Regulation of mTORC1 signaling by mTOR S1261 phosphorylation

Model for regulation of mTORC1 signaling by mTOR S1261 phosphorylation. We propose that insulin activates mTORC1 via a series of tightly regulated biochemical steps, allowing mTORC1 to respond appropriately to divergent and dynamic environmental cues. Insulin signals via PI3K and Akt to suppress TSC and thus activate Rheb. Akt directly phosphorylates TSC2 () and PRAS40 (, ) to cooperatively activate mTORC1. Insulin signaling via PI3K/TSC/Rheb promotes mTOR S1261 phosphorylation (step 1) (see Discussion for more details), which likely cooperates with other inputs to activate the mTORC1 kinase (step 2). Active mTORC1 phosphorylates itself (on S2481) as well as its partners (e.g., raptor [our data and reference ] and PRAS40 [, , ]) (step 3), culminating in the phosphorylation of substrates (e.g., S6K1, 4EBP1) (step 4) and cell growth (step 5). Not shown is the recently described AMPK-mediated phosphorylation of raptor upon induction of energy stress () and the RSK-mediated phosphorylation of raptor upon mitogenic stimulation of the MAPK pathway (), events that inhibit and activate mTORC1 signaling, respectively. Taken together, the emerging data suggest that multiple phosphorylation events on mTOR and its partners cooperate to regulate the activation state of mTORC1, both positively and negatively.

Publication

Site-Specific mTOR Phosphorylation Promotes mTORC1-Mediated Signaling and Cell Growth . (2009) Hugo A. Acosta-Jaquez, et al. Mol Cell Biol. 2009 Aug;29(15):4308-4324. Figure: F8. All organisms Drosophila melanogaster Homo sapiens

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