Figure 4. Proposed mechanism for reciprocal regulation of mTORC1 and AMPK at the cytoplasmic surface of the lysosome.

The model is based on (Bar-Peled and Sabatini, 2014) and (Zhang et al., 2014). (1) Activation of mTORC1: nutrient availability (amino acids and/or glucose) within the lysosome are sensed by a mechanism requiring the v-ATPase proton pump, and this effect is transmitted to the Ragulator, which converts RagA/B^GDP to RagA/B^GTP, while the folliculin:FNIP complex converts RagC/D^GTP to RagC/D^GDP. The RagA^GTP:RagC^GDP complex binds the Raptor component of mTORC1, whose activation also requires Rheb:GTP. Formation of the latter complex is promoted by growth factors via phosphorylation and dissociation from the lysosome of TSC1:TSC2, a Rheb-GAP (Menon et al., 2014). (2) Activation of AMPK: nutrient lack causes the Ragulator to recruit the axin:LKB1 complex, and elevated AMP also recruits AMPK to this complex. LKB1 phosphorylates and activates AMPK, which then presumably dissociates from the complex to phosphorylate downstream targets. Two of these targets are Raptor and the TSC1:TSC2 complex. Phosphorylation of Raptor by AMPK, coupled with conversion of RagA^GTP:RagC^GDP to RagA^GDP:RagC^GTP, may promote the dissociation of mTORC1 from the lysosome. Phosphorylation of the TSC1:TSC2 complex appears to increase its Rheb-GAP activity, thus converting Rheb:GTP to the inactive Rheb:GDP form, although the exact mechanism remains unclear.