Requirement for Akt-mediated survival in cell transformation by the dbl oncogene.
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.
Morley
S
S
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
Wagner
J
J
Kauppinen
K
K
Sherman
M
M
Manor
D
D
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D051379:Mice; D051058:Oncogene Protein v-akt / Q000502:physiology*; D009857:Oncogenes / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D051025:bcl-Associated Death Protein / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
D064413:3-Phosphoinositide-Dependent Protein Kinases; D020662:Guanine Nucleotide Exchange Factors; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051025:bcl-Associated Death Protein; D020764:cdc42 GTP-Binding Protein; C494820:Bad protein, mouse; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse