Figure 3. Integration of amino acid and insulin sensing at the lysosome by spatial-temporal regulation of mTORC1 and TSC.
Recent data suggest a model in which amino acids and insulin control mTORC1 activity at the lysosome by spatial-temporal regulation of not only mTORC1 but also its inhibitor TSC. In the absence of amino acids and insulin, inactive mTORC1 localizes to the cytosol while active TSC localizes to lysosomal membranes in a Rag-dependent manner. Upon stimulation with amino acids, active RagA/BGTP-RagC/DGDP heterodimers recruit mTORC1 to lysosomal membranes where Rheb resides to mediate basal mTORC1 activity; simultaneously, amino acids induce TSC dissociation from lysosomal membranes partially. Similar to amino acids, insulin stimulation induces TSC dissociation from lysosomal membranes. mTORC1 dissociates from lysosomes completely only when both Rag heterodimers and Rheb exist in their inactive states. Conversely, mTORC1 associates with lysosomal membranes fully only when Rag heterodimers and Rheb exist in their active states in the presence of both amino acids and insulin.