Figure 2. Akt-independent mechanisms of mTOR regulation.
The mTOR pathway is regulated by mitogen-responsive signaling pathways (shown in green), as well as by pathways that signal the availability of nutrients, such as amino acids (shown in yellow), and intracellular energy (shown in blue). Mitogens activate mTOR independently of Akt through the Ras/Mek/ERK pathway, the Wnt signaling pathway, and through activation of phospholipase D. Amino acids also activate mTOR through multiple mechanisms: activation of Vps34, MAP4K3, the Rag family of GTPases, and phospholipase D. However, the mechanisms by which some of these proteins activate mTOR are not well understood, and there may be crosstalk between these pathway components. Conversely, conditions that deplete intracellular energy, such as hypoxia, inhibit the mTOR pathway. One mechanism by which this occurs is through activation of AMPK. AMPK is activated by increases in intracellular AMP, as well as by the upstream kinases, LKB1 and CaMKKβ. AMPK inhibits the mTOR pathway directly through phosphorylation of Raptor and indirectly through phosphorylation and activation of TSC2. Although hypoxia can inhibit the mTOR pathway through activation of AMPK, it also inhibits mTOR through increased expression of the hypoxia-inducible-factor-1 target gene, REDD1. The tuberous sclerosis complex TSC1/TSC2 and Rheb GTPase (shown in grey) integrate signals from mitogen-responsive and energy and nutrient-sensing pathways to regulate mTORC1 (shown in red).