A systems study reveals concurrent activation of AMPK and mTOR by amino acidsPezze, P. D., Ruf, S., Sonntag, A. G., Langelaar-Makkinje, M., Hall, P., Heberle, A. M., Navas, P. R., 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., 21-Nov-2016, In : Nature Communications. 7, p. 1-19 19 p., 13254.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||19|
|Publication status||Published - 21-Nov-2016|
- INSULIN-RECEPTOR SUBSTRATE-1, MAMMALIAN TARGET, PROTEIN-KINASE, PHOSPHOINOSITIDE 3-KINASE, LKB1-INDEPENDENT MANNER, CA2+-SENSING RECEPTOR, BETA-CELLS, IN-VITRO, PHOSPHORYLATION, RAPAMYCIN