The Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to identify potential targetable effectors. Recently, the mechanistic target of rapamycin complex 2 (mTORC2) was identified as an evolutionarily conserved Ras effector. mTORC2 regulates essential cellular processes, including metabolism, survival, growth, proliferation and migration. Moreover, increasing evidence implicate mTORC2 in oncogenesis. Little is known about the regulation of mTORC2 activity, but proposed mechanisms include a role for phosphatidylinositol (3,4,5)-trisphosphate – which is produced by class I phosphatidylinositol 3-kinases (PI3Ks), well-characterized Ras effectors. Therefore, the relationship between Ras, PI3K and mTORC2, in both normal physiology and cancer is unclear; moreover, seemingly conflicting observations have been reported. Here, we review the evidence on potential links between Ras, PI3K and mTORC2. Interestingly, data suggest that Ras and PI3K are both direct regulators of mTORC2 but that they act on distinct pools of mTORC2: Ras activates mTORC2 at the plasma membrane, whereas PI3K activates mTORC2 at intracellular compartments. Consequently, we propose a model to explain how Ras and PI3K can differentially regulate mTORC2, and highlight the diversity in the mechanisms of mTORC2 regulation, which appear to be determined by the stimulus, cell type, and the molecularly and spatially distinct mTORC2 pools.

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To my parents, Denise and Leon, and my wife, Patricia. I would like to express my gratitude to the many people who helped make this dissertation possible. In particular, I would like to thank: My parents and my wife for their love and support throughout all these years; My advisor, Mark Fox, for his guidance, enthusiasm and unfailing support; The other members of my thesis committee, Tom Mitchell, Tom Morton, Judea Pearl, and Steve Smith, for many helpful comments on this research; All present and past members of the CORTES project for many stimulating discussions-Special thanks to Bob Frederking, who volunteered to proofread parts of this dissertation; All my friends and colleagues at the Center for Integrated Manufacturing Decision Systems and in the School of Computer Science for having made these past four years such a unique experience; Les Gasser for his friendship and support during my earlier graduate life in Los Angeles. I would also like to acknowledge the financial support I received directly or indirectly from DARPA, Digital Equipment Corporation, and McDonnell Douglas, while a student at Carnegie Mellon, as well as the financial support of the Belgian American Educational Foundation during my first year in the U.S..