mTORC1 complex, hormones and growth factors responses
The mTORC1 system responds to and integrates many cues that include energy status, oxygen, stress, growth factors and amino acids. mTORC1 signaling positively controls ribosome biogenesis and protein translation, and negatively, autophagy. The activity of mTORC1 is promoted by the GTP-bound small G protein Rheb. Under unstimulated conditions Rheb is inhibited by the TSC complex which has inhibitory GAP activity towards it; the function is dependent on the Tsc2 component. While usually depicted as a trimer composed of Tsc1, Tsc2 (both shown separately) and Tbc1d7, evidence indicates that this complex is present as a large oligomeric structure with multiple copies of each subunit. Insulin and growth factors activate PI3K-Akt and the Raf/Mek/Erk intracellular signaling pathways, resulting in inhibition of Tsc2 and activation of mTorc1. Akt can also activate mTOR downstream of Tsc2 by relieving the inhibition by Akt1s1 (known as Pras40). Interestingly, Akt is among the substrates of mTORC2. Eif4bp1 and Rps6k1, targets and effectors of mTORC1, lead to activation of translation initiation and ribosome biogenesis. mTORC1 signaling can negatively impact on insulin signaling and its downstream-activated events; a regulatory feedback loop is provided by the Rps6k1 effector which phosphorylates insulin receptor substrate 1. Phosphorylation of Ulk1 by mTORC1 leads to inhibition of autophagy. mTORC1 can stimulate the activity of Nfe2l2 (known as Nrf2) transcription factor by phosphorylating Sqstm1. When modified, Sqstm1 becomes a potent inhibitor of Keap1 protein, a redox sensor that under basal conditions targets Nfe2l2 for ubiquitination and proteasomal degradation. Nfe2l2 signaling is one of the most important regulators of antioxidant and electrophilic stress responses. mTORC1 is negatively regulated by a low energy status of the cell and positively regulated by amino acid availability, consistent with its role in protein biosynthesis and metabolism. The energy 'sensor' Amp-activated protein kinase (AMPK) of the Lkb1-AMPK axis inhibits energy-consuming pathways while promoting ATP-generating ones. AMPK phosphorylates and activates Tsc2; downstream of Tsc2 it can inhibit mTORC1 by phosphorylating Raptor.

mTORC1 complex, amino acid responses
Amino acid availability stimulates mTORC1 and is dependent on the Rrag (known as Rag) proteins: RragA, B, C and D. The Rag proteins constitute a family of related small GTPases that function as obligate heterodimers. GTP-bound RragA or B complexed with GDP-bound RragC or D, are the heterodimers that stimulate mTORC1 activity. As such, they bind the Raptor component of mTORC1, prompting the translocation of the complex to lysosomal surfaces. There, Rags dock onto a multisubunit complex known as the 'Ragulator', essential for the activation of mTORC1 by amino acids. The lysosome is the final destination of many catabolic events and a major recycling center. The lysosomal localization allows mTORC1 to respond to amino acid availability; several amino acid lysosomal protein transporters may act as 'sensors' (not shown). The 'Ragulator' is composed of five Lamtor protein subunits of which Lamtor1 acts as a scaffold for two heterodimers of Lamtor2/3 and Lamtor4/5. The complex can act as a guanine exchange factor (GEF) for RragA and B. Inhibitory GAP activity for RragA and B is provided by the Gator1 complex while regulatory GAP activity towards RragC and D is provided by folliculin (Flcn) in complex with its Fnip partners. Gator1 inhibition is relieved by the Gator2 complex. How Gator2 functions remains to be elucidated; however, it is known that the function is modulated by amino acid availability. In the absence of amino acids, Gator2 is inhibited by Gatsl3/2 (Castor1/2) and by sestrin2 proteins. The interaction of these proteins with Gator2 is inhibited when leucine binds sestrin2 or arginine binds Castor1. Castor1 functions as a homodimer or a heterodimer with Castor2, which by itself does not bind arginine. On the lysosomal surface, mTORC1 is activated by a GTP-loaded Rheb. Insulin, and likely growth factors, prompt the departure of inhibitory TSC from the lysosome, where it can be found in their absence.

mTORC2 complex Growth factors activate mTorc2 by mechanisms that are incompletely understood. mTORC2 promotes PI3k-Akt signaling via Akt phosphorylation. Full activity of Akt members requires two phosphorylation events; the second phosphorylation is provided by mTORC2. mTORC2 regulates several members of the protein kinase C family and recently it has been shown that it negatively regulates a component of the Hippo signaling pathway (not shown). The mTORC2 arm of the pathway plays a role in cytoskeletal rearrangements and like mTORC1, can modulate cell growth.
The detailed picture of mTOR signaling is still incomplete but research increasingly points to its central role in the modulation of cell growth and metabolism. mTOR can be deregulated at many levels and its alteration, including deregulation of its cross talk with the PI3K-Akt system, has been implicated in numerous conditions. To see the ontology report for annotations, GViewer and download, click here....(less)