Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy.

Petherick, Katy J.; Conway, Owen; Mpamhanga, Chido; Osborne, Simon A.; Kamal, Ahmad; Saxty, Barbara; Ganley, Ian G.

doi:10.1074/jbc.a114.627778

Cited by 118 publications

(135 citation statements)

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“…1g,h). The reduced ULK1 and ULK2 kinase activity in presence of TTM was similar to inhibition achieved with the ULK1/2 inhibitor MRT68921 16 (Fig. 1f,g and Supplementary Fig.…”

supporting

confidence: 75%

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Tsang

Posimo

Gudiel

et al. 2019

Preprint

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Targeting aberrant kinase activity in cancer relies on unmasking cellular inputs such as growth factors, nutrients, and metabolites that contribute to cancer initiation and progression 1 . While the transition metal copper (Cu) is an essential nutrient that is traditionally viewed as a static cofactor within enzyme active sites 2 , a newfound role for Cu as a modulator of kinase signaling is emerging 3,4 . We discovered that Cu is required for the activity of the autophagic kinases ULK1/2 through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt Cu-binding reduced ULK1/2-dependent signaling and autophagosome complex formation. Elevated intracellular Cu levels are associated with starvation induced autophagy and sufficient to enhance ULK1 kinase activity and in turn autophagic flux. Targeting autophagy machinery is a promising therapeutic strategy in cancers 5 , but is limited by the absence of potent inhibitors and the emergence of resistance. The growth and survival of lung tumors driven by KRAS G12D is diminished in the absence of Ctr1, depends on ULK1 Cu-binding, and is associated with reduced autophagy levels and signaling. These findings suggest a new molecular basis for exploiting Cu-chelation therapy to forestall autophagy signaling to limit proliferation and survival in cancer.By default, the dynamic and adaptive nature of signaling networks allows them to respond and, in some cases, sense extracellular and intracellular inputs 6 . While growth factors, nutrients, and metabolites are well-appreciated regulators of cell proliferation, the contribution of transition metals to cellular processes that support proliferation and contribute to malignant transformation are understudied. The transition metal copper (Cu) is essential for a diverse array of biological processes from cellular proliferation, neuropeptide processing, free radical detoxification, and

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“…1g,h). The reduced ULK1 and ULK2 kinase activity in presence of TTM was similar to inhibition achieved with the ULK1/2 inhibitor MRT68921 16 (Fig. 1f,g and Supplementary Fig.…”

supporting

confidence: 75%

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Tsang

Posimo

Gudiel

et al. 2019

Preprint

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“…When the 757 serine was phosphorylated by mTOR, the kinase activity was inactivated and lead to the overall functional destruction of autophagy initiation complex, then autophagy was inhibited. [28,29] Compared with the H/R group, after treatment of H/R cells with medium/high concentration of GAS, the expression level of ULK1 was decreased. After addition of AKT inhibitors, its expression level was obviously increased.…”

Section: Discussionmentioning

confidence: 95%

Gastrodin protects myocardial cells against hypoxia/reoxygenation injury in neonatal rats by inhibiting cell autophagy through the activation of mTOR signals in PI3K-Akt pathway

Zhu

Liu

et al. 2018

Journal of Pharmacy and Pharmacology

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“…Several groups have developed ATP-competitive inhibitors of ULK1 kinase (the apical kinase important for initiating autophagosome formation) that block autophagy in cells in vitro (Egan et al 2015;Lazarus and Shokat 2015;Petherick et al 2015). The most characterized of these started with a FAK inhibitor that potently inhibited ULK1 function (Russell et al 2013;Egan et al 2015).…”

Section: Ulk1mentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumorpromoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.The core autophagy machinery is encoded by autophagyrelated (ATG) genes, of which there are now >30 (Ktistakis and Tooze 2016). These genes and their protein products are regulated by numerous upstream signals, including nutrient availability, stressors, defective organelles, and pathogenic conditions. ATG gene products control the formation of the hallmark double-membrane vesicle, the autophagosome. Other genes encode cargo receptors that direct the cargo to the forming autophagosome. Control of the trafficking machinery then orchestrates fusion of the cargo-laden autophagosomes with lysosomes. Degradative enzymes, contributed by lysosomes, break down the cargo, and the products are exported into the cytoplasm, where they are recycled into metabolic and biosynthetic pathways (Rabinowitz and White 2010;Guo et al. 2016). Under normal nutrient conditions, autophagy functions at a constitutive, low basal level to maintain protein and organelle quality, quantity, and functionality. The ATG genes and autophagy are dramatically induced by starvation and other stressors, which enable cellular and organismal survival. Up-regulation of autophagy is a means to survive nutrient stress, which is conserved from yeast to mammals. More recently, there is a growing appreciation of the role played by ATG genes in modulating intracellular trafficking, endocytosis, exoc...

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Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy.

Abstract: In Fig. 1A, the molecular structures of the compounds for MRT67307 and MRT68921 were mistakenly switched. The corrected figure is shown below. This correction does not affect the interpretation of the results or conclusions of this work.

Cited by 118 publications

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Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Gastrodin protects myocardial cells against hypoxia/reoxygenation injury in neonatal rats by inhibiting cell autophagy through the activation of mTOR signals in PI3K-Akt pathway

Recent insights into the function of autophagy in cancer

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