Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation

Peng, Changmin; Zhu, Yue; Zhang, Wanjun; Liao, Qinchao; Chen, Yali; Zhao, Xinyuan; Guo, Qiang; Shen, Pan; Zhen, Bei; Qian, Xiaohong; Yang, Dong; Zhang, Jin‐San; Xiao, Dongguang; Qin, Weijie; Pei, Huadong

doi:10.1016/j.molcel.2017.10.010

Cited by 204 publications

(185 citation statements)

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“…However, two recent reports have revealed a novel post-transcriptional modification of YAP regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients (Fig. 2b) [30, 31]. The HBP is an important glucose metabolism pathway, which controls metabolic flux and O-GlcNAcylation.…”

Section: Main Textmentioning

confidence: 99%

“…In high glucose conditions, O-GlcNAc transferase (OGT), which is a key enzyme of the HBP, O-GlcNAcylates YAP at different O-GlcNAc sites, such as Ser109 and Thr241, while the TAZ could not be O-GlcNAcylated. YAP O-GlcNAcylation promotes its expression, enhances its stability, prevents its phosphorylation, and activates its transcriptional activity [30, 31]. Mechanistically, Peng et al found that YAP O-GlcNAcylation prevents LATS1-induced YAP phosphorylation by directly blocking its interaction with LATS1, the O-GlcNAcylation of YAP does not compete with phosphorylation at serine 109, it indicates that perhaps glycosylation is the main modification and functional regulator rather than phosphorylation at serine 109 [30].…”

Section: Main Textmentioning

confidence: 99%

“…YAP O-GlcNAcylation promotes its expression, enhances its stability, prevents its phosphorylation, and activates its transcriptional activity [30, 31]. Mechanistically, Peng et al found that YAP O-GlcNAcylation prevents LATS1-induced YAP phosphorylation by directly blocking its interaction with LATS1, the O-GlcNAcylation of YAP does not compete with phosphorylation at serine 109, it indicates that perhaps glycosylation is the main modification and functional regulator rather than phosphorylation at serine 109 [30]. In contrast, Zhang et al revealed that O-GlcNAcylation of YAP at Thr241 antagonizes LATS1-mediated phosphorylation of YAP at Ser127, which promotes YAP transcriptional activity; Moreover, YAP is O-GlcNAcylated on its second WW domain, while TAZ has only one WW domain that might not be O-GlcNAcylated, and this may support why YAP is more important than TAZ [31].…”

Section: Main Textmentioning

confidence: 99%

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The role of YAP/TAZ activity in cancer metabolic reprogramming

et al. 2018

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In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.

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Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

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The role of YAP/TAZ activity in cancer metabolic reprogramming

et al. 2018

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“…Loss of GFPT1 protein (HBP) using this method blocks nuclear localization of YAP1 ( Figure 5G, H) but has no effect on AP-2γ expression ( Figure 5K requires O-linked glycosylation at 1-4 specific sites on the protein (Peng et al, 2017;. This is a likely explanation for loss of YAP1 localization when this protein modification is blocked.…”

