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Gene Review

RAPGEF3  -  Rap guanine nucleotide exchange factor...

Homo sapiens

Synonyms: CAMP-GEFI, CGEF1, EPAC, EPAC 1, EPAC1, ...
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Disease relevance of RAPGEF3

  • The discovery of Epac ('exchange nucleotide protein directly activated by cAMP'), a novel cAMP-binding protein, which is strongly expressed in the thyroid, raised the possibility of a role for this protein in the generation of the unexplained cold thyroid follicular adenomas [1].
  • In male rats, intradermal injection of an Epac activator or estrogen alone induces mechanical hyperalgesia through a PKCepsilon-dependent mechanism [2].
  • In the heart, signaling events such as the onset of cardiac hypertrophy are influenced by muscle-specific mAKAP signaling complexes that target protein kinase A (PKA), the cAMP-responsive guanine-nucleotide exchange factor EPAC and cAMP-selective phosphodiesterase 4 (PDE4) [3].

Psychiatry related information on RAPGEF3

  • We first became interested in EPAC when we discovered that the expression levels of both EPAC1 and EPAC2 were altered in those regions of the brain associated with Alzheimer's disease [McPhee, Breslin, Kewney, MacKenzie, Cooreman, Gibson and Hammond (2004) International Patent number WO 2004/096199 A2] [4].
  • We investigated the role of the human ortholog of Epac in tobacco smoking and nicotine dependence (ND) [5].

High impact information on RAPGEF3

  • Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP [6].
  • We have cloned the gene encoding a guanine-nucleotide-exchange factor (GEF) which we have named Epac (exchange protein directly activated by cAMP) [6].
  • These methods use FRET probes based upon either protein kinase A (PKA) or EPAC, cAMP-gated ion channels, or the selective activation of AKAP-anchored PKA isoforms [7].
  • Cyclic nucleotides function by binding to and activating their effectors - protein kinase A, protein kinase G, cyclic-nucleotide-regulated ion channels and the guanine nucleotide-exchange factor Epac [8].
  • Structural analysis of the cAMP-binding domains of Epac2 has identified a unifying mechanism for how cAMP activates proteins, and the design and synthesis of an Epac-specific cAMP analogue has paved the way for future discoveries [9].

Biological context of RAPGEF3

  • Communication between the regulatory and the catalytic region of the cAMP-responsive guanine nucleotide exchange factor Epac [10].
  • Therefore, through rational drug design we have developed a novel cAMP analogue, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8CPT-2Me-cAMP), which activates Epac, but not PKA, both in vitro and in vivo [11].
  • Second messenger cAMP regulates many cellular functions through its effectors, such as cAMP-dependent protein kinase (PKA) and Epac (exchange proteins directly activated by cAMP) [12].
  • We here examine whether varying expression of EPAC accounts for the discrepant sensitivity of B-CLL and T cells to PDE4 inhibitor-induced apoptosis [13].
  • Activation of Epac also counteracts thrombin-induced hyperpermeability through down-regulation of Rho GTPase activation, suggesting cross-talk between Rap and Rho GT-Pases [14].

Anatomical context of RAPGEF3


Associations of RAPGEF3 with chemical compounds

  • Epac-1 and -2 (exchange proteins directly activated by cyclic AMP) are guanine-nucleotide exchange factors for the GTPases Rap1 and -2 [18].
  • Furthermore, mutation of the conserved VLVLE sequence at the C-terminal end of the LID into five alanine residues makes Epac constitutively active [10].
  • Two principal effector proteins for cAMP are protein kinase A (PKA) and EPAC (exchange protein directly activated by cAMP), a Rap guanosine 5'-diphosphate (GDP) exchange factor [13].
  • Consistent with a role of EPAC1 in controlling integrin activity, we found that cell adhesion to laminin was enhanced in LC2- and EPAC1-transfected cells stimulated with 8-CPT-2Me-cAMP [16].
  • It is also reported that Epac mediates the cAMP-dependent mobilization of Ca(2+) from intracellular Ca(2+) stores [19].
  • These data demonstrate that activation of Epac1 increases integrin activity and integrin-dependent homing functions of progenitor cells and enhances their in vivo therapeutic potential [20].

Physical interactions of RAPGEF3

  • Exchange protein directly activated by cAMP (EPAC) interacts with the light chain (LC) 2 of MAP1A [21].
  • We subsequently developed a novel, high-throughput screen based on the displacement of [3H]cAMP from the EPAC cAMP-binding site and identified small molecule hits from the Scottish Biomedical Lead Generation Library. These compounds selectively bind to the cAMP-binding sites of EPAC1 and EPAC2 and are structurally dissimilar to cAMP [4].

Regulatory relationships of RAPGEF3

  • Consistent with this, an isolated Ras exchange motif domain from Epac is sufficient to activate JNK [22].

Other interactions of RAPGEF3

  • In addition to the cAMP binding domains, both Epac1 and Epac2 have a DEP domain [23].
  • Furthermore, we conclude that the catalytic activity of Epac1 is constrained by a direct interaction between GEF and high affinity cAMP binding domains in the absence of cAMP [23].
  • In cellular models where Rap1 is activated via endogenous GEFs, the Rap1[S17A] mutant inhibits both the cAMP-Epac and EGF-C3G pathways, whereas Rap1[G15D] selectively interferes with the latter [24].
  • Rap1 activation by Epac-CAAX, but not wild-type Epac, triggers its association with B-Raf [15].
  • From these results, we conclude that all three members of the Epac family regulate both Rap1 and Rap2 [23].

