The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR

Molecular and Cell Biology Laboratory, Dulbecco Center for Cancer Research, University of California at San Diego, La Jolla, USA.
Autophagy (Impact Factor: 11.75). 06/2011; 7(6):643-4. DOI: 10.4161/auto.7.6.15123
Source: PubMed


The serine/threonine kinase ULK1 is a mammalian homolog of Atg1, part of the Atg1 kinase complex, which is the most upstream component of the core autophagy machinery conserved from yeast to mammals. In budding yeast, activity of the Atg1 kinase complex is inhibited by TORC1 (target of rapamycin complex 1), but how the counterpart ULK1 complex in mammalian cells is regulated has been unknown. Our laboratories recently discovered that AMPK associates with, and directly phosphorylates, ULK1 on several sites and this modification is required for ULK1 activation after glucose deprivation. In contrast, when nutrients are plentiful, the mTORC1 complex phosphorylates ULK1, preventing its association and activation by AMPK. These studies have revealed a molecular mechanism of ULK1 regulation by nutrient signals via the actions of AMPK and mTORC1.

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    • "Adjuvant potential of AMPK activators and nicotinamide riboside A feasible alternative strategy for boosting cerebral autophagy is to administer brain-permeable activators of AMP-activated kinase (AMPK); this enzyme activates autophagy by inhibiting mTORC1 activation while conferring an activating phosphorylation on ULK1 [87] [111] [112]. The currently available agents metformin and berberine, both employed in the management of diabetes, appear to have potential in this regard [113] [114] [115] [116] [117] [118]; resveratrol, which likewise activates AMPK in rodents, has been shown to increase cerebral autophagy in mice, thereby suppress extracellular accumulation of amyloid-beta, and also is beneficial in a rotenone-induced Parkinsonian syndrome [94] [101] [119]. "
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    ABSTRACT: Ketogenic diets are markedly neuroprotective, but the basis of this effect is still poorly understood. Recent studies demonstrate that ketone bodies increase neuronal levels of hypoxia-inducible factor-1α (HIF-1α), possibly owing to succinate-mediated inhibition of prolyl hydroxylase activity. Moreover, there is reason to suspect that ketones can activate Sirt1 in neurons, in part by increasing cytoplasmic and nuclear levels of Sirt1's obligate cofactor NAD(+). Another recent study has observed reduced activity of mTORC1 in the hippocampus of rats fed a ketogenic diet - an effect plausibly attributable to Sirt1 activation. Increased activities of HIF-1 and Sirt1, and a decrease in mTORC1 activity, could be expected to collaborate in the induction of neuronal macroautophagy. Considerable evidence points to moderate up-regulation of neuronal autophagy as a rational strategy for prevention of neurodegenerative disorders; elimination of damaged mitochondria that overproduce superoxide, as well as clearance of protein aggregates that mediate neurodegeneration, presumably contribute to this protection. Hence, autophagy may mediate some of the neuroprotective benefits of ketogenic diets. Brain-permeable agents which activate AMP-activated kinase, such as metformin and berberine, as well as the Sirt1 activator nicotinamide riboside, can also boost neuronal autophagy, and may have potential for amplifying the impact of ketogenesis on this process. Since it might not be practical for most people to adhere to ketogenic diets continuously, alternative strategies are needed to harness the brain-protective potential of ketone bodies. These may include ingestion of medium-chain triglycerides or coconut oil, intermittent ketogenic dieting, and possibly the use of supplements that promote hepatic ketogenesis - notably carnitine and hydroxycitrate - in conjunction with dietary regimens characterized by long daily episodes of fasting or carbohydrate avoidance.
    Medical Hypotheses 08/2015; DOI:10.1016/j.mehy.2015.08.002 · 1.07 Impact Factor
    • "While AMPK activates ULK1 by phosphorylating at least four sites (Egan et al., 2011a), mTORC1 inactivates ULK1 by phosphorylating a single site, Ser757 (Kang et al., 2013; Kim et al., 2011). As several physiological stresses result in both AMPK activation and mTOR inhibition, ULK1 activation proceeds through positive signals from AMPK and loss of inhibitory signals from mTORC1 (Egan et al., 2011a). It is notable, however, that mTORC1 is inactivated by many stresses beyond just those affecting AMPK, and the data to date suggest that pharmacological suppression of mTORC1 is sufficient to induce ULK1 kinase activity (Russell et al., 2013). "
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    ABSTRACT: Many tumors become addicted to autophagy for survival, suggesting inhibition of autophagy as a potential broadly applicable cancer therapy. ULK1/Atg1 is the only serine/threonine kinase in the core autophagy pathway and thus represents an excellent drug target. Despite recent advances in the understanding of ULK1 activation by nutrient deprivation, how ULK1 promotes autophagy remains poorly understood. Here, we screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered 15 phosphorylation sites in core autophagy proteins that were verified as in vivo ULK1 targets. We utilized these ULK1 substrates to perform a cell-based screen to identify and characterize a potent ULK1 small molecule inhibitor. The compound SBI-0206965 is a highly selective ULK1 kinase inhibitor in vitro and suppressed ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. SBI-0206965 greatly synergized with mechanistic target of rapamycin (mTOR) inhibitors to kill tumor cells, providing a strong rationale for their combined use in the clinic. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 06/2015; 59(2). DOI:10.1016/j.molcel.2015.05.031 · 14.02 Impact Factor
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    • "j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t response to nutrient depletion leads to ULK1 activation and autophagy induction [17] [18] [19] [20]. Therefore, since the Rottlerin uncoupling effects have been documented in different cancer cells [21] [22] [23], we hypothesized that AMPK could be the Rottlerin target responsible for MCF-7 autophagic death. "
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    ABSTRACT: We recently found that Rottlerin not only inhibits proliferation but also causes Bcl-2- and Beclin 1-independent autophagic death in apoptosis-resistant breast adenocarcinoma MCF-7 cells. Having excluded a role for canonical signaling pathways, the current study was aimed to investigate the contribution of the AMPK/mTOR axis in autophagy induction and to search for the upstream signaling molecules potentially targeted by Rottlerin. Using several enzyme inhibitors, Western blotting analysis, mTOR siRNA and pull down assay, we demonstrate that the Rottlerin-triggered autophagy is mediated by inhibition of mTORC1 activity through a novel AMPK and mTORC1 phosphorylation-independent mechanism, likely mediated by the direct interaction between Rottlerin and mTOR. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer Letters 02/2015; 360(1). DOI:10.1016/j.canlet.2015.01.040 · 5.62 Impact Factor
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