Journal
ELIFE
Volume 8, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.43038
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Funding
- Cancer Prevention and Re-search Institute of Texas [RR150032, RP160713]
- Welch Foundation [1-1927-20170325]
- National Institutes of Health [T32CA121938, R01GM129097, T32GM007752, T32GM008203, RO1GM51586, RO1CA108941]
- Hartwell Foundation
- University of Texas Southwestern Medical Center
- American Cancer Society [ACS-IRG-17-174-13]
- National Cancer Institute
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The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth, metabolism, and autophagy. Extensive research has focused on pathways that activate mTORC1 like growth factors and amino acids; however, much less is known about signaling cues that directly inhibit mTORC1 activity. Here, we report that G-protein coupled receptors (GPCRs) paired to G alpha(s) proteins increase cyclic adenosine 3'5' monophosphate (cAMP) to activate protein kinase A (PKA) and inhibit mTORC1. Mechanistically, PKA phosphorylates the mTORC1 component Raptor on Ser 791, leading to decreased mTORC1 activity. Consistently, in cells where Raptor Ser 791 is mutated to Ala, mTORC1 activity is partially rescued even after PKA activation. G alpha(s)-coupled GPCRs stimulation leads to inhibition of mTORC1 in multiple cell lines and mouse tissues. Our results uncover a signaling pathway that directly inhibits mTORC1, and suggest that GPCRs paired to G alpha(s) proteins may be potential therapeutic targets for human diseases with hyperactivated mTORC1.
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