mTORC1 Regulation by Upstream Stimuli

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ABSTRACT The mammalian target of rapamycin (mTOR) is an evolutionary conserved Ser/Thr kinase that senses multiple upstream stimuli to regulate cell growth, metabolism, and autophagy. mTOR is the catalytic component of a multi-protein complex called mTOR complex 1 (mTORC1). Elevated mTORC1 activation is common in multiple human disease including cancer, type 2 diabetes, metabolic disorders, and neurodegeneration. Small molecules like rapamycin that target and inhibit mTORC1 are used in the clinic with limited success. Thus, deciphering the molecular mechanisms by which mTORC1 is regulated is crucial to treat mTORC1-mediated disease. The overall objective of this proposal is to decipher the molecular mechanisms by which mTORC1 is regulated by upstream stimuli. Specifically, this proposal is focused on mTORC1 regulation by amino acids and G-protein coupled receptors (GPCRs). We anticipate that the studies in this proposal will yield new insights into mTORC1 regulation by upstream stimuli and will uncover novel therapeutic targets to perturb mTORC1-mediated disease.