Q8WZA2 (RPGF4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Rap guanine nucleotide exchange factor 4

Alternative name(s):
Exchange factor directly activated by cAMP 2
Exchange protein directly activated by cAMP 2
Short name=EPAC 2
cAMP-regulated guanine nucleotide exchange factor II
Short name=cAMP-GEFII

Gene names

Name:	RAPGEF4
Synonyms:	CGEF2, EPAC2

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	1011 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Guanine nucleotide exchange factor (GEF) for RAP1A, RAP1B and RAP2A small GTPases that is activated by binding cAMP. Seems not to activate RAB3A. Involved in cAMP-dependent, PKA-independent exocytosis through interaction with RIMS2 By similarity. Ref.1 Ref.5
Subunit structure	Interacts with RIMS1 and RIMS2. Probably part of a complex with RIMS2 and GTP-activated RAB3A By similarity.
Subcellular location	Cytoplasm. Membrane; Peripheral membrane protein By similarity.
Tissue specificity	Predominantly expressed in brain and adrenal gland. Isoform 2 is expressed in liver. Isoform 1 is expressed in liver at very low levels.
Domain	The N-terminal nucleotide phosphate binding region cAMP 1 has a much lower affinity for cAMP as compared to cAMP 2. The DEP domain is involved in membrane localization independent from regulation by cAMP By similarity.
Sequence similarities	Contains 2 cyclic nucleotide-binding domains. Contains 1 DEP domain. Contains 1 N-terminal Ras-GEF domain. Contains 1 Ras-GEF domain.

Ontologies

Keywords
Biological process	Exocytosis
Cellular component	Cytoplasm Membrane
Coding sequence diversity	Alternative promoter usage Alternative splicing
Domain	Repeat
Ligand	Nucleotide-binding cAMP cAMP-binding
Molecular function	Guanine-nucleotide releasing factor
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G-protein coupled receptor signaling pathway Traceable author statement Ref.1. Source: ProtInc cAMP-mediated signaling Inferred from electronic annotation. Source: Compara calcium ion-dependent exocytosis Inferred from electronic annotation. Source: Compara energy reserve metabolic process Traceable author statement. Source: Reactome insulin secretion Inferred from electronic annotation. Source: Compara platelet activation Traceable author statement. Source: Reactome regulation of exocytosis Inferred from electronic annotation. Source: Compara regulation of insulin secretion Traceable author statement. Source: Reactome regulation of small GTPase mediated signal transduction Inferred from electronic annotation. Source: InterPro 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 cytosol Inferred from electronic annotation. Source: Compara plasma membrane Traceable author statement. Source: Reactome
Molecular_function	Ras GTPase binding Inferred from sequence or structural similarity. Source: UniProtKB Ras guanyl-nucleotide exchange factor activity Inferred from sequence or structural similarity. Source: UniProtKB cAMP binding Inferred from sequence or structural similarity. Source: UniProtKB cAMP-dependent protein kinase regulator activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative promoter usage and alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q8WZA2-1)

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.

Note: Produced by alternative promoter usage. Promoter analysis was carried out in mouse.

Isoform 2 (identifier: Q8WZA2-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-315: Missing.

Note: Produced by alternative promoter usage. Promoter analysis was carried out in mouse.

Isoform 3 (identifier: Q8WZA2-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-144: Missing.
     145-148: ALWE → MLYK

