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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 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.
Highlights
Amino acids are building blocks for proteins, and signalling molecules, with the mammalian target of rapamycin complex 1 acting as a key mediator
When testing models with two aa inputs, we found that the model assuming aa inputs on mammalian target of rapamycin complex 1 (mTORC1) and IRS reported an Akaike information criterion (AIC) of input at TSC1–TSC2-pT1462, p70-S6K-pT389 or PRAS40-pS183 B953, improving the model fit as compared to the model with did not improve by at least 1% (AIC41,401, red text in Table 1), one single aa input
We found that aa enhanced Unc-51-like kinase-1 (ULK1)-S757 phosphorylation, and this was insensitive to calmodulindependent protein kinase kinase b (CaMKKb) inhibition, again validating that mTORC1 activation by aa is insensitive to the CaMKKb-AMPK signalling axis
Summary
Amino acids (aa) are building blocks for proteins, and signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. 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. 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. The best characterized amino acids (aa) input to the mTOR signalling network is mediated via the Ragulator-Rag GTPase (Ras-related GTPase) complex that recruits mTORC1 to lysosomal membranes, where mTORC1 can be further activated by insulin[5,6]. MTORC1 and AMPK are often perceived as antagonists that suppress or induce autophagy under nutrient sufficiency or shortage, respectively[15] This notion is further strengthened by the fact that under conditions of low-energy (high AMP/ATP ratio) AMPK phosphorylates and activates TSC1–TSC2, thereby inhibiting mTORC1 (refs 5, 15). An activating role of AMPK during aa stimulation has so far to the best of our knowledge not been reported, and it remains open whether AMPK sustains autophagy during nutrient sufficiency
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