Section: Molecular Mechanisms Linking Glucose Metabolism To Cdx2 Exprmentioning

confidence: 99%

Glucose metabolism distinguishes TE from ICM fate during mammalian embryogenesis

Chi

Sharpley

Nagaraj

et al. 2019

Preprint

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The mouse embryo undergoes compaction at the 8-cell stage and its transition to 16 cells generates polarity such that the outer apical cells are trophectoderm (TE) precursors and the inner cell mass (ICM) gives rise to the embryo. We report here, that this first cell fate specification event is controlled by glucose metabolism. Glucose does not fuel mitochondrial ATP (energy) generation and glycolysis is dispensable for blastocyst formation. Glucose does not help synthesize amino acids, fatty acids, and nucleobases. Instead, glucose metabolized by the hexosamine biosynthetic pathway (HBP) allows nuclear localization of YAP1, and the pentose phosphate pathway (PPP), along with sphingolipid (S1P) signaling, activates mTOR and allows translation of AP-2γ. YAP1, TEAD4 and AP-2γ physically interact to form a nuclear complex that controls TE-specific gene transcription. Glucose signaling has no role in ICM specification, but this cascade of events constituting "Developmental Metabolism" specifically controls the fate of TE cells. KeywordsDevelopmental metabolism, preimplantation embryo, glucose, trophectoderm, pentose phosphate pathway, hexosamine biosynthetic pathway, YAP1, S1P signaling, AP-2 Trim- Away, morula-blastocystWe would like to thank all members of our laboratory for their suggestions and support.Yonggang Zhou performed RNA seq analysis that was used in this manuscript. We thank Daniel Braas, and Johanna ten Hoeve-Scott at the UCLA Metabolomics Center for their generous help with metabolomics analysis. We appreciate many inputs by Tom Graeber, Heather Christofk and Hilary Coller. Christofk and Coller also helped by providing several antibody reagents. We thank Wei Liao, Qin An, Wanlu Liu and Steve Jacobsen for help with RNA sequencing experiments and bioinformatics analysis of RNA expression data, and Huachun Liu for help with molecular cloning and related molecular analysis. We thank Bin Gu at Sick Kids, Toronto for useful suggestions including for microinjection, and Bin Zhao at Zhejiang University for valuable discussions.

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“…In contrast, a protein phosphatase PP2A complex called STRIPAK (Bae et al, ; Praskova et al, ; Zheng et al, ), Dachsous–Fat system (Irvine & Harvey, ; Mao et al, ), and extracellular matrix (ECM) sensing integrins (Chakraborty & Hong, ; Dobrokhotov, Samsonov, Sokabe, & Hirata, ) are responsible for inactivation of the Hippo pathway. In high‐energy conditions, enzyme O‐GlcNac transferase deactivates Hippo signaling allowing the expression of YAP‐regulated growth‐promoting genes (Peng et al, ). This signaling pathway is also deactivated by Ajuba LIM proteins (Das Thakur et al, ; Rauskolb, Sun, Sun, Pan, & Irvine, ), by changes in actomyosin contractility under mechanical stress conditions (Furukawa, Yamashita, Sakurai, & Ohno, ) and by HIF‐1α in hypoxic conditions (Xiang et al, ).…”

Section: Overview Of the Hippo Signaling Networkmentioning

confidence: 99%

The emerging role of Hippo signaling in neurodegeneration

Sahu

Mondal

2019

J of Neuroscience Research

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Neurodegeneration refers to the complex process of progressive degeneration or neuronal apoptosis leading to a set of incurable and debilitating conditions. Physiologically, apoptosis is important in proper growth and development. However, aberrant and unrestricted apoptosis can lead to a variety of degenerative conditions including neurodegenerative diseases. Although dysregulated apoptosis has been implicated in various neurodegenerative disorders, the triggers and molecular mechanisms underlying such untimely and faulty apoptosis are still unknown. Hippo signaling pathway is one such apoptosis‐regulating mechanism that has remained evolutionarily conserved from Drosophila to mammals. This pathway has gained a lot of attention for its tumor‐suppressing task, but recent studies have emphasized the soaring role of this pathway in inflaming neurodegeneration. In addition, strategies promoting inactivation of this pathway have aided in the rescue of neurons from anomalous apoptosis. So, a thorough understanding of the relationship between the Hippo pathway and neurodegeneration may serve as a guide for the development of therapy for various degenerative diseases. The current review focuses on the mechanism of the Hippo signaling pathway, its upstream and downstream regulatory molecules, and its role in the genesis of numerous neurodegenerative diseases. The recent efforts employing the Hippo pathway components as targets for checking neurodegeneration have also been highlighted.

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Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation

Cited by 204 publications

References 68 publications

The role of YAP/TAZ activity in cancer metabolic reprogramming

The role of YAP/TAZ activity in cancer metabolic reprogramming

Glucose metabolism distinguishes TE from ICM fate during mammalian embryogenesis

The emerging role of Hippo signaling in neurodegeneration

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