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Q9EQZ6 (RPGF4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 126. 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·Interactions·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-dependent Rap1 guanine-nucleotide exchange factor
cAMP-regulated guanine nucleotide exchange factor II
Short name=cAMP-GEFII
Gene names
Name:Rapgef4
Synonyms:Cgef2, Epac2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

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. Ref.2

Subunit structure

Interacts with RAP1B, RIMS1 and RIMS2. Probably part of a complex with RIMS2 and GTP-activated RAB3A. Ref.2 Ref.6

Subcellular location

Cytoplasm. Membrane; Peripheral membrane protein By similarity.

Tissue specificity

Expressed in cerebellum, pituitary, adrenal gland and liver. Ref.2

Domain

The N-terminal nucleotide phosphate binding region cAMP 1 has a much lower affinity for cAMP as compared to cAMP 2 By similarity.

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 term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcAMP-mediated signaling

Inferred from direct assay Ref.2PubMed 11598134PubMed 12401793. Source: MGI

calcium ion-dependent exocytosis

Inferred from direct assay Ref.2. Source: MGI

insulin secretion

Inferred from direct assay PubMed 11598134PubMed 12401793. Source: MGI

regulation of GTPase activity

Inferred from direct assay Ref.2. Source: GOC

regulation of Ras GTPase activity

Inferred from direct assay Ref.6. Source: GOC

regulation of exocytosis

Inferred from direct assay PubMed 12401793. Source: MGI

small GTPase mediated signal transduction

Inferred from electronic annotation. Source: InterPro

   Cellular_componentcAMP-dependent protein kinase complex

Inferred from electronic annotation. Source: InterPro

cytosol

Inferred from direct assay Ref.2. Source: MGI

membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionRas GTPase binding

Inferred from physical interaction Ref.6. Source: UniProtKB

Ras guanyl-nucleotide exchange factor activity

Inferred from direct assay Ref.6. Source: UniProtKB

cAMP binding

Inferred from direct assay Ref.6. Source: UniProtKB

cAMP-dependent protein kinase regulator activity

Inferred from electronic annotation. Source: InterPro

guanyl-nucleotide exchange factor activity

Inferred from direct assay Ref.2. Source: MGI

protein binding

Inferred from physical interaction PubMed 16316996. Source: IntAct

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

HRASP011123EBI-772212,EBI-350145From a different organism.

Alternative products

This entry describes 3 isoforms produced by alternative promoter usage and alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9EQZ6-1)

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.
Isoform 2 (identifier: Q9EQZ6-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-315: Missing.
Note: Produced by alternative promoter usage.
Isoform 3 (identifier: Q9EQZ6-3)

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 10111011Rap guanine nucleotide exchange factor 4
PRO_0000068871

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_007614
Alternative sequence180 – 19718Missing in isoform 3.
VSP_007615

Experimental info

Mutagenesis4671L → A: Less than 10% of the wild-type maximal activity. Ref.6
Mutagenesis4981Y → F: 2-fold reduction in maximal activity. Ref.6
Mutagenesis5691Y → A: 2-fold reduction in maximal activity. Ref.6
Mutagenesis5691Y → F: 2-fold reduction in maximal activity. Ref.6
Sequence conflict3131Q → E in BAB23633. Ref.4
Sequence conflict4521D → E in BAB23633. Ref.4

Secondary structure

......................................................................................................................................................... 1011
Helix Strand Turn

Details...

Sequences

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

Last modified March 1, 2001. Version 1.
Checksum: 449BC537475B03AA

FASTA1,011115,491
        10         20         30         40         50         60 
MVAAHAAHSQ SSAEWIACLD KRPLERSSED VDIIFTRLKG VKAFEKFHPN LLRQICLCGY 

        70         80         90        100        110        120 
YENLEKGITL FRQGDIGTNW YAVLAGSLDV KVSETSSHQD AVTICTLGIG TAFGESILDN 

       130        140        150        160        170        180 
TPRHATIVTR ESSELLRIEQ EDFKALWEKY RQYMAGLLAP PYGVMETGSN NDRIPDKENT 

       190        200        210        220        230        240 
PLIEPHVPLR PAHTITKVPS EKILRAGKIL RIAILSRAPH MIRDRKYHLK TYRQCCVGTE 

       250        260        270        280        290        300 
LVDWMIQQTS CVHSRTQAVG MWQVLLEDGV LNHVDQERHF QDKYLFYRFL DDEREDAPLP 

       310        320        330        340        350        360 
TEEEKKECDE ELQDTMLLLS QMGPDAHMRM ILRKPPGQRT VDDLEIIYDE 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 
PAGNRAANQG NSQPQQKYTV MSGTPEKILE HFLETIRLEP SLNEATDSVL NDFVMMHCVF 

       550        560        570        580        590        600 
MPNTQLCPAL VAHYHAQPSQ GTEQERMDYA LNNKRRVIRL VLQWAAMYGD LLQEDDVAMA 

       610        620        630        640        650        660 
FLEEFYVSVS DDARMMAAFK EQLPELEKIV KQISEDAKAP QKKHKVLLQQ FNTGDERAQK 

