FIGURE 10-32 The mTORC1 pathway. mTORC1 is an active protein kinase when bound by a complex of Rheb and an associated GTP (lower left). In contrast, mTORC1 is inactive when bound by a complex of Rheb associated with GDP (lower right). When active, the TSC1/TSC2 Rheb-GTPase activating protein (Rheb-GAP) causes hydrolysis of Rheb-bound GTP to GDP, thereby inactivating mTORC1. The TSC1/TSC2 Rheb-GAP is activated (arrows) by phosphorylation by AMP kinase (AMPK) when cellular energy is low and by other cellular stress responses. Signal transduction pathways activated by cell-surface growth-factor receptors lead to phosphorylation of inactivating sites on TSC1/TSC2, inhibiting its GAP activity. Consequently, they leave a higher fraction of cellular Rheb in the GTP conformation that activates mTORC1 protein kinase activity. Low nutrient concentrations also regulate Rheb GTPase activity by a mechanism that does not require TSC1/TSC2. Active mTORC1 phosphorylates 4E-BP, causing it to release eIF4E, stimulating translation initiation. It also phosphorylates and activates S6 kinase (S6K), which in turn phosphorylates ribosomal proteins, stimulating translation. Activated mTORC1 also activates transcription factors for RNA polymerases I, II, and III, leading to synthesis and assembly of ribosomes, tRNAs, and translation factors. In the absence of mTORC1 activity, all of these processes are inhibited. In contrast, activated mTORC1 inhibits autophagy, which is stimulated in cells with inactive mTORC1. See S. Wullschleger et al., 2006, Cell 124:471.