	923	Rap guanine nucleotide exchange factor 3		PRO_0000068867
Regions
	Domain	110 – 186	77	DEP
	Domain	384 – 518	135	N-terminal Ras-GEF
	Domain	662 – 889	228	Ras-GEF
	Nucleotide binding	245 – 363	119	cAMP
	Region	218 – 242	25	Interaction with PDE3B
	Region	398 – 422	25	Interaction with PDE3B
Natural variations
	Alternative sequence	533 – 598	66	ARNLP…GWTKG → VSAWPQFLSSAPPGLQAPPS PPDPEGLCGRGKLSSHRHTL GSLIGVHGALAACGALGQAV PGGAEA in isoform 2.		VSP_007608
	Alternative sequence	599 – 923	325	Missing in isoform 2.		VSP_007609
	Natural variant	16	1	A → P. Ref.3 Corresponds to variant rs11168230 [ dbSNP | Ensembl ].		VAR_047924
	Natural variant	193	1	R → G. Ref.1 Ref.3 Ref.4 Corresponds to variant rs2016123 [ dbSNP | Ensembl ].		VAR_047925
	Natural variant	374	1	G → S. Corresponds to variant rs12422983 [ dbSNP | Ensembl ].		VAR_047926
	Natural variant	517	1	C → Y. Corresponds to variant rs61709815 [ dbSNP | Ensembl ].		VAR_061784
Experimental info
	Mutagenesis	315	1	L → W: Abolishes activation of RAP1A. Ref.6
	Mutagenesis	321	1	R → K: Reduces activation of RAP1A. Ref.1
	Mutagenesis	342	1	F → A or T: Diminishes GEF activity dependence on cAMP concentration. Ref.6
	Mutagenesis	412	1	D → A: Abolishes interaction with PDE3B. Ref.7
	Mutagenesis	415	1	E → A: Abolishes interaction with PDE3B. Ref.7
	Mutagenesis	417	1	F → A: Abolishes interaction with PDE3B. Ref.7
	Mutagenesis	420	1	D → A: Abolishes interaction with PDE3B. Ref.7
	Mutagenesis	421	1	F → A: Abolishes interaction with PDE3B. Ref.7
	Sequence conflict	64	1	R → H in AAD12740. Ref.1
	Sequence conflict	64	1	R → H in AAD02890. Ref.1
	Sequence conflict	106	1	R → Q in AAD12740. Ref.1
	Sequence conflict	106	1	R → Q in AAD02890. Ref.1
	Sequence conflict	116	1	I → T in AAC83381. Ref.4
	Sequence conflict	330	1	D → Y in AAD12740. Ref.1
	Sequence conflict	330	1	D → Y in AAD02890. Ref.1
	Sequence conflict	394	1	E → D in AAD12740. Ref.1
	Sequence conflict	394	1	E → D in AAD02890. Ref.1
	Sequence conflict	406	1	P → L in AAD12740. Ref.1
	Sequence conflict	406	1	P → L in AAD02890. Ref.1
	Sequence conflict	414	1	T → K in AAD12740. Ref.1
	Sequence conflict	414	1	T → K in AAD02890. Ref.1
	Sequence conflict	491	1	Q → H in AAD12740. Ref.1
	Sequence conflict	638	1	V → A in AAC83381. Ref.4
	Sequence conflict	736	1	R → K in AAD12740. Ref.1
	Sequence conflict	751	1	L → V in AAD12740. Ref.1
	Sequence conflict	765	1	A → P in AAD12740. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 11, 2011. Version 6. Checksum: 8B3A24341F20515F	FASTA	923	103,751
	10 20 30 40 50 60 MKVGWPGESC WQVGLAVEDS PALGAPRVGA LPDVVPEGTL LNMVLRRMHR PRSCSYQLLL 70 80 90 100 110 120 EHQRPSCIQG LRWTPLTNSE ESLDFSESLE QASTERVLRA GRQLHRHLLA TCPNLIRDRK 130 140 150 160 170 180 YHLRLYRQCC SGRELVDGIL ALGLGVHSRS QVVGICQVLL DEGALCHVKH DWAFQDRDAQ 190 200 210 220 230 240 FYRFPGPEPE PVRTHEMEEE LAEAVALLSQ RGPDALLTVA LRKPPGQRTD EELDLIFEEL 250 260 270 280 290 300 LHIKAVAHLS NSVKRELAAV LLFEPHSKAG TVLFSQGDKG TSWYIIWKGS VNVVTHGKGL 310 320 330 340 350 360 VTTLHEGDDF GQLALVNDAP RAATIILRED NCHFLRVDKQ DFNRIIKDVE AKTMRLEEHG 370 380 390 400 410 420 KVVLVLERAS QGAGPSRPPT PGRNRYTVMS GTPEKILELL LEAMGPDSSA HDPTETFLSD 430 440 450 460 470 480 FLLTHRVFMP SAQLCAALLH HFHVEPAGGS