Among the properties that distinguish tumor cells from normal cells are uncontrolled proliferation, invasion of other tissues, and resistance to apoptosis. Our long term goals are to understand how oncogenes, especially Ras, promote these properties. The major effector that Ras binds and activates is the Raf protein kinase, but critical transformation signals are mediated by direct binding to other effectors including phosphatidylinositol-3-OH kinase (PI 3-kinase). PI 3-kinase signals to Akt to inhibit apoptosis and to small GTPases such as Rac to promote cell invasion. Rac regulates a serine threonine protein kinase called Pak. Our studies provided the first evidence that Pak mediates cell transformation signals from Ras. In addition to its requirement for Ras transformation, we found that Pak stimulates cell survival by phosphorylating Raf-1 and causing it to translocate to mitochondria, bind Bcl-2 and phosphorylate the cell survival factor BAD. Pak also regulates cell motility through its effects on the actin cytoskeleton. We have been studying the role of Akt in cell migration and have implicated Pak in the process. Interestingly, the Akt1 and Akt2 isoforms have opposing roles in cell migration and regulation of Pak. We have found that Akt1 promotes motility and cell migration, while Akt2 inhibits cell migration and Pak activation. We hypothesize that Pak has central roles in survival and motility through its interactions with Raf-1 and Akt. We propose to (1) Identify the mechanisms underlying the effects of Pak on cell survival (2) Determine the mechanism responsible for the distinct effects of Akt1 and Akt2 on Pak and cell motility (3) Determine the roles of Pak and Akt in migration and survival of malignant Peripheral Nerve Sheath Tumors (MPNST) and the Schwann cells from which they originate: Relevance to public health-Several properties distinguish cancer cells from normal cells, including the ability to invade surrounding tissues and resistance to programmed cell death. This grant proposes to study some of the genes that control cell death and invasion with the long term goal of understanding how the knowledge could be used to design better cancer therapies.
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