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Gene Review

RAPGEF4  -  Rap guanine nucleotide exchange factor...

Homo sapiens

Synonyms: CAMP-GEFII, CGEF2, EPAC, EPAC 2, EPAC2, ...
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Psychiatry related information on RAPGEF4

  • 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] [1].

High impact information on RAPGEF4

  • 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 [2].
  • The RAP1 guanine nucleotide exchange factor Epac2 couples cyclic AMP and Ras signals at the plasma membrane [3].
  • Whereas translocation of Epac2 was not mimicked by challenge with epidermal growth factor alone, costimulation with forskolin, prostaglandin E2, or an Epac-selective cyclic AMP analog-induced rapid relocation of GFP-Epac2 but not -Epac1 to the plasma membrane in a Ras-dependent manner [3].
  • This domain specifically bound Ras-GTP, enabling oncogenic Ras to translocate Epac2 from the cytosol to the plasma membrane [3].
  • Localization of cAMP-GEFII overlaps with that of Rim2 in plasma membrane of insulin-secreting MIN6 cells [4].

Biological context of RAPGEF4


Anatomical context of RAPGEF4


Associations of RAPGEF4 with chemical compounds


Physical interactions of RAPGEF4

  • 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 [1].

Other interactions of RAPGEF4


  1. 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]
  2. Epac: a new cAMP target and new avenues in cAMP research. Bos, J.L. Nat. Rev. Mol. Cell Biol. (2003) [Pubmed]
  3. 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]
  4. Interaction of ATP sensor, cAMP sensor, Ca2+ sensor, and voltage-dependent Ca2+ channel in insulin granule exocytosis. Shibasaki, T., Sunaga, Y., Fujimoto, K., Kashima, Y., Seino, S. J. Biol. Chem. (2004) [Pubmed]
  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. (2000) [Pubmed]
  6. 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 (2001) [Pubmed]
  7. Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene. Bacchelli, E., Blasi, F., Biondolillo, M., Lamb, J.A., Bonora, E., Barnby, G., Parr, J., Beyer, K.S., Klauck, S.M., Poustka, A., Bailey, A.J., Monaco, A.P., Maestrini, E. Mol. Psychiatry (2003) [Pubmed]
  8. cAMP sensor Epac as a determinant of ATP-sensitive potassium channel activity in human pancreatic beta cells and rat INS-1 cells. Kang, G., Chepurny, O.G., Malester, B., Rindler, M.J., Rehmann, H., Bos, J.L., Schwede, F., Coetzee, W.A., Holz, G.G. J. Physiol. (Lond.) (2006) [Pubmed]
  9. 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]
  10. Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims. Dwivedi, Y., Mondal, A.C., Rizavi, H.S., Faludi, G., Palkovits, M., Sarosi, A., Conley, R.R., Pandey, G.N. Arch. Gen. Psychiatry (2006) [Pubmed]
  11. Roles of cAMP in regulating microtubule sliding and flagellar bending in demembranated hamster spermatozoa. Kinukawa, M., Oda, S., Shirakura, Y., Okabe, M., Ohmuro, J., Baba, S.A., Nagata, M., Aoki, F. FEBS Lett. (2006) [Pubmed]
  12. Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential. Gromada, J., Brock, B., Schmitz, O., Rorsman, P. Basic & clinical pharmacology & toxicology. (2004) [Pubmed]
  13. Valproate-induced alterations in human theca cell gene expression: clues to the association between valproate use and metabolic side effects. Wood, J.R., Nelson-Degrave, V.L., Jansen, E., McAllister, J.M., Mosselman, S., Strauss, J.F. Physiol. Genomics (2005) [Pubmed]
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