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Q8WZA2 (RPGF4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 117. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1011 AA.
Sequence statusComplete.
Protein existenceEvidence 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.6

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 processExocytosis
   Cellular componentCytoplasm
Membrane
   Coding sequence diversityAlternative promoter usage
Alternative splicing
   DomainRepeat
   LigandcAMP
cAMP-binding
Nucleotide-binding
   Molecular functionGuanine-nucleotide releasing factor
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processG-protein coupled receptor signaling pathway

Traceable author statement Ref.1. Source: ProtInc

blood coagulation

Traceable author statement. Source: Reactome

cAMP-mediated signaling

Inferred from electronic annotation. Source: Ensembl

calcium ion-dependent exocytosis

Inferred from electronic annotation. Source: Ensembl

energy reserve metabolic process

Traceable author statement. Source: Reactome

insulin secretion

Inferred from electronic annotation. Source: Ensembl

platelet activation

Traceable author statement. Source: Reactome

regulation of GTPase activity

Traceable author statement Ref.1. Source: GOC

regulation of Ras GTPase activity

Inferred from sequence or structural similarity. Source: GOC

regulation of exocytosis

Inferred from electronic annotation. Source: Ensembl

regulation of insulin secretion

Traceable author statement. Source: Reactome

small GTPase mediated signal transduction

Inferred from electronic annotation. Source: InterPro

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentcAMP-dependent protein kinase complex

Inferred from electronic annotation. Source: InterPro

cytosol

Inferred from electronic annotation. Source: Ensembl

membrane

Traceable author statement Ref.6. Source: ProtInc

plasma membrane

Traceable author statement. Source: Reactome

   Molecular_functionRas 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

guanyl-nucleotide exchange factor activity

Traceable author statement Ref.1. Source: ProtInc

protein binding

Inferred from physical interaction PubMed 11438518. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 5 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.
Isoform 4 (identifier: Q8WZA2-4)

The sequence of this isoform differs from the canonical sequence as follows:
     1-153: Missing.
Note: No experimental confirmation available.
Isoform 5 (identifier: Q8WZA2-5)

The sequence of this isoform differs from the canonical sequence as follows:
     1-153: Missing.
     180-197: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 10111011Rap guanine nucleotide exchange factor 4
PRO_0000068870

Regions

Domain216 – 29176DEP
Domain496 – 634139N-terminal Ras-GEF
Domain772 – 1009238Ras-GEF
Nucleotide binding43 – 166124cAMP 1
Nucleotide binding356 – 476121cAMP 2

Natural variations

Alternative sequence1 – 315315Missing in isoform 2.
VSP_007611
Alternative sequence1 – 153153Missing in isoform 4 and isoform 5.
VSP_054423
Alternative sequence1 – 144144Missing in isoform 3.
VSP_007612
Alternative sequence145 – 1484ALWE → MLYK in isoform 3.
VSP_007613
Alternative sequence180 – 19718Missing in isoform 5.
VSP_054424

Experimental info

Sequence conflict3241P → R in AAH40183. Ref.5
Sequence conflict5111H → R in AAH40183. Ref.5
Sequence conflict6471L → I in AAH40183. Ref.5
Sequence conflict6791H → P in AAH24004. Ref.5
Sequence conflict7321T → M in AAH24004. Ref.5
Sequence conflict8731V → I in AAD03422. Ref.1
Sequence conflict9021P → T in AAH40183. Ref.5

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified March 1, 2002. Version 1.
Checksum: 9427C5F92F2FFAD1

FASTA1,011115,522
        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 

« Hide

Isoform 2 [UniParc].

Checksum: 936C1CEC6FA169C8
Show »

FASTA69679,492
Isoform 3 [UniParc].

Checksum: 5CA711EAD3DBEE66
Show »

FASTA86799,523
Isoform 4 [UniParc].

Checksum: AD52D5D0637CF299
Show »

FASTA85898,248
Isoform 5 [UniParc].

