The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs

Dite, Toby A.; Ling, Naomi X.Y.; Scott, John W.; Hoque, Ashfaqul; Galić, Sandra; Parker, Benjamin L.; Ngoei, Kevin R.W.; Langendorf, Christopher G.; O’Brien, Matthew T.; Kundu, Mondira; Viollet, Benoı̂t; Steinberg, Gregory R.; Sakamoto, Kei; Kemp, Bruce E.; Oakhill, Jonathan S.

doi:10.1038/s41467-017-00628-y

Cited by 69 publications

(82 citation statements)

References 59 publications

(94 reference statements)

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“…Nonetheless, the dramatic increase in binding affinity for ADaM site ligands following phosphorylation of Ser108 in β1 raises the possibility that modulation of Ser108 phosphorylation could provide a potential strategy for targeting drugs to β1-containing AMPK complexes. The recent finding that ULK1 phosphorylates Ser108 in β1 under conditions that favour an increase in the AMP/ADP:ATP ratio provides a potential way to exploit this possibility 177 . By increasing Ser108 phosphorylation, through ULK1, it might be possible to increase the potency of AMPK β1 activation.…”

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confidence: 99%

AMP-activated protein kinase: the current landscape for drug development

Steinberg

Carling

2019

Nat Rev Drug Discov

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464

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Since the discovery of AMP-activated protein kinase (AMPK) as a central regulator of energy homeostasis, many exciting insights into its structure, regulation and physiological roles have been revealed. While exercise, caloric restriction, metformin and many natural products increase AMPK activity and exert a multitude of health benefits, developing direct activators of AMPK to elucidate the role of AMPK in these beneficial effects has been challenging. However, in recent years, direct AMPK activators have been identified and tested in preclinical models, and a small number have entered clinical trials. Despite these advances, which disease(s) represent the best indications for therapeutic AMPK activation and the long-term safety of such approaches remain to be established. Commented [WS2]: Au: "The optimal consensus motif of AMPK substrates has been established (BOX 3)" OK?

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Section: ) (Table 1)mentioning

confidence: 99%

AMP-activated protein kinase: the current landscape for drug development

Steinberg

Carling

2019

Nat Rev Drug Discov

Self Cite

464

405

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“…Tumor cells can reuse proteins and damaged organelles through autophagy, and therefore survive despite drug treatment. Indeed, here, inhibiting autophagy can promote the death of tumor cells [21].…”

Section: Introductionmentioning

confidence: 99%

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Liu

Liao

et al. 2020

Cancers

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The difficulty of early diagnosis and the development of drug resistance are two major barriers to the successful treatment of cancer. Autophagy plays a crucial role in several cellular functions, and its dysregulation is associated with both tumorigenesis and drug resistance. Unc-51-like kinase 1 (ULK1) is a serine/threonine kinase that participates in the initiation of autophagy. Many studies have indicated that compounds that directly or indirectly target ULK1 could be used for tumor therapy. However, reports of the therapeutic effects of these compounds have come to conflicting conclusions. In this work, we reviewed recent studies related to the effects of ULK1 on the regulation of autophagy and the development of drug resistance in cancers, with the aim of clarifying the mechanistic underpinnings of this therapeutic target.

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“…In addition, AMPK suppresses the energy-intensive protein biosynthesis process by phosphorylating tuberous sclerosis complex 2 (TSC2) which regulates activity of mammalian target of rapamycin complex 1(mTORC1) promoting protein synthesis [20,63]. AMPK regulates autophagy by directly and indirectly activating Unc-51 like autophagy activating kinase (ULK1) [64,65] and mitochondrial biogenesis by regulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) which in turn promotes gene transcription in the mitochondria [66,67]. AMPK participates in the cellular redox regulation and anti-inflammation response.…”

Section: Downstream Targets Of Ampk Downstream Targets Ofmentioning

confidence: 99%

The Roles of AMPK in Revascularization

Chen

2020

Cardiology Research and Practice

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Coronary heart disease (CHD) is the most common and serious illness in the world and has been researched for many years. However, there are still no real effective ways to prevent and save patients with this disease. When patients present with myocardial infarction, the most important step is to recover ischemic prefusion, which usually is accomplished by coronary artery bypass surgery, coronary artery intervention (PCI), or coronary artery bypass grafting (CABG). These are invasive procedures, and patients with extensive lesions cannot tolerate surgery. It is, therefore, extremely urgent to search for a noninvasive way to save ischemic myocardium. After suffering from ischemia, cardiac or skeletal muscle can partly recover blood flow through angiogenesis (de novo capillary) induced by hypoxia, arteriogenesis, or collateral growth (opening and remodeling of arterioles) triggered by dramatical increase of fluid shear stress (FSS). Evidence has shown that both of them are regulated by various crossed pathways, such as hypoxia-related pathways, cellular metabolism remodeling, inflammatory cells invasion and infiltration, or hemodynamical changes within the vascular wall, but still they do not find effective target for regulating revascularization at present. 5′-Adenosine monophosphate-activated protein kinase (AMPK), as a kinase, is not only an energy modulator but also a sensor of cellular oxygen-reduction substances, and many researches have suggested that AMPK plays an essential role in revascularization but the mechanism is not completely understood. Usually, AMPK can be activated by ADP or AMP, upstream kinases or other cytokines, and pharmacological agents, and then it phosphorylates key molecules that are involved in energy metabolism, autophagy, anti-inflammation, oxidative stress, and aging process to keep cellular homeostasis and finally keeps cell normal activity and function. This review makes a summary on the subunits, activation and downstream targets of AMPK, the mechanism of revascularization, the effects of AMPK in endothelial cells, angiogenesis, and arteriogenesis along with some prospects.

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The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs

Cited by 69 publications

References 59 publications

AMP-activated protein kinase: the current landscape for drug development

AMP-activated protein kinase: the current landscape for drug development

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

The Roles of AMPK in Revascularization

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