GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor

Jenna L Jewell, Vivian Fu, Audrey W. Hong, Fa Xing Yu, Delong Meng, Chase H. Melick, Huanyu Wang, Wai Ling Macrina Lam, Hai Xin Yuan, Susan S. Taylor, Kun Liang Guan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - May 21 2019

Fingerprint

Raptors
Phosphorylation
G-Protein-Coupled Receptors
Cyclic AMP-Dependent Protein Kinases
mechanistic target of rapamycin complex 1
Autophagy
Cell growth
Metabolism
Adenosine
Cues
Intercellular Signaling Peptides and Proteins
Proteins
Chemical activation
Cells

Keywords

  • cancer biology
  • cancer cells
  • cell biology
  • cells
  • human
  • mouse

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Jewell, J. L., Fu, V., Hong, A. W., Yu, F. X., Meng, D., Melick, C. H., ... Guan, K. L. (2019). GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor. eLife, 8. https://doi.org/10.7554/eLife.43038

GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor. / Jewell, Jenna L; Fu, Vivian; Hong, Audrey W.; Yu, Fa Xing; Meng, Delong; Melick, Chase H.; Wang, Huanyu; Lam, Wai Ling Macrina; Yuan, Hai Xin; Taylor, Susan S.; Guan, Kun Liang.

In: eLife, Vol. 8, 21.05.2019.

Research output: Contribution to journalArticle

Jewell, JL, Fu, V, Hong, AW, Yu, FX, Meng, D, Melick, CH, Wang, H, Lam, WLM, Yuan, HX, Taylor, SS & Guan, KL 2019, 'GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor', eLife, vol. 8. https://doi.org/10.7554/eLife.43038
Jewell, Jenna L ; Fu, Vivian ; Hong, Audrey W. ; Yu, Fa Xing ; Meng, Delong ; Melick, Chase H. ; Wang, Huanyu ; Lam, Wai Ling Macrina ; Yuan, Hai Xin ; Taylor, Susan S. ; Guan, Kun Liang. / GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor. In: eLife. 2019 ; Vol. 8.
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