GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor.

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

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.

Highlights

Cells sense their environment and respond by coordinating anabolic and catabolic processes to control cell growth, metabolism, and autophagy
Despite extensive research mapping signaling cascades that activate mammalian target of rapamycin (mTOR) complex 1 (mTORC1) like amino acids and growth factors, less is known about signals that can directly inhibit mTORC1
By performing a small G-protein coupled receptors (GPCRs) screen, we found that overexpression of GPCRs coupled to Gas proteins in human embryonic kidney cells (HEK293A) potently inhibited mTORC1 activity (Figure 1A)

Summary

Introduction

Cells sense their environment and respond by coordinating anabolic and catabolic processes to control cell growth, metabolism, and autophagy. Sufficient nutrients fuel anabolism such as protein synthesis, whereas nutrient deficiency results in catabolism like autophagy. When this sensing mechanism is lost, the end result can be unfavorable, often leading to human disease. The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr kinase that is a key component of a complex referred to as mTOR complex 1 (mTORC1), and is essential in cell growth regulation (Jewell et al, 2013a; Zoncu et al, 2011a; Gomes and Blenis, 2015). Elevated mTORC1 activity is typically seen in many human diseases including cancer, obesity, type two diabetes, neurodegeneration, and metabolic disorders. Because high mTORC1 activation is commonly seen in human disease, therapeutics like rapamycin and rapamycin

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