Aptamer-derived peptides as potent inhibitors of the oncogenic RhoGEF Tgat.

Nathalie Bouquier (1) , Sylvie Fromont (1) , Jean-Christophe Zeeh (2) , Camille Auziol (1) , Pauline Larrousse (1) , Bruno Robert (3) , Mahel Zeghouf (2) , Jacqueline Cherfils (2) , Anne Debant (1) , Susanne Schmidt (1)

1 CRBM - Centre de recherche en Biologie Cellulaire
2 LEBS - Laboratoire d'enzymologie et biochimie structurales
3 IRCM - U896 Inserm - UM1 - Institut de recherche en cancérologie de Montpellier

Guanine nucleotide exchange factors (GEFs) activate the Rho GTPases by accelerating their GDP/GTP exchange rate. Some RhoGEFs have been isolated based on their oncogenic potency, and strategies to inhibit their activity are therefore actively being sought. In this study we devise a peptide inhibitor screening strategy to target the GEF activity of Tgat, an oncogenic isoform of the RhoGEF Trio, based on random mutations of the Trio inhibitor TRIP alpha, which we previously isolated using a peptide aptamer screen. This identifies one peptide, TRIP(E32G), which specifically inhibits Tgat GEF activity in vitro and significantly reduces Tgat-induced RhoA activation and foci formation. Furthermore, subcutaneous injection of cells expressing Tgat and TRIP(E32G) into nude mice reduces the formation of Tgat-induced tumors. Our approach thus demonstrates that peptide aptamers are potent inhibitors that can be used to interfere with RhoGEF functions in vivo.

Domaines: Biochimie, Biologie Moléculaire

Nathalie Bouquier, Sylvie Fromont, Jean-Christophe Zeeh, Camille Auziol, Pauline Larrousse, et al.. Aptamer-derived peptides as potent inhibitors of the oncogenic RhoGEF Tgat.. Chemistry and Biology, 2009, 16 (4), pp.391-400. ⟨10.1016/j.chembiol.2009.02.006⟩. ⟨hal-00392842⟩