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Department of Pathology, College of Medicine and H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida 33612 [A. L., R. J., S. V. N., J. Q. C.], and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [J. R. T., T. C. H.]
Three members have been identified in the protein kinase B (PKB) family, i.e., Akt/PKB
, AKT2/PKBß, and AKT3/PKB
. Previous studies have demonstrated that only AKT2 is predominantly involved in human 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, including epidermal growth factor, insulin-like growth factor I, insulin-like growth factor II, basic fibroblast growth factor, platelet-derived growth factor, and insulin, in human ovarian epithelial cancer cells. The 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, the activated Ras and v-Src, two proteins that transduce growth factor-generated signals, also activated AKT2, and this activation was not significantly enhanced by growth factor stimulation but was abrogated by wortmannin. These results indicate that AKT2 is a downstream target of PI 3-kinase and that Ras and Src function upstream of PI 3-kinase and mediate the activation of AKT2 by growth factors. The findings also provide further evidence that AKT2, in cooperation with Ras and Src, is important in the development of some human malignancies.
1 Supported by National Cancer Institute Grant CA77935 (to J. Q. C.) and University of South Florida Ovarian Cancer Pathobiology Grant 6115-000-20 (to S. V. N.).
2 To whom requests for reprints should be addressed, at Department of Pathology, University of South Florida, College of Medicine and H. Lee Moffitt Cancer Center, 12901 Bruce B. Downs Boulevard, MDC Box 11, Tampa, FL 33612.
Received 3/17/98. Accepted 5/29/98.
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