Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity

  1. Bernadette Carroll
  2. Dorothea Maetzel
  3. Oliver DK Maddocks
  4. Gisela Otten
  5. Matthew Ratcliff
  6. Graham R Smith
  7. Elaine A Dunlop
  8. João F Passos
  9. Owen R Davies
  10. Rudolf Jaenisch
  11. Andrew R Tee
  12. Sovan Sarkar
  13. Viktor I Korolchuk  Is a corresponding author
  1. Newcastle University, United Kingdom
  2. Massachusetts Institute of Technology, United States
  3. The Beatson Institute for Cancer Research, United Kingdom
  4. Cardiff University, United Kingdom
  5. University of Birmingham, United Kingdom

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) is the key signalling hub that regulates cellular protein homeostasis, growth and proliferation. Herein, we demonstrate that amino acid arginine acts independent of its metabolism to allow maximal activation of mTORC1 by growth factors, via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signalling.

Article and author information

Author details

  1. Bernadette Carroll

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Dorothea Maetzel

    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Oliver DK Maddocks

    The Beatson Institute for Cancer Research, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Gisela Otten

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Matthew Ratcliff

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Graham R Smith

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Elaine A Dunlop

    Institute of Cancer and Genetics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. João F Passos

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Owen R Davies

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Rudolf Jaenisch

    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Andrew R Tee

    Institute of Cancer and Genetics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Sovan Sarkar

    Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Viktor I Korolchuk

    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom
    For correspondence
    viktor.korolchuk@ncl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Noboru Mizushima, The University of Tokyo, Japan

Version history

  1. Received: August 21, 2015
  2. Accepted: December 30, 2015
  3. Accepted Manuscript published: January 7, 2016 (version 1)
  4. Version of Record published: February 10, 2016 (version 2)
  5. Version of Record updated: December 16, 2020 (version 3)

Copyright

© 2016, Carroll et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Bernadette Carroll
  2. Dorothea Maetzel
  3. Oliver DK Maddocks
  4. Gisela Otten
  5. Matthew Ratcliff
  6. Graham R Smith
  7. Elaine A Dunlop
  8. João F Passos
  9. Owen R Davies
  10. Rudolf Jaenisch
  11. Andrew R Tee
  12. Sovan Sarkar
  13. Viktor I Korolchuk
(2016)
Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity
eLife 5:e11058.
https://doi.org/10.7554/eLife.11058

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https://doi.org/10.7554/eLife.11058

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