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

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.

System-wide Benefits of Intermeal Fasting by Autophagy

“…S2E, S2F). Indeed, recent work has shown that availability of nutrients concurrently activates AMPK and mTOR (Dalle Pezze et al, 2016). Since mTOR suppresses autophagy, and because autophagy is active between 7–11am in ITAD mice (Fig.…”

Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

“…Knowing that AMPK can induce autophagy in mTORC1‐independent pathways27, 28, 29 and that mTORC1 is a negative regulator of autophagy,29 the obtained data suggest a dissociative AMPK‐mTORC1 axis with AMPK sustaining autophagy in KG‐1 cells. In fact, the reports of Sujobert et al and Pezze et al also showed a direct induction of autophagy by AMPK even in the presence of mTORC1 activation 21, 53…”

“…A similar contradictory metabolic scenario was already reported in myoblasts in response to amino acids. 53 The authors proposed that the concurrent activation of AMPK and mTORC1 is implicated in the maintenance of protein homoeostasis and on the fuel of metabolites for biosynthetic processes. 53 The relevance of amino acid signalling and mTORC1 PI3K/AKT-independent activation in the context of AML remains to be explored.…”

“…53 The authors proposed that the concurrent activation of AMPK and mTORC1 is implicated in the maintenance of protein homoeostasis and on the fuel of metabolites for biosynthetic processes. 53 The relevance of amino acid signalling and mTORC1 PI3K/AKT-independent activation in the context of AML remains to be explored. To the best of our knowledge, this is the first time that the mechanism of AMPK and mTORC1 constitutive co-activation is described in KG-1 cells, which deserves future exploration in the regulation of AML cells metabolism.…”

Roles of Dietary Amino Acids and Their Metabolites in Pathogenesis of Inflammatory Bowel Disease

“…In T cells, AAs work as signaling molecules with mTORC1 acting as a key mediator. AAs regulate the intracellular localization and activation of mTORC1 by the lysosome-based signaling system composed of Ras-related GTPases (Rags) and Regulator v-ATPase, GAP activity towards Rags, and folliculin complexes [59, 60]. AAs could protect whole body and muscle from protein loss via mTOR activation and downstream signaling to protein synthesis through mTORC1 in the acute phase of inflammation [61, 62].…”