Wei Huang

University of Notre Dame, South Bend, Indiana, United States

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Publications (8)25.87 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The Hippo pathway is crucial in organ size control, whereas its dysregulation contributes to organ degeneration or tumorigenesis. The kinase cascade of MST1/2 and LATS1/2 and the coupling transcription co-activators YAP/TAZ represent the core components of the Hippo pathway. Extensive studies have identified a number of upstream regulators of the Hippo pathway, including contact inhibition, mechanic stress, extracellular matrix stiffness, cytoskeletal rearrangement, and some molecular of cell polarity and cell junction. However, how the diffuse extracellular signals regulate the Hippo pathway puzzles the researchers for a long time. Unexpectedly, recent elegant studies demonstrated that stimulation of some G protein-coupled receptors (GPCRs), such as lysophosphatidic acid receptor, sphingosine-1-phosphate receptor, or the protease activated receptor PAR1, causes potent YAP/TAZ dephosphorylation and activation by promoting actin cytoskeleton assemble. In this review, we briefly describe the components of the Hippo pathway and focus on the recent progress with respect to the regulation of the Hippo pathway by GPCRs and G proteins in cancer cells. In addition, we also discuss the potential therapeutic roles targeting the Hippo pathway in human cancers. © The Author 2014. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
    Acta Biochimica et Biophysica Sinica 12/2014; DOI:10.1093/abbs/gmu108 · 2.09 Impact Factor
  • Wei Huang, Zhen Wang, Qun-Ying Lei
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    ABSTRACT: Metabolic reprogramming is one of the critical features in cancer. Tumor cells preferentially utilize glycolysis instead of oxidative phosphorylation in the presence of oxygen, namely 'Warburg Effect'. Recent studies have provided new insights into the Warburg effect, elucidating metabolic-dependent and independent mechanisms of metabolic enzymes regulated by post-translational modifications and providing further evidence for the critical role of these tricks in cancer metabolism and tumorigenesis. Of particular interest, we summarized the latest advances in both the metabolic and the non-metabolic functions of metabolic enzymes via the acetylation regulation in the Warburg effect. In addition, their potential roles in cancer metabolism therapy will also be briefly discussed.
    Acta Biochimica et Biophysica Sinica 01/2014; 46(3). DOI:10.1093/abbs/gmt154 · 2.09 Impact Factor
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    ABSTRACT: Lysine acetylation plays an essential role in metabolism. Five individual studies have identified that a large number of cellular proteins are potentially acetylated. Notably, almost every enzyme involved in central metabolic pathways such as glycolysis, the TCA cycle, fat acid metabolism, urea cycle and glycogen metabolism, is acetylated in response to nutrition fluctuations. Metabolic reprogramming is a critical hallmark during cancer development. Tumor cells preferentially utilize glycolysis instead of oxidative phosphorylation to produce more lactate and metabolic intermediates even under normal oxygen pressure, which was first noted as the "Warburg Effect". This review focuses on recent advances in the acetylation regulation of metabolic enzymes involved in the Warburg effect, the dysfunction of acetylation regulation in tumorigenesis and their potential role in cancer metabolism therapy.
    Current pharmaceutical design 06/2013; · 3.29 Impact Factor
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    ABSTRACT: The Hippo tumor suppressor pathway plays a major role in development and organ size control, and its dysregulation contributes to tumorigenesis. TAZ (transcriptional co-activator with PDZ-binding motif; also known as WWTR1) is a transcription co-activator acting downstream of the Hippo pathway, and increased TAZ protein levels have been associated with human cancers, such as breast cancer. Previous studies have shown that TAZ is inhibited by large tumor suppressor (LATS)-dependent phosphorylation, leading to cytoplasmic retention and ubiquitin-dependent degradation. The LATS kinase, a core component of the Hippo pathway, phosphorylates the C-terminal phosphodegron in TAZ to promote its degradation. In this study, we have found that the N-terminal phosphodegron of TAZ also plays a role in TAZ protein level regulation, particularly in response to different status of cellular PI3K signaling. GSK3, which can be inhibited by high PI3K via AKT-dependent inhibitory phosphorylation, phosphorylates the N-terminal phosphodegron in TAZ, and the phosphorylated TAZ binds to β-TrCP subunit of the SCF(β-TrCP) E3 ubiquitin ligase, thereby leading to TAZ ubiquitylation and degradation. We observed that the TAZ protein level is elevated in tumor cells with high PI3K signaling, such as in PTEN mutant cancer cells. This study provides a novel mechanism of TAZ regulation and suggests a role of TAZ in modulating tissue growth and tumor development in response to PI3K signaling.
