@article{249bb612f5ba42168f9af3538b609334,
title = "GPCR signaling inhibits mTORC1 via PKA phosphorylation of raptor",
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{\textquoteright}5{\textquoteright} 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.",
author = "Jewell, {Jenna L.} and Vivian Fu and Hong, {Audrey W.} and Yu, {Fa Xing} and Delong Meng and Melick, {Chase H.} and Huanyu Wang and Lam, {Wai Ling Macrina} and Yuan, {Hai Xin} and Taylor, {Susan S.} and Guan, {Kun Liang}",
note = "Funding Information: The authors are grateful to their colleagues in the Guan and Jewell laboratory for critical comments and valuable discussions. We thank Yanhui Xu for incorporating the Ser 791 Raptor phosphorylation site into the mTORC1 complex. We thank Greg Urquhart, Jessica Zhou, Rishika Navlani, and Thu Nguyen for technical help. This work was supported by grants from National Institutes of Health (R01GM51586 and R01CA108941 to KLG, T32CA121938 and R01GM129097-01 to JLJ); The Hart-well Foundation to JLJ; Cancer Prevention Research Institute of Texas (CPRIT) Scholar Recruitment of First-Time, Tenure-Track Faculty Member (RR150032), Cancer Prevention Research Institute of Texas (CPRIT) High-Impact/High-Risk Research Award (RP160713), The Welch Foundation (I-1927– 20170325), 2017 UT Southwestern President{\textquoteright}s Research Council Distinguished Researcher Award, and American Cancer Society Institutional Research Grant (ACS-IRG-17-174-13) to JLJ. CHM is supported by National Institutes of Health grant (T32GM008203) and AWH and VF is supported by National Institutes of Health grant (T32GM007752). Funding Information: The authors are grateful to their colleagues in the Guan and Jewell laboratory for critical comments and valuable discussions. We thank Yanhui Xu for incorporating the Ser 791 Raptor phosphorylation site into the mTORC1 complex. We thank Greg Urquhart, Jessica Zhou, Rishika Navlani, and Thu Nguyen for technical help. This work was supported by grants from National Institutes of Health (R01GM51586 and R01CA108941 to KLG, T32CA121938 and R01GM129097-01 to JLJ); The Hartwell Foundation to JLJ; Cancer Prevention Research Institute of Texas (CPRIT) Scholar Recruitment of First-Time, Tenure-Track Faculty Member (RR150032), Cancer Prevention Research Institute of Texas (CPRIT) High-Impact/High-Risk Research Award (RP160713), The Welch Foundation (I-1927?20170325), 2017 UT Southwestern President?s Research Council Distinguished Researcher Award, and American Cancer Society Institutional Research Grant (ACS-IRG-17-174-13) to JLJ. CHM is supported by National Institutes of Health grant (T32GM008203) and AWH and VF is supported by National Institutes of Health grant (T32GM007752). Publisher Copyright: {\textcopyright} Jewell et al.",
year = "2019",
month = may,
doi = "10.7554/eLife.43038",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}