Requirement for Akt-mediated survival in cell transformation by the dbl oncogene

Abstract

The dbl oncogene product is the founding member of a large family of oncogenic proteins that function by activating the small GTP-binding proteins Cdc42, Rac and Rho. Through its substrate GTPases, Dbl transduces proliferative signals from cell-surface receptors to diverse cellular effectors and signaling pathways. The mechanisms by which these multiple signals are integrated, as well as their relative contribution to Dbl-induced cell transformation, are presently poorly understood. We investigated the role of the survival regulators PI3-kinase and Akt in Dbl-induced cell transformation. We found that Dbl induced the phosphorylation of Akt on threonine 308, through the GTPases Rac and Cdc42 and in a PI3-kinase dependent manner. Pharmacological or biochemical interference with this pathway lead to a marked, dose-dependent inhibition of the focus formation activity exhibited by Dbl-expressing cells. Dbl expression stimulated the phosphorylation of the anti-apoptotic Akt substrate Bad, and caused a marked decrease in basal levels of apoptosis. Finally, we found that activated Cdc42 existed in cells in complex with phosphoionositide-dependent kinase-1 (PDK1), the downstream mediator of PI3-kinase action. The data indicate that Dbl signaling stimulate the formation of a novel survival complex, through which anti-apoptotic signals are generated and propagated.