EQERSTYVCN KRQQILRLVS QWVALYGSML 490 500 510 520 530 540 HTDPVATSFL QKLSDLVGRD TRLSNLLREQ WPERRRCHRL ENGCGNASPQ MKARNLPVWL 550 560 570 580 590 600 PNQDEPLPGS SCAIQVGDKV PYDICRPDHS VLTLQLPVTA SVREVMAALA QEDGWTKGQV 610 620 630 640 650 660 LVKVNSAGDA IGLQPDARGV ATSLGLNERL FVVNPQEVHE LIPHPDQLGP TVGSAEGLDL 670 680 690 700 710 720 VSAKDLAGQL TDHDWSLFNS IHQVELIHYV LGPQHLRDVT TANLERFMRR FNELQYWVAT 730 740 750 760 770 780 ELCLCPVPGP RAQLLRKFIK LAAHLKEQKN LNSFFAVMFG LSNSAISRLA HTWERLPHKV 790 800 810 820 830 840 RKLYSALERL LDPSWNHRVY RLALAKLSPP VIPFMPLLLK DMTFIHEGNH TLVENLINFE 850 860 870 880 890 900 KMRMMARAAR MLHHCRSHNP VPLSPLRSRV SHLHEDSQVA RISTCSEQSL STRSPASTWA 910 920 YVQQLKVIDN QRELSRLSRE LEP
	Isoform 2 [UniParc]. Checksum: 8F67017CA93D36F8	FASTA	598	66,067
	10 20 30 40 50 60 MKVGWPGESC WQVGLAVEDS PALGAPRVGA LPDVVPEGTL LNMVLRRMHR PRSCSYQLLL 70 80 90 100 110 120 EHQRPSCIQG LRWTPLTNSE ESLDFSESLE QASTERVLRA GRQLHRHLLA TCPNLIRDRK 130 140 150 160 170 180 YHLRLYRQCC SGRELVDGIL ALGLGVHSRS QVVGICQVLL DEGALCHVKH DWAFQDRDAQ 190 200 210 220 230 240 FYRFPGPEPE PVRTHEMEEE LAEAVALLSQ RGPDALLTVA LRKPPGQRTD EELDLIFEEL 250 260 270 280 290 300 LHIKAVAHLS NSVKRELAAV LLFEPHSKAG TVLFSQGDKG TSWYIIWKGS VNVVTHGKGL 310 320 330 340 350 360 VTTLHEGDDF GQLALVNDAP RAATIILRED NCHFLRVDKQ DFNRIIKDVE AKTMRLEEHG 370 380 390 400 410 420 KVVLVLERAS QGAGPSRPPT PGRNRYTVMS GTPEKILELL LEAMGPDSSA HDPTETFLSD 430 440 450 460 470 480 FLLTHRVFMP SAQLCAALLH HFHVEPAGGS EQERSTYVCN KRQQILRLVS QWVALYGSML 490 500 510 520 530 540 HTDPVATSFL QKLSDLVGRD TRLSNLLREQ WPERRRCHRL ENGCGNASPQ MKVSAWPQFL 550 560 570 580 590 SSAPPGLQAP PSPPDPEGLC GRGKLSSHRH TLGSLIGVHG ALAACGALGQ AVPGGAEA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A family of cAMP-binding proteins that directly activate rap1." Kawasaki H., Springett G.M., Mochizuki N., Toki S., Nakaya M., Matsuda M., Housman D.E., Graybiel A.M. Science 282:2275-2279(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, MUTAGENESIS OF ARG-321, VARIANT GLY-193.
[2]	"The finished DNA sequence of human chromosome 12." Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A. Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANTS PRO-16 AND GLY-193. Tissue: Kidney.
[4]	"Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP." de Rooij J., Zwartkruis F.J.T., Verheijen M.H., Cool R.H., Nijman S.M., Wittinghofer A., Bos J.L. Nature 396:474-477(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 43-923 (ISOFORM 1), FUNCTION, VARIANT GLY-193. Tissue: Muscle.
[5]	"Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs." de Rooij J., Rehmann H., van Triest M., Cool R.H., Wittinghofer A., Bos J.L. J. Biol. Chem. 275:20829-20836(2000) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DOMAIN DEP, SUBCELLULAR LOCATION.
[6]	"Structure and regulation of the cAMP-binding domains of Epac2." Rehmann H., Prakash B., Wolf E., Rueppel A., De Rooij J., Bos J.L., Wittinghofer A. Nat. Struct. Biol. 10:26-32(2003) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF LEU-315 AND PHE-342.