    Journal of Biological Chemistry 06/2012; 287(31):26245-53. DOI:10.1074/jbc.M112.382036 · 4.60 Impact Factor
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    ABSTRACT: TAZ (WWTR1), identified as a 14-3-3 binding protein with a PDZ binding motif, is implicated in mesenchymal stem cell differentiation. TAZ has been shown to be negatively regulated by phosphorylation-dependent and phosphorylation-independent mechanisms. Coupled with ASPP2, PP1 dephosphorylates TAZ to activate TAZ. TEADs mediate TAZ function in promoting cell proliferation and epithelial-mesenchymal transition (EMT). TAZ senses different cellular signals such as cell density and the extracellular matrix stiffness. Significantly, TAZ is overexpressed in breast cancer samples and papillary thyroid carcinoma tissues. These results indicate that TAZ plays an important role in cancer development and presents a novel target for TAZ overexpressed cancer therapy.
    01/2011; 2(3):247-56.
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    ABSTRACT: The TAZ transcription co-activator promotes cell proliferation and epithelial-mesenchymal transition. TAZ is inhibited by the Hippo tumor suppressor pathway, which promotes TAZ cytoplasmic localization by phosphorylation. We report here that TAZ protein stability is controlled by a phosphodegron recognized by the F-box protein β-TrCP and ubiquitylated by the SCF/CRL1(β-TrCP) E3 ligase. The interaction between TAZ and β-TrCP is regulated by the Hippo pathway. Phosphorylation of a phosphodegron in TAZ by LATS primes it for further phosphorylation by CK1ε and subsequent binding by β-TrCP. Therefore, the Hippo pathway negatively regulates TAZ function by both limiting its nuclear accumulation and promoting its degradation. The phosphodegron-mediated TAZ degradation plays an important role in negatively regulating TAZ biological functions.
    Journal of Biological Chemistry 11/2010; 285(48):37159-69. DOI:10.1074/jbc.M110.152942 · 4.60 Impact Factor
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    ABSTRACT: The TAZ transcription co-activator promotes cell proliferation and epithelial-mesenchymal transition. TAZ is inhibited by the Hippo tumor suppressor pathway, which promotes TAZ cytoplasmic localization by phosphorylation. We report here that TAZ protein stability is controlled by a phosphodegron recognized by the F-box protein β-TrCP and ubiquitylated by the SCF/CRL1β-TrCP E3 ligase. The interaction between TAZ and β-TrCP is regulated by the Hippo pathway. Phosphorylation of a phosphodegron in TAZ by LATS primes it for further phosphorylation by CK1ϵ and subsequent binding by β-TrCP. Therefore, the Hippo pathway negatively regulates TAZ function by both limiting its nuclear accumulation and promoting its degradation. The phosphodegron-mediated TAZ degradation plays an important role in negatively regulating TAZ biological functions.
    Journal of Biological Chemistry 11/2010; 285(48):37159-37169. · 4.60 Impact Factor
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    ABSTRACT: Ornithine carbamoyltransferase (OTC) is a key enzyme in the urea cycle to detoxify ammonium produced from amino acid catabolism. OTC deficiency is an X-linked genetic disorder ranging from fatal in newborns to hyperammonemia and anorexia in adults. Through affinity purification of acetylated peptides and mass spectrometry, we identified that OTC is acetylated on lysine residues, including Lys88, which is also mutated in OTC-deficient patients. OTC acetylation was confirmed to occur under physiological conditions. Biochemical characterizations revealed that OTC Lys88 acetylation decreases the affinity for carbamoyl phosphate, one of the two OTC substrates, and the maximum velocity, whereas the K(m) for ornithine, the other OTC substrate, is not affected. Furthermore, Lys88 acetylation is regulated by both extracellular glucose and amino acid availability, indicating that OTC activity may be regulated by cellular metabolic status. Our results provide an example of the novel mechanism of regulating metabolic enzyme activity through protein acetylation.
    Journal of Biological Chemistry 04/2009; 284(20):13669-75. DOI:10.1074/jbc.M901921200 · 4.60 Impact Factor

Publication Stats

140 Citations
25.87 Total Impact Points

Institutions

  • 2014
    • University of Notre Dame
      • Department of Biological Sciences
      South Bend, Indiana, United States
  • 2009–2013
    • Fudan University
      • • Department of Biochemistry and Molecular Biology
      • • School of Life Sciences
      Shanghai, Shanghai Shi, China