PI 3-KINASE AND VSRC TRANSFORMATION

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The overall objective of this proposal is to determine the role that phosphatidylinositide 3-kinase (PI3-K) plays in malignant transformation by v-Src. Activation of PI3-K and its downstream signaling pathways may cooperate with the Ras-MAP kinase pathway in mediating v-Src transformation. Therefore, the activation of PI 3-K by v-Src will be monitored in cells in which Ras activation is blocked. The role of this PI3-K activation in transformation will be examined by determining the effect of inhibiting PI3-K on v-Src transformation. To identify which of the known PI3-K effectors is necessary for transformation by v-Src, the activation of Rac, Akt, and p70S6k will be monitored in cells expressing v-Src and the extent of inhibition of transformation will be determined when each of these three pathways is blocked. Finally, the mechanism by which v-Src activates PI3-K will be studied by examining the respective contributions of direct activation by v-Src and activation through a docking intermediate. A complete understanding of the signaling pathways involved in malignant transformation by v-Src may serve as a basis for understanding the alterations in cell growth responsible for cancer.