Portal de Periódicos da CAPES

A RasGAP SH3 Peptide Aptamer Inhibits RasGAP-Aurora Interaction and Induces Caspase-Independent Tumor Cell Death

2008; Public Library of Science; Volume: 3; Issue: 8 Linguagem: Inglês

10.1371/journal.pone.0002902

1932-6203

Perayot Pamonsinlapatham, Réda Hadj-Slimane, Florence I. Raynaud, Marc Bickle, Claudine Corneloup, Audrey Barthelaix, Yves Lepelletier, Perrine Mercier, Matthieu Schapira, Jérôme Samson, Anne‐Laure Mathieu, Nicolas Hugo, Olivier Moncorgé, Ivan Mikaélian, Sylvie Dufour, Christiane Garbay, Pierre Colas,

Protein Kinase Regulation and GTPase Signaling

The Ras GTPase-activating protein RasGAP catalyzes the conversion of active GTP-bound Ras into inactive GDP-bound Ras. However, RasGAP also acts as a positive effector of Ras and exerts an anti-apoptotic activity that is independent of its GAP function and that involves its SH3 (Src homology) domain. We used a combinatorial peptide aptamer approach to select a collection of RasGAP SH3 specific ligands. We mapped the peptide aptamer binding sites by performing yeast two-hybrid mating assays against a panel of RasGAP SH3 mutants. We examined the biological activity of a peptide aptamer targeting a pocket delineated by residues D295/7, L313 and W317. This aptamer shows a caspase-independent cytotoxic activity on tumor cell lines. It disrupts the interaction between RasGAP and Aurora B kinase. This work identifies the above-mentioned pocket as an interesting therapeutic target to pursue and points its cognate peptide aptamer as a promising guide to discover RasGAP small-molecule drug candidates.