Figure 9. Model for MAP4K3 amino acid-dependent activation of the mTORC1 complex.

Amino acids activate MAP4K3, which turns off SIRT1 by directly phosphorylating it. With SIRT1 inhibited, LKB1 remains acetylated in the nucleus and cannot activate AMPK. Inactivation of AMPK elicits two downstream effects: (i) the TSC1/2 complex is repressed, and thus cannot inhibit Rheb; and (ii) Raptor is engaged. Rheb activation and Raptor stabilization promote robust activation of the mTORC1 complex. In parallel, when amino acids are plentiful, mTORC1 is recruited to the surface of the lysosome by interaction of the Ragulator complex with the Rag proteins, which are activated by GATOR1. MAP4K3 likely affects the lysosomal localization of the mTORC1 complex, though the regulatory basis for this cross-talk (?) is unknown. In the absence of amino acids, activated SIRT1 deacetylates LKB1, which phosphorylates AMPK to activate it, resulting in phospho-activation of the TSC1/2 complex and phospho-inhibition of Raptor, destabilizing its incorporation into the mTORC1 complex. Amino acid scarcity also disfavors mTORC1 localization to the lysosome preventing activation of the mTORC1 complex.