GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor

Author:

Jewell Jenna L123ORCID,Fu Vivian45,Hong Audrey W45,Yu Fa-Xing6,Meng Delong123,Melick Chase H123,Wang Huanyu123,Lam Wai-Ling Macrina45,Yuan Hai-Xin45,Taylor Susan S47ORCID,Guan Kun-Liang45

Affiliation:

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

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.

Funder

Cancer Prevention and Research Institute of Texas

Welch Foundation

National Institutes of Health

The Hartwell Foundation

University of Texas Southwestern Medical Center

American Cancer Society

National Cancer Institute

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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