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

Carroll, Bernadette, Maetzel, Dorothea, Maddocks, Oliver DK, Otten, Gisela, Ratcliff, Matthew, Smith, Graham R, Dunlop, Elaine A, Passos, João F, Davies, Owen R, Jaenisch, Rudolf, Tee, Andrew R, Sarkar, Sovan, Korolchuk, Viktor I·2016·eLife
DOI 10.7554/elife.11058PMC PMC4764560
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Abstract

The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently 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 cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. 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 signaling.

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Metadata

Authors
Carroll, B., Maetzel, D., Maddocks, O. D., Otten, G., Ratcliff, M., Smith, G. R., Dunlop, E. A., Passos, J. F., Davies, O. R., Jaenisch, R., Tee, A. R., Sarkar, S., & Korolchuk, V. I.
Affiliations
  • Institute for Cell and Molecular Biosciences, Newcastle University
  • Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology
  • The Beatson Institute for Cancer Research
  • Institute of Cancer and Genetics, Cardiff University
  • Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham
ORCID
Dunlop, Elaine A
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2016-01-07
Volume
5
ISSN
2050-084X
DOI
10.7554/elife.11058
PMC
PMC4764560
Cited by
183
References
16
Language
en
Update notices
Licence
Funders
  • Biotechnology and Biological Sciences Research Council
  • Medical Research Council
  • British Skin Foundation
  • National Institute for Health Research

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