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Molecular logic of mTORC1 signalling as a metabolic rheostat

Abstract

The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) serves as a key conduit between growth signals and the metabolic processes underlying cell growth. The activation state of mTORC1 is controlled by intracellular nutrients and energy, as well as exogenous hormones and growth factors, thereby integrating local and systemic growth signals. Here we discuss the molecular logic of the mTORC1 signalling network and its importance in coupling growth signals to the control of cellular metabolism. After activation, mTORC1 promotes the conversion of available nutrients and energy into the major macromolecular species contributing to cellular mass, including proteins, nucleic acids and lipids, while suppressing the autophagic recycling of these macromolecules back into their nutrient constituents. Given that uncoupling of mTORC1 from its normal regulatory inputs contributes to many diseases—including cancer, genetic tumour syndromes, metabolic diseases, autoimmune diseases and neurological disorders—understanding the molecular logic of the mTORC1 network and how to modulate it may present therapeutic opportunities for treatment of a broad range of diseases and potentially even for the extension of lifespan.

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Fig. 1: mTORC1 links nutrient and energy availability to the controlled switch between anabolic and catabolic metabolism.
Fig. 2: Major molecular mechanisms of mTORC1-mediated stimulation of protein synthesis.
Fig. 3: mTORC1 signalling activates a coordinated metabolic network, thereby supporting macromolecular synthesis.
Fig. 4: Logic of mTORC1 regulation and function.
Fig. 5: Amino acid and growth-factor signals to mTORC1 are integrated by regulation of the Rag and Rheb GTPases at the lysosome.

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Acknowledgements

Studies in the laboratory of B.D.M. related to this subject were supported by American Cancer Society postdoctoral fellowship 127106-PF-14-254-01-TBE to A.J.V., NIH grants R35-CA197459 and P01-CA120964 to B.D.M., and a Rothberg Courage Award from the Tuberous Sclerosis Alliance to B.D.M.

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B.D.M. is a shareholder and scientific advisory board member of Navitor Pharmaceuticals and LAM Therapeutics.

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Valvezan, A.J., Manning, B.D. Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat Metab 1, 321–333 (2019). https://doi.org/10.1038/s42255-019-0038-7

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