AKT2, A MEMBER OF THE PROTEIN-KINASE-B FAMILY, IS ACTIVATED BY GROWTH-FACTORS, V-HA-RAS, AND V-SRC THROUGH PHOSPHATIDYLINOSITOL 3-KINASE INHUMAN OVARIAN EPITHELIAL CANCER-CELLS

Three members have been identified in the protein kinase B (PKB) famil y, i.e., Akt/PKB alpha, AKT2/PKB beta, and AKT3/PKB gamma. Previous st udies have demonstrated that only AKT2 is predominantly involved in hu man malignancies and has oncogenic activity. However, the mechanism of transforming activity of AKT2 is still not well understood. Here, we demonstrate the activation of AKT2 with several growth factors, includ ing epidermal growth factor, insulin-like growth factor I, insulin-lik e growth factor II, basic fibroblast growth factor, platelet-derived g rowth factor, and insulin, in human ovarian epithelial cancer cells. T he kinase activity and the phosphorylation of AKT2 were induced by the growth factors and blocked by the phosphatidylinositol (PI) 3-kinase inhibitor, wortmannin, and dominant-negative Ras (N17Ras). Moreover, t he activated Pas and v-Src, two proteins that transduce growth factor- generated signals, also activated AKT2, and this activation was not si gnificantly enhanced by growth factor stimulation but was abrogated by wortmannin. These results indicate that AKT2 is a downstream target o f PI 3-kinase and that Pas and Src function upstream of PI 3-kinase an d mediate the activation of AKT2 by growth factors. The findings also provide further evidence that AKT2, in cooperation with Pas and Src, i s important in the development of some human malignancies.