Note: Produced by alternative splicing of isoform 1. No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1011	1011	Rap guanine nucleotide exchange factor 4		PRO_0000068870
Regions
	Domain	216 – 291	76	DEP
	Domain	496 – 634	139	N-terminal Ras-GEF
	Domain	772 – 1009	238	Ras-GEF
	Nucleotide binding	43 – 166	124	cAMP 1
	Nucleotide binding	356 – 476	121	cAMP 2
Amino acid modifications
	Modified residue	681	1	Phosphotyrosine By similarity
Natural variations
	Alternative sequence	1 – 315	315	Missing in isoform 2.		VSP_007611
	Alternative sequence	1 – 144	144	Missing in isoform 3.		VSP_007612
	Alternative sequence	145 – 148	4	ALWE → MLYK in isoform 3.		VSP_007613
Experimental info
	Sequence conflict	324	1	P → R in AAH40183. Ref.4
	Sequence conflict	511	1	H → R in AAH40183. Ref.4
	Sequence conflict	647	1	L → I in AAH40183. Ref.4
	Sequence conflict	679	1	H → P in AAH24004. Ref.4
	Sequence conflict	732	1	T → M in AAH24004. Ref.4
	Sequence conflict	873	1	V → I in AAD03422. Ref.1
	Sequence conflict	902	1	P → T in AAH40183. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified March 1, 2002. Version 1. Checksum: 9427C5F92F2FFAD1	FASTA	1,011	115,522
	10 20 30 40 50 60 MVAAHAAHSS SSAEWIACLD KRPLERSSED VDIIFTRLKE VKAFEKFHPN LLHQICLCGY 70 80 90 100 110 120 YENLEKGITL FRQGDIGTNW YAVLAGSLDV KVSETSSHQD AVTICTLGIG TAFGESILDN 130 140 150 160 170 180 TPRHATIVTR ESSELLRIEQ KDFKALWEKY RQYMAGLLAP PYGVMETGSN NDRIPDKENT 190 200 210 220 230 240 PLIEPHVPLR PANTITKVPS EKILRAGKIL RNAILSRAPH MIRDRKYHLK TYRQCCVGTE 250 260 270 280 290 300 LVDWMMQQTP CVHSRTQAVG MWQVLLEDGV LNHVDQEHHF QDKYLFYRFL DDEHEDAPLP 310 320 330 340 350 360 TEEEKKECDE ELQDTMLLLS QMGPDAHMRM ILRKPPGQRT VDDLEIIYEE LLHIKALSHL 370 380 390 400 410 420 STTVKRELAG VLIFESHAKG GTVLFNQGEE GTSWYIILKG SVNVVIYGKG VVCTLHEGDD 430 440 450 460 470 480 FGKLALVNDA PRAASIVLRE DNCHFLRVDK EDFNRILRDV EANTVRLKEH DQDVLVLEKV 490 500 510 520 530 540 PAGNRASNQG NSQPQQKYTV MSGTPEKILE HFLETIRLEA TLNEATDSVL NDFIMMHCVF 550 560 570 580 590 600 MPNTQLCPAL VAHYHAQPSQ GTEQEKMDYA LNNKRRVIRL VLQWAAMYGD LLQEDDVSMA 610 620 630 640 650 660 FLEEFYVSVS DDARMIAALK EQLPELEKIV KQISEDAKAP QKKHKVLLQQ FNTGDERAQK 670 680 690 700 710 720 RQPIRGSDEV LFKVYCMDHT YTTIRVPVAT SVKEVISAVA DKLGSGEGLI IVKMSSGGEK 730 740 750 760 770 780 VVLKPNDVSV FTTLTINGRL FACPREQFDS LTPLPEQEGP TVGTVGTFEL MSSKDLAYQM 790 800 810 820 830 840 TIYDWELFNC VHELELIYHT FGRHNFKKTT ANLDLFLRRF NEIQFWVVTE ICLCSQLSKR 850 860 870 880 890 900 VQLLKKFIKI AAHCKEYKNL NSFFAIVMGL SNVAVSRLAL TWEKLPSKFK KFYAEFESLM 910 920 930 940 950 960 DPSRNHRAYR LTVAKLEPPL IPFMPLLIKD MTFTHEGNKT FIDNLVNFEK MRMIANTART 970 980 990 1000 1010 VRYYRSQPFN PDAAQANKNH QDVRSYVRQL NVIDNQRTLS QMSHRLEPRR P
	Isoform 2 [UniParc]. Checksum: 936C1CEC6FA169C8	FASTA	696	79,492
	10 20 30 40 50 60 MLLLSQMGPD AHMRMILRKP PGQRTVDDLE IIYEELLHIK ALSHLSTTVK RELAGVLIFE 70 80 90 100 110 120 SHAKGGTVLF NQGEEGTSWY IILKGSVNVV IYGKGVVCTL HEGDDFGKLA LVNDAPRAAS 130 140 150 160 170 180 IVLREDNCHF LRVDKEDFNR ILRDVEANTV RLKEHDQDVL VLEKVPAGNR ASNQGNSQPQ 190 200 210 220 230 240 QKYTVMSGTP EKILEHFLET IRLEATLNEA TDSVLNDFIM MHCVFMPNTQ LCPALVAHYH 250 260 270 280 290 300 AQPSQGTEQE KMDYALNNKR RVIRLVLQWA AMYGDLLQED DVSMAFLEEF YVSVSDDARM 310 320 330 340 350 360 IAALKEQLPE LEKIVKQISE DAKAPQKKHK VLLQQFNTGD ERAQKRQPIR GSDEVLFKVY 370 380 390 400 410 420 CMDHTYTTIR VPVATSVKEV ISAVADKLGS GEGLIIVKMS SGGEKVVLKP NDVSVFTTLT 430 440 450 460 470 480 INGRLFACPR EQFDSLTPLP EQEGPTVGTV GTFELMSSKD LAYQMTIYDW ELFNCVHELE 490 500 510 520 530 540 LIYHTFGRHN FKKTTANLDL FLRRFNEIQF WVVTEICLCS QLSKRVQLLK KFIKIAAHCK 550 560 570 580 590 600 EYKNLNSFFA IVMGLSNVAV SRLALTWEKL PSKFKKFYAE FESLMDPSRN HRAYRLTVAK 610 620 630 640 650 660 LEPPLIPFMP LLIKDMTFTH EGNKTFIDNL VNFEKMRMIA NTARTVRYYR SQPFNPDAAQ 670 680 690 ANKNHQDVRS YVRQLNVIDN QRTLSQMSHR LEPRRP
	Isoform 3 [UniParc]. Checksum: 5CA711EAD3DBEE66	FASTA	867	99,523
	10 20 30 40 50 60 MLYKKYRQYM AGLLAPPYGV METGSNNDRI PDKENTPLIE PHVPLRPANT ITKVPSEKIL 70 80 90 100 110 120 RAGKILRNAI LSRAPHMIRD RKYHLKTYRQ CCVGTELVDW MMQQTPCVHS RTQAVGMWQV 130 140 150 160 170 180 LLEDGVLNHV DQEHHFQDKY LFYRFLDDEH EDAPLPTEEE KKECDEELQD TMLLLSQMGP 190 200 210 220 230 240 DAHMRMILRK PPGQRTVDDL EIIYEELLHI KALSHLSTTV KRELAGVLIF ESHAKGGTVL 250 260 270 280 290 300 FNQGEEGTSW YIILKGSVNV VIYGKGVVCT LHEGDDFGKL ALVNDAPRAA SIVLREDNCH 310 320 330 340 350 360 FLRVDKEDFN RILRDVEANT VRLKEHDQDV LVLEKVPAGN RASNQGNSQP QQKYTVMSGT 370 380 390 400 410 420 PEKILEHFLE TIRLEATLNE ATDSVLNDFI MMHCVFMPNT QLCPALVAHY HAQPSQGTEQ 430 440 450 460 470 480 EKMDYALNNK RRVIRLVLQW AAMYGDLLQE DDVSMAFLEE FYVSVSDDAR MIAALKEQLP 490 500 510 520 530 540 ELEKIVKQIS EDAKAPQKKH KVLLQQFNTG DERAQKRQPI RGSDEVLFKV YCMDHTYTTI 550 560 570 580 590 600 RVPVATSVKE VISAVADKLG SGEGLIIVKM SSGGEKVVLK PNDVSVFTTL TINGRLFACP 610 620 630 640 650 660 REQFDSLTPL PEQEGPTVGT VGTFELMSSK DLAYQMTIYD WELFNCVHEL ELIYHTFGRH 670 680 690 700 710 720 NFKKTTANLD LFLRRFNEIQ FWVVTEICLC SQLSKRVQLL KKFIKIAAHC KEYKNLNSFF 730 740 750 760 770 780 AIVMGLSNVA VSRLALTWEK LPSKFKKFYA EFESLMDPSR NHRAYRLTVA KLEPPLIPFM 790 800 810 820 830 840 PLLIKDMTFT HEGNKTFIDN LVNFEKMRMI ANTARTVRYY RSQPFNPDAA QANKNHQDVR 850 860 SYVRQLNVID NQRTLSQMSH RLEPRRP

