Figure 1. mTOR signaling pathway. mTOR is part of two major complexes, mTORC1 and mTORC2. Insulin and growth factor receptors induce PI3K, which results in phosphoinositide-dependent kinase-1 (PDK1)-dependent phosphorylation of T308 of AKT. mTORC1 is negatively regulated by TSC1 and TSC2 and positively regulated by the small G protein RHEB. Akt phosphorylates TSC2 and disrupts the complex of mTORC1, which inhibits the GTPase activating function (GAP activity) of the TSC1-TSC2 complex toward RHEB and favors the GTP bound form of RHEB (active). S6K regulates cell size, ribosomal biogenesis and protein synthesis. In addition, S6K signaling inhibits insulin signaling by phosphorylation of IRS1 and possibly IRS2. mTORC1 phosphorylates 4E-BP at multiple sites, leading to dissociation of eIF4E and resulting in cap-dependent translation. Additional mTORC1 targets include ATG1, PPARγ, PGC1α and HIF-1. Energy depletion and glucose starvation increase the AMP/ATP ratio resulting in augmented AMPK activity. Amino acid activation of mTORC1 is more complex and not completely understood but several pathways have been proposed (Rag GTPases, hVPS34, MAP4K3 and RalA). Stress condition such as hypoxia can regulate TSC complex through REDD1/2.