Dissecting the biology of mTORC1 beyond rapamycin

Yang, Guang, Francis, Deanne, Krycer, James R., Larance, Mark, Zhang, Ziyang, Novotny, Chris J., Diaz-Vegas, Alexis, Shokat, Kevan M., and James, David E. (2021) Dissecting the biology of mTORC1 beyond rapamycin. Science Signaling, 14 (701). eabe0161.

[img] PDF (Published Version) - Published Version
Restricted to Repository staff only

View at Publisher Website: https://doi.org/10.1126/scisignal.abe016...


Rapamycin extends maximal life span and increases resistance to starvation in many organisms. The beneficial effects of rapamycin are thought to be mediated by its inhibitory effects on the mechanistic target of rapamycin complex 1 (mTORC1), although it only partially inhibits the kinase activity of mTORC1. Other mTOR kinase inhibitors have been developed, such as Torin-1, but these readily cross-react with mTORC2. Here, we report the distinct characteristics of a third-generation mTOR inhibitor called RapaLink1. We found that low doses of RapaLink1 inhibited the phosphorylation of all mTORC1 substrates tested, including those whose phosphorylation is sensitive or resistant to inhibition by rapamycin, without affecting mTORC2 activity even after prolonged treatment. Compared with rapamycin, RapaLink1 showed better efficacy for inhibiting mTORC1 and potently blocked cell proliferation and induced autophagy. Moreover, using RapaLink1, we demonstrated that mTORC1 and mTORC2 exerted differential effects on cell glycolysis and glucose uptake. Last, we found that RapaLink1 and rapamycin had opposing effects on starvation resistance in Drosophila. Consistent with the effects of RapaLink1, genetic blockade of mTORC1 activity made flies more sensitive to starvation, reflecting the complexity of the mTORC1 network that extends beyond effects that can be inhibited by rapamycin. These findings extend our understanding of mTOR biology and provide insights into some of the beneficial effects of rapamycin.

Item ID: 72341
Item Type: Article (Research - C1)
ISSN: 1937-9145
Copyright Information: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No Claim to original U.S. Government Works.
Funders: National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC GNT120201
Date Deposited: 09 Feb 2022 13:48
FoR Codes: 31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310102 Cell development, proliferation and death @ 100%
Downloads: Total: 1
More Statistics

Actions (Repository Staff Only)

Item Control Page Item Control Page