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The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling

Two structurally and functionally distinct mammalian TOR complexes control cell growth and metabolism in physiological and pathological contexts including cancer. Upregulated glutaminolysis is part of the metabolic reprogramming occurring in cancer, providing fuels for growth but also liberating amm...

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Autores principales: Merhi, Ahmad, Delrée, Paul, Marini, Anna Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355986/
https://www.ncbi.nlm.nih.gov/pubmed/28303961
http://dx.doi.org/10.1038/srep44602
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author Merhi, Ahmad
Delrée, Paul
Marini, Anna Maria
author_facet Merhi, Ahmad
Delrée, Paul
Marini, Anna Maria
author_sort Merhi, Ahmad
collection PubMed
description Two structurally and functionally distinct mammalian TOR complexes control cell growth and metabolism in physiological and pathological contexts including cancer. Upregulated glutaminolysis is part of the metabolic reprogramming occurring in cancer, providing fuels for growth but also liberating ammonium, a potent neurotoxic waste product. Here, we identify ammonium as a novel dose-dependent signal mediating rapid mTORC2 activation and further regulating mTORC1. We show that ammonium induces rapid RICTOR-dependent phosphorylation of AKT-S473, a process requiring the PI3K pathway and further involving the Src-family kinase YES1, the FAK kinase and the ITGβ1 integrin. Release of calcium from the endoplasmic reticulum store triggers rapid mTORC2 activation, similar to ammonium-induced activation, the latter being conversely prevented by calcium chelation.Moreover, in analogy to growth factors, ammonium triggers the AKT-dependent phosphoinhibition of the TSC complex and of PRAS40, two negative regulators of mTORC1. Consistent with mTORC1 stimulation, ammonium induces the inhibitory phosphorylation of 4EBP1, a negative regulator of protein biogenesis. Ammonium however dually impacts on the phosphorylation of p70S6K1 triggering a transient AKT-independent decrease in the phosphorylation of this second mTORC1 readout. Finally, we reveal ammonium as a dose-dependent stimulator of proliferation. This study underscores an mTORC2 and mTORC1 response to the so-called ammonium waste.
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spelling pubmed-53559862017-03-22 The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling Merhi, Ahmad Delrée, Paul Marini, Anna Maria Sci Rep Article Two structurally and functionally distinct mammalian TOR complexes control cell growth and metabolism in physiological and pathological contexts including cancer. Upregulated glutaminolysis is part of the metabolic reprogramming occurring in cancer, providing fuels for growth but also liberating ammonium, a potent neurotoxic waste product. Here, we identify ammonium as a novel dose-dependent signal mediating rapid mTORC2 activation and further regulating mTORC1. We show that ammonium induces rapid RICTOR-dependent phosphorylation of AKT-S473, a process requiring the PI3K pathway and further involving the Src-family kinase YES1, the FAK kinase and the ITGβ1 integrin. Release of calcium from the endoplasmic reticulum store triggers rapid mTORC2 activation, similar to ammonium-induced activation, the latter being conversely prevented by calcium chelation.Moreover, in analogy to growth factors, ammonium triggers the AKT-dependent phosphoinhibition of the TSC complex and of PRAS40, two negative regulators of mTORC1. Consistent with mTORC1 stimulation, ammonium induces the inhibitory phosphorylation of 4EBP1, a negative regulator of protein biogenesis. Ammonium however dually impacts on the phosphorylation of p70S6K1 triggering a transient AKT-independent decrease in the phosphorylation of this second mTORC1 readout. Finally, we reveal ammonium as a dose-dependent stimulator of proliferation. This study underscores an mTORC2 and mTORC1 response to the so-called ammonium waste. Nature Publishing Group 2017-03-17 /pmc/articles/PMC5355986/ /pubmed/28303961 http://dx.doi.org/10.1038/srep44602 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Merhi, Ahmad
Delrée, Paul
Marini, Anna Maria
The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling
title The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling
title_full The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling
title_fullStr The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling
title_full_unstemmed The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling
title_short The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling
title_sort metabolic waste ammonium regulates mtorc2 and mtorc1 signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355986/
https://www.ncbi.nlm.nih.gov/pubmed/28303961
http://dx.doi.org/10.1038/srep44602
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