Skip to main content
. Author manuscript; available in PMC: 2018 Jun 1.
Published in final edited form as: Cytokine Growth Factor Rev. 2017 May 22;35:47–62. doi: 10.1016/j.cytogfr.2017.04.005

Figure 3. Model of mTORC1 regulation by amino acids and growth factors.

Figure 3

(i) When nutrients are abundant, the lysosomal v-ATPase is activated by amino acids (leucine and arginine in particular) transported into the lysosome, which stimulates the GEF activity of the Ragulator towards the RagA/B GTPases (“inside-out signaling”), resulting in mTORC1 recruitment to the lysosome. Concurrent growth factor and/or BCR stimulation results in phosphorylation and inhibition the TSC complex, permitting mTORC1 activation at the lysosome by Rheb-GTP.

(ii) During amino acid starvation, the AMPK/Flcn/Fnip1/2 complex is bound to inactive v-ATPases through Axin, which inhibits the GEF activity of the Ragulator and switches the Rag GTPases to an inactive state, leading to dissociation of mTORC1 from the lysosome. The Gator1 complex also prevents mTORC1 activation under conditions of amino acid insufficiency by acting as a GTPase activating protein (GAP) for Rag A/B.

(iii) When energy is also low, high AMP levels increase the affinity of AMPK for LKB1 bound to Axin, which increases recruitment of LKB1/Axin complexes to the lysosome, and subsequently AMPK activation by LKB1. Activated AMPK further inhibits mTORC1 by phosphorylation of Raptor and TSC2.