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

Dalle Pezze, Piero, Ruf, Stefanie, Sonntag, Annika G., Langelaar-Makkinje, Miriam, Hall, Philip, Heberle, Alexander M., Razquin Navas, Patricia, van Eunen, Karen, Tölle, Regine C., Schwarz, Jennifer J., Wiese, Heike, Warscheid, Bettina, Deitersen, Jana, Stork, Björn, Fäßler, Erik, Schäuble, Sascha, Hahn, Udo, Horvatovich, Peter, Shanley, Daryl P., Thedieck, Kathrin·2016·Nature Communications
DOI 10.1038/ncomms13254PMC PMC5121333
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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 Ca 2+/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.

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Metadata

Authors
Dalle Pezze, P., Ruf, S., Sonntag, A. G., Langelaar-Makkinje, M., Hall, P., Heberle, A. M., Razquin Navas, P., van Eunen, K., Tölle, R. C., Schwarz, J. J., Wiese, H., Warscheid, B., Deitersen, J., Stork, B., Fäßler, E., Schäuble, S., Hahn, U., Horvatovich, P., Shanley, D. P., & Thedieck, K.
ORCID
Wiese, Heike
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-11-21
Volume
7
Issue
1
ISSN
2041-1723
DOI
10.1038/ncomms13254
PMC
PMC5121333
Cited by
148
References
16
Language
en
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