[7]	"A phosphodiesterase 3B-based signaling complex integrates exchange protein activated by cAMP 1 and phosphatidylinositol 3-kinase signals in human arterial endothelial cells." Wilson L.S., Baillie G.S., Pritchard L.M., Umana B., Terrin A., Zaccolo M., Houslay M.D., Maurice D.H. J. Biol. Chem. 286:16285-16296(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PDE3B, MUTAGENESIS OF ASP-412; GLU-415; PHE-417; ASP-420 AND PHE-421.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U78168 mRNA. Translation: AAD12740.1. Different initiation. U78169 mRNA. Translation: AAD02890.1. Different initiation. AC004241 Genomic DNA. No translation available. BC017728 mRNA. Translation: AAH17728.2. AF103905 mRNA. Translation: AAC83381.1.
IPI	IPI00329727. IPI00793799.
UniGene	Hs.8578.
3D structure databases
ProteinModelPortal	O95398.
SMR	O95398. Positions 89-923.
ModBase	Search...
Protein-protein interaction databases
IntAct	O95398. 2 interactions.
MINT	MINT-6741771.
STRING	9606.ENSP00000395708.
PTM databases
PhosphoSite	O95398.
Proteomic databases
PaxDb	O95398.
PRIDE	O95398.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000389212; ENSP00000373864; ENSG00000079337. ENST00000395358; ENSP00000378764; ENSG00000079337. ENST00000449771; ENSP00000395708; ENSG00000079337.
UCSC	uc001rpz.4. human. uc001rqb.3. human.
Organism-specific databases
GeneCards	GC12M048128.
HGNC	HGNC:16629. RAPGEF3.
HPA	CAB004386.
MIM	606057. gene.
neXtProt	NX_O95398.
PharmGKB	PA134910959.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0664.
HOGENOM	HOG000230545.
InParanoid	O95398.
OMA	NSFFAVM.
OrthoDB	EOG4WDDB1.
Enzyme and pathway databases
Reactome	REACT_111102. Signal Transduction. REACT_111217. Metabolism. REACT_604. Hemostasis. REACT_6900. Immune System.
Gene expression databases
ArrayExpress	O95398.
Bgee	O95398.
CleanEx	HS_RAPGEF3.
Genevestigator	O95398.
GermOnline	ENSG00000079337. Homo sapiens.
Family and domain databases
Gene3D	1.10.10.10. 1 hit. 1.10.840.10. 1 hit. 2.60.120.10. 1 hit.
InterPro	IPR002373. cAMP/cGMP_kin. IPR018490. cNMP-bd-like. IPR000595. cNMP-bd_dom. IPR000591. DEP_dom. IPR000651. Ras-like_Gua-exchang_fac_N. IPR019804. Ras_G-nucl-exch_fac_CS. IPR008937. Ras_GEF. IPR023578. Ras_GEF_dom. IPR001895. RasGRF_CDC25. IPR014710. RmlC-like_jellyroll. IPR011991. WHTH_DNA-bd_dom. [Graphical view]
PANTHER	PTHR23113. PTHR23113. 1 hit.
Pfam	PF00027. cNMP_binding. 1 hit. PF00610. DEP. 1 hit. PF00617. RasGEF. 1 hit. PF00618. RasGEF_N. 1 hit. [Graphical view]
PRINTS	PR00103. CAMPKINASE.
SMART	SM00100. cNMP. 1 hit. SM00049. DEP. 1 hit. SM00147. RasGEF. 1 hit. SM00229. RasGEFN. 1 hit. [Graphical view]
SUPFAM	SSF51206. cNMP_binding. 1 hit. SSF48366. Ras_GEF. 1 hit.
PROSITE	PS00888. CNMP_BINDING_1. False negative. PS00889. CNMP_BINDING_2. False negative. PS50042. CNMP_BINDING_3. 1 hit. PS50186. DEP. 1 hit. PS00720. RASGEF. 1 hit. PS50009. RASGEF_CAT. 1 hit. PS50212. RASGEF_NTER. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	RAPGEF3. human.
NextBio	13603411.
SOURCE	Search...

Entry information

Entry name

RPGF3_HUMAN

Accession

Primary (citable) accession number: O95398
Secondary accession number(s): O95634, Q8WVN0

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 20, 2003
Last sequence update:	January 11, 2011
Last modified:	May 1, 2013
This is version 121 of the entry and version 6 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.