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] (ISOFORM 1), FUNCTION.
[2]	"Characterization of the gene EPAC2: structure, chromosomal localization, tissue expression, and identification of the liver-specific isoform." Ueno H., Shibasaki T., Iwanaga T., Takahashi K., Yokoyama Y., Liu L.M., Yokoi N., Ozaki N., Matsukura S., Yano H., Seino S. Genomics 78:91-98(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), ALTERNATIVE PROMOTER USAGE.
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). Tissue: Hippocampus and Trachea.
[4]	"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] (ISOFORMS 1 AND 3). Tissue: Hypothalamus and Testis.
[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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U78516 mRNA. Translation: AAD03422.1. AB027471 mRNA. Translation: BAB72179.1. AK304278 mRNA. Translation: BAH14148.1. AK313084 mRNA. Translation: BAG35910.1. BC024004 mRNA. Translation: AAH24004.1. BC040183 mRNA. Translation: AAH40183.1.
IPI	IPI00329560. IPI00329561. IPI00329562.
RefSeq	NP_001093867.1. NM_001100397.1. NP_008954.2. NM_007023.3.
UniGene	Hs.470646.
3D structure databases
ProteinModelPortal	Q8WZA2.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q8WZA2. 1 interaction.
MINT	MINT-2869318.
STRING	9606.ENSP00000380271.
PTM databases
PhosphoSite	Q8WZA2.
Polymorphism databases
DMDM	32171491.
Proteomic databases
PaxDb	Q8WZA2.
PRIDE	Q8WZA2.
Protocols and materials databases
DNASU	11069.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000397081; ENSP00000380271; ENSG00000091428. ENST00000397087; ENSP00000380276; ENSG00000091428.
GeneID	11069.
KEGG	hsa:11069.
UCSC	uc002uhv.4. human. uc002uhw.4. human.
Organism-specific databases
CTD	11069.
GeneCards	GC02P173600.
HGNC	HGNC:16626. RAPGEF4.
HPA	CAB004388.
MIM	606058. gene.
neXtProt	NX_Q8WZA2.
PharmGKB	PA134861108.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0664.
HOGENOM	HOG000230545.
HOVERGEN	HBG056985.
InParanoid	Q8WZA2.
KO	K04351.
OMA	TIYDWEL.
OrthoDB	EOG4W0XC9.
Enzyme and pathway databases
Reactome	REACT_111102. Signal Transduction. REACT_111217. Metabolism. REACT_604. Hemostasis. REACT_6900. Immune System.
Gene expression databases
ArrayExpress	Q8WZA2.
Bgee	Q8WZA2.
CleanEx	HS_RAPGEF4.
Genevestigator	Q8WZA2.
GermOnline	ENSG00000091428. Homo sapiens.
Family and domain databases
Gene3D	1.10.10.10. 1 hit. 1.10.840.10. 1 hit. 2.60.120.10. 2 hits.
InterPro	IPR002373. cAMP/cGMP_kin. IPR018490. cNMP-bd-like. IPR000595. cNMP-bd_dom. IPR000591. DEP_dom. IPR000159. Ras-assoc. 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. 2 hits. PF00610. DEP. 1 hit. PF00788. RA. 1 hit. PF00617. RasGEF. 1 hit. PF00618. RasGEF_N. 1 hit. [Graphical view]
PRINTS	PR00103. CAMPKINASE.
SMART	SM00100. cNMP. 2 hits. SM00049. DEP. 1 hit. SM00147. RasGEF. 1 hit. SM00229. RasGEFN. 1 hit. [Graphical view]
SUPFAM	SSF51206. cNMP_binding. 2 hits. SSF48366. Ras_GEF. 1 hit.
PROSITE	PS00888. CNMP_BINDING_1. False negative. PS00889. CNMP_BINDING_2. False negative. PS50042. CNMP_BINDING_3. 2 hits. PS50186. DEP. 1 hit. PS00720. RASGEF. 1 hit. PS50009. RASGEF_CAT. 1 hit. PS50212. RASGEF_NTER. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	RAPGEF4. human.
GenomeRNAi	11069.
NextBio	42080.
SOURCE	Search...

Entry information

Entry name

RPGF4_HUMAN

Accession

Primary (citable) accession number: Q8WZA2
Secondary accession number(s): B2R7R3 , B7Z912, O95636, Q8IXK6, Q8TAA4

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 20, 2003
Last sequence update:	March 1, 2002
Last modified:	May 1, 2013
This is version 106 of the entry and version 1 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.