Fig. 5 |. Amino acid and growth-factor signals to mTORC1 are integrated by regulation of the Rag and Rheb GTPases at the lysosome.
a, The nucleotide-binding status of the Rag heterodimer and Rheb is controlled by the indicated GAPs and GEFs, thus facilitating the switch between the OFF and ON states with respect to their ability to promote mTORC1 activation. b–e, Current model for Rag and Rheb regulation on the cytosolic face of the lysosome, where the Rag heterodimer binds the Ragulator and SLC38A9, and farnesylated Rheb is present. b, Under conditions of amino acid depletion, GATOR1 is an active GAP that promotes the conversion to RagA/B-GDP, thus generating Rag heterodimers that cannot bind mTORC1. c, Under amino acid–replete conditions, leucine, arginine and methionine-derived SAM directly bind Sestrin, CASTOR and SAMTOR, respectively, and GATOR1 is consequently inhibited. Release of Sestrin and CASTOR from GATOR2 allows GATOR2 to inhibit or override GATOR1’s GAP activity through an unknown mechanism. Intralumenal arginine stimulates the SLC38A9-mediated release of leucine and other neutral amino acids into the cytosol while also stimulating RagA/B GEF activity for the Ragulator and SLC38A9. Collectively, these events promote conversion to Rag heterodimers containing RagA/B-GTP, which can recruit inactive mTORC1 to the lysosome; this conversion can occur independently of growth-factor status. d, In the absence of growth-factor signals, the TSC complex localizes to the lysosome and keeps Rheb in the GDP-bound state, which cannot activate mTORC1. e, Growth-factor-mediated activation of PI3K–Akt signalling results in phosphorylation-dependent dissociation of the TSC complex from lysosomal Rheb, thus enabling Rheb–GTP accumulation and direct activation of mTORC1.