title: A systems study reveals concurrent activation of AMPK and mTOR by amino acids.
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.
authors.affiliation: Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University, Newcastle upon Tyne NE2 4HH, UK.|Centre for Integrated Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle upon Tyne NE4 5PL, UK.|Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Piero
authors.initials: P
authors.lastname: Dalle Pezze
authors.affiliation: Department of Bioinformatics and Molecular Genetics (Faculty of Biology), Institute for Biology 3, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.|Research Training Group (RTG) 1104, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.|Department of Pediatrics, University of Groningen, University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ruf
authors.affiliation: Department of Bioinformatics and Molecular Genetics (Faculty of Biology), Institute for Biology 3, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
authors.forename: Annika G
authors.initials: AG
authors.lastname: Sonntag
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Langelaar-Makkinje
authors.affiliation: Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University, Newcastle upon Tyne NE2 4HH, UK.|Centre for Integrated Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle upon Tyne NE4 5PL, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Hall
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Heberle
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands.|Department of Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Razquin Navas
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: van Eunen
authors.affiliation: Department of Bioinformatics and Molecular Genetics (Faculty of Biology), Institute for Biology 3, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
authors.forename: Regine C
authors.initials: RC
authors.lastname: Tölle
authors.affiliation: Department of Bioinformatics and Molecular Genetics (Faculty of Biology), Institute for Biology 3, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.|Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany.|Department of Biochemistry and Functional Proteomics, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Schwarz
authors.affiliation: Department of Biochemistry and Functional Proteomics, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.|Institute of Pharmacology and Toxicology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Heike
authors.identifier: 0000-0002-8941-3762
authors.initials: H
authors.lastname: Wiese
authors.affiliation: Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany.|Department of Biochemistry and Functional Proteomics, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Warscheid
authors.affiliation: Institute of Molecular Medicine I, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Deitersen
authors.affiliation: Institute of Molecular Medicine I, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Stork
authors.affiliation: Jena University Language &Information Engineering (JULIE) Lab, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Fäßler
authors.affiliation: Jena University Language &Information Engineering (JULIE) Lab, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Schäuble
authors.affiliation: Jena University Language &Information Engineering (JULIE) Lab, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Hahn
authors.affiliation: Faculty of Mathematics and Natural Sciences, Department of Pharmacy, Analytical Biochemistry, University of Groningen, 9713 AV Groningen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Horvatovich
authors.affiliation: Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University, Newcastle upon Tyne NE2 4HH, UK.|Centre for Integrated Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle upon Tyne NE4 5PL, UK.
authors.forename: Daryl P
authors.initials: DP
authors.lastname: Shanley
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands.|Department of Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Thedieck
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000494:pharmacology*; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000235:genetics / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D055372:AMP-Activated Protein Kinases; D000596:Amino Acids; D000071189:Autophagy-Related Protein-1 Homolog; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D047908:Intracellular Signaling Peptides and Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484754:ULK1 protein, human