Related Experiment Video

Updated: Sep 9, 2025

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

Published on: October 23, 2018

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Amino acid-dependent TSC2 dephosphorylation by lysosome-PP2A regulates mTORC1 signaling transduction

Takanori Nakamura1,2,3,4, Shigeyuki Nada5, Masaki Matsumoto6

  • 1Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan nakamura.takanori.cb@ehime-u.ac.jp.

Life Science Alliance
|September 2, 2025
PubMed

Insights

This study models the mammalian target of rapamycin complex 1 (mTORC1) pathway, revealing how amino acids and growth factors interact. It shows mTORC1 requires both signals for full activation, crucial for understanding metabolic diseases.

Area of Science:

  • Cellular signaling
  • Metabolic regulation
  • Systems biology

Background:

  • The mammalian target of rapamycin complex 1 (mTORC1) pathway integrates nutrient and growth factor signals to control cell growth and metabolism.
  • Dysregulation of mTORC1 is implicated in metabolic diseases like cancer and diabetes.
  • The precise mechanisms of signal integration and crosstalk within the mTORC1 pathway are not fully understood.

Purpose of the Study:

  • To elucidate the complex signaling dynamics of mTORC1 regulation.
  • To investigate the interplay between amino acid (AA) and growth factor (GF) sensing axes.
  • To develop an integrated mathematical model of temporal mTORC1 regulation.

Main Methods:

  • Construction of an integrated mathematical model for temporal mTORC1 regulation.
  • Simulation of AA-sensing (Ragulator/LAMTOR-Rag) and GF-sensing (AKT-TSC1/2-Rheb) axes.
  • Integration of mathematical simulations with experimental data.

Main Results:

  • Observed robust AKT phosphorylation (P-T308/P-S473) upon insulin stimulation, independent of intracellular AA levels.
  • Demonstrated a significant decrease in AKT-mediated TSC2 phosphorylation (P-T1462) during AA deprivation.
  • Identified PP2A-mediated TSC2 dephosphorylation during AA removal, ensuring mTORC1 activation requires concurrent AA and GF sensing.

Conclusions:

  • Elucidated the intricate dynamics of mTORC1 signaling.
  • Revealed the critical interplay between AA and GF sensing for complete mTORC1 activation.
  • Provided insights into metabolic regulation and potential therapeutic targets for mTORC1-associated diseases.

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