Checksum: 6FF8498DB079C13C
Show »

FASTA84096,269

References

« Hide '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. expand/collapse author list , 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; 3; 4 AND 5).
Tissue: Amygdala, Hippocampus, Thalamus and Trachea.
[4]"Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. expand/collapse author list , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"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.
[6]"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.
AK294445 mRNA. Translation: BAH11769.1.
AK296340 mRNA. Translation: BAH12322.1.
AK304278 mRNA. Translation: BAH14148.1.
AK313084 mRNA. Translation: BAG35910.1.
AK316072 mRNA. Translation: BAH14443.1.
AC009484 Genomic DNA. No translation available.
AC018712 Genomic DNA. No translation available.
AC019046 Genomic DNA. No translation available.
AC104086 Genomic DNA. No translation available.
BC024004 mRNA. Translation: AAH24004.1.
BC040183 mRNA. Translation: AAH40183.1.
CCDSCCDS42775.1. [Q8WZA2-1]
CCDS42776.1. [Q8WZA2-3]
RefSeqNP_001093867.1. NM_001100397.1. [Q8WZA2-3]
NP_001269828.1. NM_001282899.1. [Q8WZA2-4]
NP_001269829.1. NM_001282900.1. [Q8WZA2-5]
NP_001269830.1. NM_001282901.1.
NP_008954.2. NM_007023.3. [Q8WZA2-1]
XP_006712268.1. XM_006712205.1. [Q8WZA2-5]
UniGeneHs.470646.

3D structure databases

ProteinModelPortalQ8WZA2.
SMRQ8WZA2. Positions 11-1009.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid116253. 5 interactions.
IntActQ8WZA2. 1 interaction.
MINTMINT-2869318.
STRING9606.ENSP00000380271.

Chemistry

ChEMBLCHEMBL2029198.
GuidetoPHARMACOLOGY1293.

PTM databases

PhosphoSiteQ8WZA2.

Polymorphism databases

DMDM32171491.

Proteomic databases

PaxDbQ8WZA2.
PRIDEQ8WZA2.

Protocols and materials databases

DNASU11069.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000397081; ENSP00000380271; ENSG00000091428. [Q8WZA2-1]
ENST00000397087; ENSP00000380276; ENSG00000091428. [Q8WZA2-3]
ENST00000538974; ENSP00000440135; ENSG00000091428.
ENST00000539331; ENSP00000437384; ENSG00000091428.
ENST00000540783; ENSP00000440250; ENSG00000091428.
GeneID11069.
KEGGhsa:11069.
UCSCuc002uhv.4. human. [Q8WZA2-1]
uc002uhw.4. human. [Q8WZA2-3]

Organism-specific databases

CTD11069.
GeneCardsGC02P173600.
HGNCHGNC:16626. RAPGEF4.
HPACAB004388.
HPA028968.
MIM606058. gene.
neXtProtNX_Q8WZA2.
PharmGKBPA134861108.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0664.
HOGENOMHOG000230545.
HOVERGENHBG056985.
InParanoidQ8WZA2.
KOK04351.
OMATIYDWEL.
OrthoDBEOG7ZD1TF.
PhylomeDBQ8WZA2.
TreeFamTF313184.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_111217. Metabolism.
REACT_604. Hemostasis.
REACT_6900. Immune System.

Gene expression databases

ArrayExpressQ8WZA2.
BgeeQ8WZA2.
CleanExHS_RAPGEF4.
GenevestigatorQ8WZA2.

Family and domain databases

Gene3D1.10.10.10. 1 hit.
1.10.840.10. 1 hit.
2.60.120.10. 2 hits.
InterProIPR002373. 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.
IPR023578. Ras_GEF_dom.
IPR001895. RasGRF_CDC25.
IPR014710. RmlC-like_jellyroll.
IPR029071. Ubiquitin-rel_dom.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamPF00027. cNMP_binding. 2 hits.
PF00610. DEP. 1 hit.
PF00788. RA. 1 hit.
PF00617. RasGEF. 1 hit.
PF00618. RasGEF_N. 1 hit.
[Graphical view]
PRINTSPR00103. CAMPKINASE.
SMARTSM00100. cNMP. 2 hits.
SM00049. DEP. 1 hit.
SM00147. RasGEF. 1 hit.
SM00229. RasGEFN. 1 hit.
[Graphical view]
SUPFAMSSF48366. SSF48366. 2 hits.
SSF51206. SSF51206. 2 hits.
SSF54236. SSF54236. 1 hit.
PROSITEPS50042. 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]
ProtoNetSearch...

Other

ChiTaRSRAPGEF4. human.
GeneWikiRAPGEF4.
GenomeRNAi11069.
NextBio35478932.
PROQ8WZA2.
SOURCESearch...

Entry information

Entry nameRPGF4_HUMAN
AccessionPrimary (citable) accession number: Q8WZA2
Secondary accession number(s): B2R7R3 expand/collapse secondary AC list , B7Z283, B7Z3T6, B7Z912, O95636, Q8IXK6, Q8TAA4
Entry history
Integrated into UniProtKB/Swiss-Prot: June 20, 2003
Last sequence update: March 1, 2002
Last modified: July 9, 2014
This is version 117 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM