Figure 10. Scheme showing GSK3 involvement in the regulation of mTORC1-directed signalling.

AA provision regulates RAG-mediated recruitment of the mTORC1 complex to the lysosomal membrane, but also induces phosphorylation of the mTOR scaffold protein raptor on Ser⁸⁶³ by an unknown kinase. Phosphorylation of Ser⁸⁶³ primes phosphorylation of Ser⁸⁵⁹ by GSK3, which supports mTOR–raptor interaction and mTOR-catalysed phosphorylation of multiple downstream targets such as ULK1 and TFEB (thereby suppressing autophagy/lysosomal biogenesis) and p70S6K1 and 4E-BP1 (which support cell growth and proliferation). GSK3 inhibition leads to a loss in raptor Ser⁸⁵⁹ phosphorylation, reduced mTOR and raptor association and concomitant reduction in mTORC1-directed signalling. Activation of mTORC1 is subject to enhancement by insulin that induces activation of the mTORC1 complex via the Akt–TSC2–Rheb axis. This axis appears not to influence raptor phosphorylation on Ser⁸⁶³ or Ser⁸⁵⁹.