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Journal ArticleDOI

Autophagosome formation--the role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage.

01 Oct 2013-Seminars in Cancer Biology (Semin Cancer Biol)-Vol. 23, Iss: 5, pp 301-309
TL;DR: How the mammalian ULK1 and Beclin1 complexes are controlled by post-translational modifications and protein-protein interactions is discussed and data linking these complexes together is highlighted.
About: This article is published in Seminars in Cancer Biology.The article was published on 2013-10-01. It has received 218 citations till now. The article focuses on the topics: Autophagy.
Citations
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Journal ArticleDOI
TL;DR: It is proposed that the isolation membrane forms from the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and the role of ATG proteins and the vesicular trafficking machinery in autophagosome formation is proposed.
Abstract: Autophagosome biogenesis starts at the isolation membrane (also called the phagophore). Our understanding of the molecular processes that initiate the isolation membrane, the membrane sources from which this membrane originates and how it is expanded to the autophagosome membrane by autophagy-related (ATG) proteins and the vesicular trafficking machinery, is increasing.

1,117 citations

Journal Article
TL;DR: The in vitro substrates recognized by most yeast protein kinases are described, with the use of proteome chip technology, and these results will provide insights into the mechanisms and roles of protein phosphorylation in many eukaryotes.
Abstract: Protein phosphorylation is estimated to affect 30% of the proteome and is a major regulatory mechanism that controls many basic cellular processes. Until recently, our biochemical understanding of protein phosphorylation on a global scale has been extremely limited; only one half of the yeast kinases have known in vivo substrates and the phosphorylating kinase is known for less than 160 phosphoproteins. Here we describe, with the use of proteome chip technology, the in vitro substrates recognized by most yeast protein kinases: we identified over 4,000 phosphorylation events involving 1,325 different proteins. These substrates represent a broad spectrum of different biochemical functions and cellular roles. Distinct sets of substrates were recognized by each protein kinase, including closely related kinases of the protein kinase A family and four cyclin-dependent kinases that vary only in their cyclin subunits. Although many substrates reside in the same cellular compartment or belong to the same functional category as their phosphorylating kinase, many others do not, indicating possible new roles for several kinases. Furthermore, integration of the phosphorylation results with protein-protein interaction and transcription factor binding data revealed novel regulatory modules. Our phosphorylation results have been assembled into a first-generation phosphorylation map for yeast. Because many yeast proteins and pathways are conserved, these results will provide insights into the mechanisms and roles of protein phosphorylation in many eukaryotes.

923 citations

Journal ArticleDOI
TL;DR: Mutation experiments and ectopic localization of WIPI2b to plasma membrane show that WIPi2b is a PtdIns(3)P effector upstream of Atg16L1 and is required for LC3 conjugation and starvation-induced autophagy through recruitment of the Atg12–5- 16L1 complex.

622 citations


Cites background from "Autophagosome formation--the role o..."

  • ...The class III Vps34 lipid kinase, part of the Beclin1 complex, is then activated (Wirth et al., 2013), translocates to ER sites, and produces a pool of phosphatidylinositol 3-phosphate (PtdIns(3)P)....

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Journal ArticleDOI
27 Mar 2014-Cell
TL;DR: The progress that has been made in the last few decades in determining the fates of damaged organelles and damaged cells through discrete, but genetically overlapping, pathways involving the selective autophagy and cell death machinery is considered.

588 citations


Cites background from "Autophagosome formation--the role o..."

  • ...For starvation-induced autophagy, it is also necessary to unleash negative regulators of the Beclin 1-VPS34 initiation complex, such as Bcl-2/Bcl-xL (Wirth et al., 2013)....

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  • ...Similarly, deprivation from growth factors and/or amino acids leads to the inhibition of TORC1, which, when active, represses conventional autophagy....

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  • ...The lower affinity of antiapoptotic proteins for the BH3 domain of Beclin 1—versus those for the BH3 domains of proapoptotic proteins—may account for the early activation of autophagy in response to stress (which involves disruption of Bcl-2/Bcl-xLBeclin 1 binding) which, if unsuccessful in keeping the cell alive, ultimately results in the cell’s transition to a proapoptotic state (which, as noted above, involves the release of proapoptotic molecules such as Bax and Bak) (Sinha and Levine, 2008)....

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  • ...This preinitiation complex is, in turn, activated by AMPK and inhibited by TORC1 (Wirth et al., 2013), and as we have discussed, starvation conditions result in AMPK activation and TORC1 inhibition....

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  • ...As a result of AMPK induction and/or TORC1 inhibition, autophagy is engaged, although other signals may bypass AMPK and TORC1 to engage autophagy (Figure 1)....

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Journal ArticleDOI
TL;DR: As dysregulated mTORC1 underlies a variety of human diseases, including cancer, diabetes, autoimmune diseases, and neurological disorders, understanding the metabolic program downstream of m TORC1 provides insights into its role in these pathological states.

421 citations

References
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01 Apr 2012
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.

6,268 citations

Journal ArticleDOI
28 Feb 2008-Nature
TL;DR: Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health, and to play a role in cell death.
Abstract: Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

5,831 citations

Journal ArticleDOI
13 Apr 2012-Cell
TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.

5,792 citations

Journal ArticleDOI
TL;DR: A molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1, is demonstrated and a signalling mechanism for UlK1 regulation and autophagic induction in response to nutrient signalling is revealed.
Abstract: Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

5,314 citations

Journal ArticleDOI
26 Nov 2003-Cell
TL;DR: It is described that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway and its phosphorylation by AMPK protect cells from energy deprivation-induced apoptosis.

3,647 citations