Related Experiment Video

Updated: Aug 21, 2026

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
08:04

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method

Published on: October 23, 2018

Substrate-specific regulation of the mTORC1 pathway by G protein-coupled receptors

Samuel J Atkinson1, Florentina Negoita2, Yuichiro Ioi3

  • 1Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K.

The Biochemical Journal
|August 20, 2026
PubMed

Insights

Mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling selectivity allows distinct regulation of cell growth and metabolism. G protein-coupled receptors (GPCRs) differentially control canonical and non-canonical mTORC1 substrates.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Metabolic Regulation

Background:

  • The mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway is a central regulator of cell growth, metabolism, and protein synthesis.
  • mTORC1 integrates diverse extracellular and intracellular signals to control cellular processes through phosphorylation of numerous substrates.
  • Evidence suggests mTORC1 exhibits signaling selectivity, differentially regulating substrates and downstream pathways in response to specific cues.

Purpose of the Study:

  • To investigate the regulation of mTORC1 by G protein-coupled receptors (GPCRs) with a focus on signaling selectivity.
  • To determine how GPCRs differentially modulate phosphorylation of canonical mTORC1 substrates (S6K1, 4EBP1) versus non-canonical substrates (TFEB).
  • To elucidate the functional consequences of differential mTORC1 substrate regulation by specific GPCRs on cellular processes like protein synthesis and lysosome biogenesis.

Main Methods:

  • Studied mTORC1 regulation by GPCRs, specifically the muscarinic acetylcholine receptor M5 (M5R).
  • Monitored phosphorylation levels of canonical mTORC1 substrates (S6K1, 4EBP1) and the non-canonical substrate transcription factor EB (TFEB).
  • Assessed the impact of M5R activation on protein synthesis and lysosome biogenesis.

Main Results:

  • GPCRs, including M5R, differentially regulate mTORC1 substrates.
  • M5R activation promoted phosphorylation of S6K1 and 4EBP1, indicating stimulation of protein synthesis.
  • M5R activation triggered TFEB dephosphorylation, suggesting independent regulation of lysosome biogenesis.
  • M5R stimulated protein synthesis without inhibiting lysosome biogenesis, demonstrating separate regulation of anabolic and catabolic processes.

Conclusions:

  • mTORC1 exhibits substrate-specific signaling in response to GPCR activation.
  • The M5R receptor can independently regulate anabolic (protein synthesis) and catabolic (lysosome biogenesis) processes via differential mTORC1 substrate control.
  • Evaluating GPCR ligands targeting the mTORC1 pathway requires concurrent monitoring of individual substrates for therapeutic considerations.
Keywords:
G protein-coupled receptor (GPCR)mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1)muscarinic acetylcholine receptor M5 (M5R)

More Related Videos

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

Identification of Kinase-substrate Pairs Using High Throughput Screening11:13

Identification of Kinase-substrate Pairs Using High Throughput Screening

Published on: August 29, 2015

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...