mTORC1 activity is supported by spatial association with focal adhesions

The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the...

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Published inThe Journal of cell biology Vol. 220; no. 5; p. 1
Main Authors Rabanal-Ruiz, Yoana, Byron, Adam, Wirth, Alexander, Madsen, Ralitsa, Sedlackova, Lucia, Hewitt, Graeme, Nelson, Glyn, Stingele, Julian, Wills, Jimi C, Zhang, Tong, Zeug, André, Fässler, Reinhard, Vanhaesebroeck, Bart, Maddocks, Oliver D K, Ponimaskin, Evgeni, Carroll, Bernadette, Korolchuk, Viktor I
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 03.05.2021
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Abstract The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.
AbstractList The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.
Rabanal-Ruiz and Byron et al. present a novel mechanism of nutrient signaling that identifies FAs as key cellular hubs that coordinate growth factor signaling and amino acid input into the cell and are required for efficient downstream activation of mTORC1. The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.
Author Vanhaesebroeck, Bart
Fässler, Reinhard
Rabanal-Ruiz, Yoana
Wills, Jimi C
Maddocks, Oliver D K
Madsen, Ralitsa
Zeug, André
Carroll, Bernadette
Sedlackova, Lucia
Byron, Adam
Nelson, Glyn
Stingele, Julian
Korolchuk, Viktor I
Ponimaskin, Evgeni
Zhang, Tong
Wirth, Alexander
Hewitt, Graeme
AuthorAffiliation 4 UCL Cancer Institute, University College London, London, UK
10 Institute of Neuroscience, Lobachevsky State University of Nizhni Novgorod, Nizhny Novgorod, Russia
1 Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
9 Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany
11 School of Biochemistry, University of Bristol, Bristol, UK
2 Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
6 Gene Center, Ludwig Maximilians University Munich, Munich, Germany
8 Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
5 DSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK
7 Department of Biochemistry, Ludwig Maximilians University Munich, Munich, Germany
3 Cellular Neurophysiology, Hannover Medical School, Hannover, Germany
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Y. Rabanal-Ruiz’s present address is Department of Medical Sciences, Faculty of Medicine, University of Castilla-la Mancha, Ciudad Real, Spain.
Y. Rabanal-Ruiz and A. Byron contributed equally to this paper.
Lucia Sedlackova’s present address is Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.
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Snippet The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino...
Rabanal-Ruiz and Byron et al. present a novel mechanism of nutrient signaling that identifies FAs as key cellular hubs that coordinate growth factor signaling...
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SubjectTerms Amino acids
Amino Acids - metabolism
Animals
Cell Line
Cell Line, Tumor
Cell Membrane - metabolism
Cell Signaling
Focal Adhesions - metabolism
Growth factors
HeLa Cells
Humans
Intracellular Membranes - metabolism
Localization
Lysosomes
Lysosomes - metabolism
Mechanistic Target of Rapamycin Complex 1 - metabolism
Membranes
Metabolism
Mice
Rapamycin
Signal Transduction - physiology
TOR protein
Translocation
Title mTORC1 activity is supported by spatial association with focal adhesions
URI https://www.ncbi.nlm.nih.gov/pubmed/33635313
https://www.proquest.com/docview/2530510059
https://search.proquest.com/docview/2494301887
https://pubmed.ncbi.nlm.nih.gov/PMC7923692
Volume 220
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