The PI3K-mTOR Pathway

Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is required for normal development, growth, and physiology. Mutations in multiple key regulators of this pathway have been reported to occur leading to aberrant signaling and have been implicated in a number of pathologies, including metabolic syndrome. This chapter will review the major proteins involved in PI3K/mTOR signaling and discuss the negative feedback loops which maintain homeostasis. The therapeutic advantages and limitations of PI3K and/or catalytic mTOR inhibitors, which are currently in clinical development, will be discussed. We also report studies using these inhibitors along with genetic models to delete or overexpress key players in PI3K/mTOR signaling pathways in yeast, worms, drosophila, and mice, which have been instrumental in elucidating the functions of these proteins in normal and disease states. Particular attention has been focused on the role of PI3K/mTOR signaling in proliferation, translation, metabolism (including energy balance regulation and metabolic syndrome), autophagy, and differentiation.