Journal Article

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

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

2016

Overview

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. mTORC1 is known to mediate the signalling activity of amino acids. Here, the authors combine modelling with experiments and find that amino acids acutely stimulate mTORC2, IRS/PI3K and AMPK, independently of mTORC1. AMPK activation through CaMKKβ sustains autophagy under non-starvation conditions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/114/2391 / 631/80/86 / 96/95 / Amino acids / Amino Acids - pharmacology / AMP-Activated Protein Kinases - genetics / AMP-Activated Protein Kinases - metabolism / Autophagy / Autophagy-Related Protein-1 Homolog - genetics / Autophagy-Related Protein-1 Homolog - metabolism / Biochemistry / Biology / Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism / Cell Line / Data mining / Gene Expression Regulation - drug effects / Humanities and Social Sciences / Humans / Insulin / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / 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 / Metabolites / Models, Biological / multidisciplinary / Phosphatidylinositol 3-Kinases - genetics / Phosphatidylinositol 3-Kinases - metabolism / Proteins / Proteomics / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Science / TOR Serine-Threonine Kinases - genetics / TOR Serine-Threonine Kinases - metabolism