title: A RasGAP SH3 peptide aptamer inhibits RasGAP-Aurora interaction and induces caspase-independent tumor cell death.
abstract: 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.
authors.affiliation: UFR Biomédicale, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, INSERM U648, Université Paris Descartes, Paris, France.
authors.forename: Perayot
authors.initials: P
authors.lastname: Pamonsinlapatham
authors.forename: Réda
authors.initials: R
authors.lastname: Hadj-Slimane
authors.forename: Françoise
authors.initials: F
authors.lastname: Raynaud
authors.forename: Marc
authors.initials: M
authors.lastname: Bickle
authors.forename: Claudine
authors.initials: C
authors.lastname: Corneloup
authors.forename: Audrey
authors.initials: A
authors.lastname: Barthelaix
authors.forename: Yves
authors.initials: Y
authors.lastname: Lepelletier
authors.forename: Perrine
authors.initials: P
authors.lastname: Mercier
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.forename: Jérôme
authors.initials: J
authors.lastname: Samson
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mathieu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hugo
authors.forename: Olivier
authors.initials: O
authors.lastname: Moncorgé
authors.forename: Ivan
authors.initials: I
authors.lastname: Mikaelian
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dufour
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.forename: Pierre
authors.initials: P
authors.lastname: Colas
mesh_terms: D000595:Amino Acid Sequence; D064127:Aurora Kinases; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism*; D017124:Conserved Sequence; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D020703:ras GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D020703:ras GTPase-Activating Proteins; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D020169:Caspases