Fig. 12.

Complexity of the direct and indirect effects of mTOR on signaling pathways. Metabolic signaling through insulin receptor substrate-1 (IRS) leads to activation of PI3K and subsequent recruitment of phosphoinositide-dependent kinase-1 (PDK1) to the cell membrane. Here, PDK1 phosphorylates Akt at Thr-308, which in turn triggers phosphorylation of Akt at Ser-473 by mTORC2. Upon its activation, Akt becomes capable of inhibiting the TSC1/2 complex, leading to the stimulation of mTORC1 and its downstream targets 4EBP1 and p70^S6K1. The resulting stimulation of p70^S6K1 activity can then cause negative feedback of the mTOR signaling cascade at several points of the pathway. Thus, increased p70^S6K1 activity can lead to phosphorylation of IRS, leading to degradation of the receptor. Active p70^S6K1 also negatively regulates Akt signaling through inhibition of PDGFR and ERK/MAPK signaling. The two mTOR complexes are also able to regulate each other in an inter-complex feedback loop, as activation of p70^S6K1 stimulates phosphorylation of the RICTOR subunit of mTORC2, causing a decrease in Akt signaling thorough impaired phosphorylation of Ser-473. In addition, mTORC2, via p70^S6K1, also inhibits IRS, leading to a reduction in Akt signaling.