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

Lookup NU author(s): Philip Hall, Dr Daryl Shanley



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 beta (CaMKK beta). 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 metadata

Author(s): Pezze PD, Ruf S, Sonntag AG, Langelaar-Makkinje M, Hall P, Heberle AM, Navas PR, van Eunen K, Tolle RC, Schwarz JJ, Wiese H, Warscheid B, Deitersen J, Stork B, Fassler E, Schauble S, Hahn U, Horvatovich P, Shanley DP, Thedieck K

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2016

Volume: 7

Online publication date: 21/11/2016

Acceptance date: 13/09/2016

Date deposited: 06/01/2017

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group


DOI: 10.1038/ncomms13254


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Funder referenceFunder name
AXA Research Fund
Rosalind-Franklin-Fellowship of the University of Groningen, NL
Ubbo Emmius Fund
Research Committee of the Medical Faculty of the Heinrich-Heine-University Dusseldorf
Stichting Michelle
01ZX1402BMBF e: Med-GlioPATH
031 5896ABMBF Gerontosys II-NephAge
031A426BBMBF e: Med-MAPTorNET
EXC 294 BIOSSExcellence Initiative of the German Federal and State Governments
FOR 1352Deutsche Forschungsgemeinschaft
LSHG-CT-2007-036894EC 6th FP NoE LifeSpan
SFB 1076CRC AquaDiva (DFG)
STO 864/3-1Deutsche Forschungsgemeinschaft
STO 864/4 1Deutsche Forschungsgemeinschaft
RTG 1104DFG Research Training Group
TRR 130Deutsche Forschungsgemeinschaft