Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States; Harold C Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
Vivian Fu
Department of Pharmacology, University of California, San Diego, La Jolla, United States; Moores Cancer Center, University of California San Diego, La Jolla, United States
Audrey W Hong
Department of Pharmacology, University of California, San Diego, La Jolla, United States; Moores Cancer Center, University of California San Diego, La Jolla, United States
Fa-Xing Yu
Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
Delong Meng
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States; Harold C Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
Chase H Melick
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States; Harold C Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
Huanyu Wang
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States; Harold C Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
Wai-Ling Macrina Lam
Department of Pharmacology, University of California, San Diego, La Jolla, United States; Moores Cancer Center, University of California San Diego, La Jolla, United States
Hai-Xin Yuan
Department of Pharmacology, University of California, San Diego, La Jolla, United States; Moores Cancer Center, University of California San Diego, La Jolla, United States
Department of Pharmacology, University of California, San Diego, La Jolla, United States; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, United States
Kun-Liang Guan
Department of Pharmacology, University of California, San Diego, La Jolla, United States; Moores Cancer Center, University of California San Diego, La Jolla, United States
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.
