2. Academic Validation
  3. GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor

GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor

  • Elife. 2019 May 21:8:e43038. doi: 10.7554/eLife.43038.
Jenna L Jewell 1 2 3,  Vivian Fu 4 5,  Audrey W Hong 4 5,  Fa-Xing Yu 6,  Delong Meng 1 2 3,  Chase H Melick 1 2 3,  Huanyu Wang 1 2 3,  Wai-Ling Macrina Lam 4 5,  Hai-Xin Yuan 4 5,  Susan S Taylor 4 7,  Kun-Liang Guan 4 5
Affiliations

Affiliations

  • 1 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.
  • 2 Harold C Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States.
  • 3 Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
  • 4 Department of Pharmacology, University of California, San Diego, La Jolla, United States.
  • 5 Moores Cancer Center, University of California San Diego, La Jolla, United States.
  • 6 Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 7 Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, United States.
PMID: 31112131 DOI: 10.7554/eLife.43038
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 Gαs 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. Gαs-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 Gαs proteins may be potential therapeutic targets for human diseases with hyperactivated mTORC1.

Keywords

cancer biology; cancer cells; cell biology; cells; human; mouse.

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