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Front Oncol. 2019 Feb 11;9:60. doi: 10.3389/fonc.2019.00060. eCollection 2019.

WW Domain-Containing Proteins YAP and TAZ in the Hippo Pathway as Key Regulators in Stemness Maintenance, Tissue Homeostasis, and Tumorigenesis.

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Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Optics and Photonics, National Central University, Chungli, Taiwan.
Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan.
Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, United States.
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan.


The Hippo pathway is a conserved signaling pathway originally defined in Drosophila melanogaster two decades ago. Deregulation of the Hippo pathway leads to significant overgrowth in phenotypes and ultimately initiation of tumorigenesis in various tissues. The major WW domain proteins in the Hippo pathway are YAP and TAZ, which regulate embryonic development, organ growth, tissue regeneration, stem cell pluripotency, and tumorigenesis. Recent reports reveal the novel roles of YAP/TAZ in establishing the precise balance of stem cell niches, promoting the production of induced pluripotent stem cells (iPSCs), and provoking signals for regeneration and cancer initiation. Activation of YAP/TAZ, for example, results in the expansion of progenitor cells, which promotes regeneration after tissue damage. YAP is highly expressed in self-renewing pluripotent stem cells. Overexpression of YAP halts stem cell differentiation and yet maintains the inherent stem cell properties. A success in reprograming iPSCs by the transfection of cells with Oct3/4, Sox2, and Yap expression constructs has recently been shown. In this review, we update the current knowledge and the latest progress in the WW domain proteins of the Hippo pathway in relevance to stem cell biology, and provide a thorough understanding in the tissue homeostasis and identification of potential targets to block tumor development. We also provide the regulatory role of tumor suppressor WWOX in the upstream of TGF-β, Hyal-2, and Wnt signaling that cross talks with the Hippo pathway.


Hippo pathway; WW domain proteins; induced pluripotent stem cells; regeneration; stem cell; tissue homeostasis; tumorigenesis

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