FIGURE 1.

mTORC1 and mTORC2 signaling pathways. A: the activation of mTORC1 occurs via distinct mechanisms that are either Rag dependent or -independent. When nutrients are present, mTORC1 is activated via Rag heterodimers (left). Ragulator serves as a GEF for RagA/B and facilitates localization of the Rag GTPases to the lysosomal surface. GATOR1 is the counteracting GAP and is engaged to the lysosomes via another large protein complex, KICSTOR. GATOR2 indirectly activates mTORC1 by binding to and blocking GATOR1 activity. By binding to regulatory proteins that modulate Rag activation, different amino acids promote mTORC1 activation. mTORC1 is also regulated by Rag-independent mechanisms (right). Glutamine and asparagine promote mTORC1 activation on the lysosomal surface via Arf-1 GTPase. mTORC1 activation is also subject to negative regulation to modulate its activity depending on levels of growth signals. TSC and PRAS40 are modulated by growth factor and energy signals. REDD1 negatively modulates mTORC1 in response to stress conditions. Signals from GPCRs also negatively regulate mTORC1 via PKA. mTORC1 is also modulated by amino acids at the surface of the Golgi via Rab1a (inset). B: mTORC2 is activated by growth factors and fluctuations in nutrient/metabolite levels. In response to growth factors, the increased PI3K signaling enhances mTORC2 activation, leading to phosphorylation of AGC kinase family members such as Akt, PKC, and SGK. mTORC2 allosterically activates these protein kinases, which have numerous cellular functions. mTORC2 activation is also enhanced by other signals including from the GPCR, translating ribosomes, nutrient fluctuations (including withdrawal or readdition), and association of mTORC2 components with other signaling molecules such as Ras, CD146, or IKK. See glossary for abbreviations.