GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31112131.
- Also identified by DOI 10.7554/eLife.43038 and PMC identifier 6529218.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 Gα<sub>s</sub> 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. Gα<sub>s</sub>-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 Gα<sub>s</sub> proteins may be potential therapeutic targets for human diseases with hyperactivated mTORC1.
Medical subject headings
- Cyclic AMP-Dependent Protein Kinases
- Mechanistic Target of Rapamycin Complex 1
- Protein Processing, Post-Translational
- Receptors, G-Protein-Coupled
- Regulatory-Associated Protein of mTOR
- Signal Transduction