Analytical, diagnostic and therapeutic context of RAPGEF3


  1. Mutation analysis of the Epac--Rap1 signaling pathway in cold thyroid follicular adenomas. Vanvooren, V., Allgeier, A., Nguyen, M., Massart, C., Parma, J., Dumont, J.E., Van Sande, J. Eur. J. Endocrinol. (2001) [Pubmed]
  2. Estrogen controls PKCepsilon-dependent mechanical hyperalgesia through direct action on nociceptive neurons. Hucho, T.B., Dina, O.A., Kuhn, J., Levine, J.D. Eur. J. Neurosci. (2006) [Pubmed]
  3. AKAP signaling complexes: getting to the heart of the matter. McConnachie, G., Langeberg, L.K., Scott, J.D. Trends in molecular medicine. (2006) [Pubmed]
  4. Cyclic nucleotide signalling: a molecular approach to drug discovery for Alzheimer's disease. McPhee, I., Gibson, L.C., Kewney, J., Darroch, C., Stevens, P.A., Spinks, D., Cooreman, A., MacKenzie, S.J. Biochem. Soc. Trans. (2005) [Pubmed]
  5. Association study of the Epac gene and tobacco smoking and nicotine dependence. Chen, X., Wu, B., Kendler, K.S. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
  6. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. de Rooij, J., Zwartkruis, F.J., Verheijen, M.H., Cool, R.H., Nijman, S.M., Wittinghofer, A., Bos, J.L. Nature (1998) [Pubmed]
  7. Arrestin times for compartmentalised cAMP signalling and phosphodiesterase-4 enzymes. Baillie, G.S., Houslay, M.D. Curr. Opin. Cell Biol. (2005) [Pubmed]
  8. Capturing cyclic nucleotides in action: snapshots from crystallographic studies. Rehmann, H., Wittinghofer, A., Bos, J.L. Nat. Rev. Mol. Cell Biol. (2007) [Pubmed]
  9. Epac: a new cAMP target and new avenues in cAMP research. Bos, J.L. Nat. Rev. Mol. Cell Biol. (2003) [Pubmed]
  10. Communication between the regulatory and the catalytic region of the cAMP-responsive guanine nucleotide exchange factor Epac. Rehmann, H., Rueppel, A., Bos, J.L., Wittinghofer, A. J. Biol. Chem. (2003) [Pubmed]
  11. A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Enserink, J.M., Christensen, A.E., de Rooij, J., van Triest, M., Schwede, F., Genieser, H.G., Døskeland, S.O., Blank, J.L., Bos, J.L. Nat. Cell Biol. (2002) [Pubmed]
  12. Fluorescent indicators of cAMP and Epac activation reveal differential dynamics of cAMP signaling within discrete subcellular compartments. DiPilato, L.M., Cheng, X., Zhang, J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  13. Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis. Tiwari, S., Felekkis, K., Moon, E.Y., Flies, A., Sherr, D.H., Lerner, A. Blood (2004) [Pubmed]
  14. Regulation of vascular endothelial barrier function by Epac, a cAMP-activated exchange factor for Rap GTPase. Cullere, X., Shaw, S.K., Andersson, L., Hirahashi, J., Luscinskas, F.W., Mayadas, T.N. Blood (2005) [Pubmed]
  15. Rap1-mediated activation of extracellular signal-regulated kinases by cyclic AMP is dependent on the mode of Rap1 activation. Wang, Z., Dillon, T.J., Pokala, V., Mishra, S., Labudda, K., Hunter, B., Stork, P.J. Mol. Cell. Biol. (2006) [Pubmed]
  16. MAP1A light chain 2 interacts with exchange protein activated by cyclic AMP 1 (EPAC1) to enhance Rap1 GTPase activity and cell adhesion. Gupta, M., Yarwood, S.J. J. Biol. Chem. (2005) [Pubmed]
  17. Cell cycle-dependent subcellular localization of exchange factor directly activated by cAMP. Qiao, J., Mei, F.C., Popov, V.L., Vergara, L.A., Cheng, X. J. Biol. Chem. (2002) [Pubmed]
  18. The RAP1 guanine nucleotide exchange factor Epac2 couples cyclic AMP and Ras signals at the plasma membrane. Li, Y., Asuri, S., Rebhun, J.F., Castro, A.F., Paranavitana, N.C., Quilliam, L.A. J. Biol. Chem. (2006) [Pubmed]
  19. Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell. Holz, G.G. Diabetes (2004) [Pubmed]
  20. Activation of Epac stimulates integrin-dependent homing of progenitor cells. Carmona, G., Chavakis, E., Koehl, U., Zeiher, A.M., Dimmeler, S. Blood (2008) [Pubmed]
  21. Exchange protein directly activated by cAMP (EPAC) interacts with the light chain (LC) 2 of MAP1A. Magiera, M.M., Gupta, M., Rundell, C.J., Satish, N., Ernens, I., Yarwood, S.J. Biochem. J. (2004) [Pubmed]
  22. Activation of JNK by Epac is independent of its activity as a Rap guanine nucleotide exchanger. Hochbaum, D., Tanos, T., Ribeiro-Neto, F., Altschuler, D., Coso, O.A. J. Biol. Chem. (2003) [Pubmed]
  23. 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. (2000) [Pubmed]
  24. Novel Rap1 dominant-negative mutants interfere selectively with C3G and Epac. Dupuy, A.G., L'Hoste, S., Cherfils, J., Camonis, J., Gaudriault, G., de Gunzburg, J. Oncogene (2005) [Pubmed]
  25. Elevation of cyclic AMP in Jurkat T-cells provokes distinct transcriptional responses through the protein kinase A (PKA) and exchange protein activated by cyclic AMP (EPAC) pathways. Fuld, S., Borland, G., Yarwood, S.J. Exp. Cell Res. (2005) [Pubmed]
  26. Epac-mediated Ca2+ mobilization and exocytosis in inner medullary collecting duct. Yip, K.P. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
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