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Novel Rap1 dominant-negative mutants interfere selectively with C3G and Epac.(Original Paper)

Dupuy, Aurelien G ; L' Hoste, Sebastien ; Cherfils, Jacqueline ; Camonis, Jacques ; Gaudriault, Georges ; De Gunzburg, Jean

Oncogene, June 30, 2005, Vol.24(28), p.4509 [Periódico revisado por pares]

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  • Título:
    Novel Rap1 dominant-negative mutants interfere selectively with C3G and Epac.(Original Paper)
  • Autor: Dupuy, Aurelien G ; L' Hoste, Sebastien ; Cherfils, Jacqueline ; Camonis, Jacques ; Gaudriault, Georges ; De Gunzburg, Jean
  • Assuntos: Medicine ; Biology ; Chemistry
  • É parte de: Oncogene, June 30, 2005, Vol.24(28), p.4509
  • Descrição: Rap1 is a Ras-related GTPase that is principally involved in integrin- and E-cadherin-mediated adhesion. Rap1 is transiently activated in response to many incoming signals via a large family of guanine nucleotide exchange factors (GEFs). The lack of potent Rap1 dominant-negative mutants has limited our ability to decipher Rap1-dependent pathways; we have therefore developed a procedure to generate such mutants consisting in the oligonucleotide-mediated mutagenesis of residues 14-19, selection of mutants presenting an enhanced interaction with Epac2 by yeast two-hybrid screening and counter-screening for mutants still interacting with Rap effectors. In detail analysis of their interaction capacity with various Rap-GEFs in the yeast two-hybrid system revealed that mutants of residues 15 and 16 interacted with Epacs, C3G and CalDAG-GEFI, whereas mutants of position 17 had selectively lost their ability to bind CalDAG-GEFI as well as, for some, C3G. 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. Finally, Rap1[S17A] is able to act as a bona fide dominant-negative mutant in vivo since it phenocopies the eye-reducing and lethal effects of D-Rap1 deficiency in Drosophila, effects that are overcome by the overexpression of D-Epac or D-Rap1. Oncogene (2005) 24, 4509-4520. doi: 10.1038/sj.onc.1208647 Published online 25 April 2005 Keywords: Rap, GEF, dominant negative, C3G, Epac
  • Idioma: English

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