Nutrient-dependent mTORC1 Association with the ULK1–Atg13–FIP200 Complex Required for Autophagy

Hosokawa, Nao; Hara, Taichi; Kaizuka, Takeshi; Kishi, Chieko; Takamura, Akito; Miura, Yutaka; Iemura, Shun Ichiro; Natsume, Tohru; Takehana, Kenji; Yamada, Naoyuki; Guan, Jun; Oshiro, Noriko; Mizushima, Noboru

doi:10.1091/mbc.e08-12-1248

Cited by 1,779 publications

(1,671 citation statements)

References 54 publications

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“…Consequently, ULK1 is activated and initiates membrane nucleation, which is followed by sequestration and degradation. [155][156][157][158][159][160] Although it has been widely accepted that autophagy is induced in response to metabolic suppression, the molecular links between metabolic and autophagic pathways have not been fully elucidated. Recently, we made the surprising discovery that HK-II facilitates autophagy in response to glucose deprivation to protect cells 117 (Figure 4).…”

Section: Hk-ii-mediated Regulation Of Mtorc1 and Autophagymentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

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Section: Hk-ii-mediated Regulation Of Mtorc1 and Autophagymentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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“…In addition, activation of mTORC1 stimulates angiogenesis by inducing hypoxia-inducible factor 1a, which increases the expression of vascular endothelial growth factor (Figure 4) (Hudson et al, 2002). Furthermore, mTORC1 activity inhibits autophagy via phosphorylation of ATG13 and ULK1/2 (Figure 4) (Hosokawa et al, 2009;Jung et al, 2009). As these processes are all essential in tumorigenesis, it is not surprising to observe that deregulation of the LKB1/ AMPK/TSC/mTORC1 signaling pathway is frequently associated with human cancer.…”

Section: Maf1 Poliiimentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…Atg9 is postulated to contribute to delivery of membranes required in autophagosome formation. [10][11][12][13][14][15][16][17][18] The core machinery of autophagy comprises of four steps. These are: a) Induction: the process of autophagosome formation starts with the dissociation of mTOR complex 1 (mTORC1) from ULK1 complex.…”

Section: Mechanism Of Autophagymentioning

confidence: 99%

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

Puri

Chandra

2014

Journal of Clinical and Experimental Hepatology

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Autophagy is a critical intracellular pathway which maintains cellular function by lysosomal degradation of damaged proteins and organelles besides elimination of invading pathogens. Its primary function is to prevent cell death. Autophagy has diverse physiological functions namely; starvation adaptation, prevention of tumorigenesis, energy homeostasis, intracellular quality control and degradation of abnormal intracellular protein aggregates. Understanding the molecular mechanisms of autophagy has given key insights into the pathogenesis of various diseases like Non Alcoholic Steato-Hepatitis, Hepatitis B and C infections, Alpha-1 antitrypsin deficiency and hepatocellular carcinoma. Pharmacological modulation of autophagy may have a therapeutic potential in management of these liver diseases. ( J CLIN EXP HEPATOL 2014;4:51-59) O urobros or Urobros is an ancient symbol depicting a serpent or a dragon eating its own tail, which symbolizes cyclicality in the sense of something recreating itself. In living organisms, cells and intracellular organelles need to be constantly remodeled and renewed. Autophagy is a term derived from Greek terminology for self-eating and signifies the process of cellular selfdigestion in which cytoplasmic components are degraded in lysosomes. Reminiscent of the serpent eating its own tail in the symbol of Ourobros, the cells are able to survive by using autophagy to remove damaged proteins and organelles, eliminate invading microbes and generate nutrients during starvation.After Metchnicoff, a Russian zoologist, first described phagocytosis, the role of lysosomes and autophagy in degrading cytoplasmic components has been elucidated. 1,2 The control of autophagy has been recently delineated by identification of over 30 Autophagy-related (ATG) genes. 3 Autophagy functions to prevent rather than promote cell death. Autophagy has effects of increased cytoprotection, decreased stem cell attrition, decreased oncogenic transformation, decreased dysfunctional mitochondria and decrease in dysfunctional aggregate prone proteins. 4

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Nutrient-dependent mTORC1 Association with the ULK1–Atg13–FIP200 Complex Required for Autophagy

Cited by 1,779 publications

References 54 publications

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

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