       670        680        690        700        710        720 
RQPIRGSDEV LFKVYCIDHT YTTIRVPVAA SVKEVISAVA DKLGSGEGLI IVKMNSGGEK 

       730        740        750        760        770        780 
VVLKSNDVSV FTTLTINGRL FACPREQFDS LTPLPEQEGP TTGTVGTFEL MSSKDLAYQM 

       790        800        810        820        830        840 
TTYDWELFNC VHELELIYHT FGRHNFKKTT ANLDLFLRRF NEIQFWVVTE VCLCSQLSKR 

       850        860        870        880        890        900 
VQLLKKFIKI AAHCKEYKNL NSFFAIVMGL SNVAVSRLAL TWEKLPSKFK KFYAEFESLM 

       910        920        930        940        950        960 
DPSRNHRAYR LTAAKLEPPL IPFMPLLIKD MTFTHEGNKT FIDNLVNFEK MRMIANTART 

       970        980        990       1000       1010 
VRYYRSQPFN PDAAQANKNH QDVRSYVRQL NVIDNQRTLS QMSHRLEPRR P 

« Hide

Isoform 2 [UniParc].

Checksum: 4006240D4B85A747
Show »

FASTA69679,440
Isoform 3 [UniParc].

Checksum: F503405FD9A9C12F
Show »

FASTA993113,489

References

« Hide 'large scale' references
[1]"A brain cAMP-dependent Rap1 guanine-nucleotide exchange factor."
Gaudriault G.E., Takaya K., Vale W.W.
Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
Tissue: Brain.
[2]"cAMP-GEFII is a direct target of cAMP in regulated exocytosis."
Ozaki N., Shibasaki T., Kashima Y., Miki T., Takahashi K., Ueno H., Sunaga Y., Yano H., Matsuura Y., Iwanaga T., Takai Y., Seino S.
Nat. Cell Biol. 2:805-811(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH RIMS1 AND RIMS2.
[3]"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] (ISOFORM 2), ALTERNATIVE PROMOTER USAGE.
Tissue: Liver.
[4]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Strain: C57BL/6J.
Tissue: Liver.
[5]"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: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-463.
[6]"Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B."
Rehmann H., Arias-Palomo E., Hadders M.A., Schwede F., Llorca O., Bos J.L.
Nature 455:124-127(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 324-1011 IN COMPLEX WITH CAMP ANALOG AND RAP1B, SUBUNIT, MUTAGENESIS OF LEU-467; TYR-498 AND TYR-569.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF115480 mRNA. Translation: AAD09132.1.
AB021132 mRNA. Translation: BAB18976.1.
AB037668 mRNA. Translation: BAB72180.1.
AK004874 mRNA. Translation: BAB23633.1.
CCDSCCDS16120.1. [Q9EQZ6-3]
CCDS57176.1. [Q9EQZ6-1]
RefSeqNP_001191094.1. NM_001204165.1. [Q9EQZ6-1]
NP_001191095.1. NM_001204166.1.
NP_062662.1. NM_019688.2. [Q9EQZ6-3]
UniGeneMm.196153.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1O7FX-ray2.50A1-481[»]
2BYVX-ray2.70E1-1011[»]
3CF6X-ray2.20E324-1011[»]
4F7ZX-ray2.60A1-1011[»]
ProteinModelPortalQ9EQZ6.
SMRQ9EQZ6. Positions 10-1009.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid208026. 3 interactions.
DIPDIP-32333N.
IntActQ9EQZ6. 2 interactions.

PTM databases

PhosphoSiteQ9EQZ6.

Proteomic databases

MaxQBQ9EQZ6.
PaxDbQ9EQZ6.
PRIDEQ9EQZ6.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000090826; ENSMUSP00000088336; ENSMUSG00000049044. [Q9EQZ6-1]
ENSMUST00000102698; ENSMUSP00000099759; ENSMUSG00000049044. [Q9EQZ6-3]
GeneID56508.
KEGGmmu:56508.
UCSCuc008kbn.2. mouse. [Q9EQZ6-1]

Organism-specific databases

CTD11069.
MGIMGI:1917723. Rapgef4.

Phylogenomic databases

eggNOGCOG0664.
GeneTreeENSGT00750000117452.
HOGENOMHOG000230545.
HOVERGENHBG056985.
InParanoidQ9EQZ6.
KOK04351.
OMATIYDWEL.
OrthoDBEOG7ZD1TF.
TreeFamTF313184.

Gene expression databases

ArrayExpressQ9EQZ6.
BgeeQ9EQZ6.
CleanExMM_RAPGEF4.
GenevestigatorQ9EQZ6.

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.
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.
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

EvolutionaryTraceQ9EQZ6.
NextBio312814.
PROQ9EQZ6.
SOURCESearch...

Entry information

Entry nameRPGF4_MOUSE
AccessionPrimary (citable) accession number: Q9EQZ6
Secondary accession number(s): Q8VIP9, Q9CW52, Q9Z1P0
Entry history
Integrated into UniProtKB/Swiss-Prot: June 20, 2003
Last sequence update: March 1, 2001
Last modified: July 9, 2014
This is version 126 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot