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; Kathrin Thedieck

doi:10.1038/ncomms13254

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

Nat Commun. 2016 Nov 21:7:13254. doi: 10.1038/ncomms13254.

Authors

Piero Dalle Pezze^{1

2

3}, Stefanie Ruf^{4

5

6}, Annika G Sonntag⁴, Miriam Langelaar-Makkinje⁶, Philip Hall^{1

2}, Alexander M Heberle⁶, Patricia Razquin Navas^{6

7}, Karen van Eunen⁶, Regine C Tölle⁴, Jennifer J Schwarz^{4

8

9}, Heike Wiese^{9

10}, Bettina Warscheid^{8

9

11}, Jana Deitersen¹², Björn Stork¹², Erik Fäßler¹³, Sascha Schäuble¹³, Udo Hahn¹³, Peter Horvatovich¹⁴, Daryl P Shanley^{1

2}, Kathrin Thedieck^{6

7}

Affiliations

¹ Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
² Centre for Integrated Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle upon Tyne NE4 5PL, UK.
³ Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
⁴ Department of Bioinformatics and Molecular Genetics (Faculty of Biology), Institute for Biology 3, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
⁵ Research Training Group (RTG) 1104, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
⁶ Department of Pediatrics, University of Groningen, University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands.
⁷ Department of Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.
⁸ Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany.
⁹ Department of Biochemistry and Functional Proteomics, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
¹⁰ Institute of Pharmacology and Toxicology, University of Ulm, 89081 Ulm, Germany.
¹¹ BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
¹² Institute of Molecular Medicine I, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
¹³ Jena University Language &Information Engineering (JULIE) Lab, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
¹⁴ Faculty of Mathematics and Natural Sciences, Department of Pharmacy, Analytical Biochemistry, University of Groningen, 9713 AV Groningen, The Netherlands.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / genetics
AMP-Activated Protein Kinases / metabolism*
Amino Acids / pharmacology*
Autophagy-Related Protein-1 Homolog / genetics
Autophagy-Related Protein-1 Homolog / metabolism
Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism
Cell Line
Gene Expression Regulation / drug effects
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Mechanistic Target of Rapamycin Complex 1 / genetics
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Mechanistic Target of Rapamycin Complex 2 / genetics
Mechanistic Target of Rapamycin Complex 2 / metabolism*
Models, Biological
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism*

Substances

Amino Acids
Intracellular Signaling Peptides and Proteins
MTOR protein, human
Autophagy-Related Protein-1 Homolog
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
ULK1 protein, human
Calcium-Calmodulin-Dependent Protein Kinase Kinase
AMP-Activated Protein Kinases