A systems study reveals concurrent activation of AMPK and mTOR by amino acids

Piero Dalle Pezze, Stefanie Ruf, Annika G. Sonntag, Miriam Langelaar-Makkinje, Philip Hall, Alexander M. Heberle, Patricia Razquin Navas, Karen van Eunen, Regine C. Tölle, Jennifer J. Schwarz, Heike Wiese, Bettina Warscheid, Jana Deitersen, Björn Stork, Erik Fäßler, Sascha Schäuble, Udo Hahn, Peter Horvatovich, Daryl P. Shanley () and Kathrin Thedieck ()
Additional contact information
Piero Dalle Pezze: Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University
Stefanie Ruf: Institute for Biology 3, Albert-Ludwigs-University Freiburg
Annika G. Sonntag: Institute for Biology 3, Albert-Ludwigs-University Freiburg
Miriam Langelaar-Makkinje: University of Groningen, University Medical Center Groningen (UMCG)
Philip Hall: Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University
Alexander M. Heberle: University of Groningen, University Medical Center Groningen (UMCG)
Patricia Razquin Navas: University of Groningen, University Medical Center Groningen (UMCG)
Karen van Eunen: University of Groningen, University Medical Center Groningen (UMCG)
Regine C. Tölle: Institute for Biology 3, Albert-Ludwigs-University Freiburg
Jennifer J. Schwarz: Institute for Biology 3, Albert-Ludwigs-University Freiburg
Heike Wiese: Faculty of Biology, University of Freiburg
Bettina Warscheid: Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg
Jana Deitersen: Institute of Molecular Medicine I, Medical Faculty, Heinrich-Heine-University
Björn Stork: Institute of Molecular Medicine I, Medical Faculty, Heinrich-Heine-University
Erik Fäßler: Jena University Language & Information Engineering (JULIE) Lab, Friedrich-Schiller-University Jena
Sascha Schäuble: Jena University Language & Information Engineering (JULIE) Lab, Friedrich-Schiller-University Jena
Udo Hahn: Jena University Language & Information Engineering (JULIE) Lab, Friedrich-Schiller-University Jena
Peter Horvatovich: Faculty of Mathematics and Natural Sciences, Analytical Biochemistry, University of Groningen
Daryl P. Shanley: Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University
Kathrin Thedieck: University of Groningen, University Medical Center Groningen (UMCG)

Nature Communications, 2016, vol. 7, issue 1, 1-19

Abstract: Abstract Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational–experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) are acutely activated by aa-readdition in an mTORC1-independent manner. AMPK activation by aa is mediated by Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). In response, AMPK impinges on the autophagy regulators Unc-51-like kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an mTORC1 antagonist that is activated by starvation. We find that aa acutely activate AMPK concurrently with mTOR. We show that AMPK under aa sufficiency acts to sustain autophagy. This may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes.

Date: 2016
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DOI: 10.1038/ncomms13254

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