Abstract
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.
Highlights
The Hippo pathway was originally identified by genetic screens of tumor suppressors for tissue growth control in Drosophila melanogaster
Mouse models harboring the deletion of Mst1/2, Sav1, Mob1A/B, Neurofibromin 2 (NF2), or Last1/2, or Yap overexpression, exhibit upregulated Tead target gene expression, and increased expansion of progenitor cells and tissue overgrowth [76,77,78,79]. thereby manifesting the importance of these genes in the Hippo pathway (Figure 2)
Effects of Hippo Signaling on Organ Size Regulation In Drosophila, dysregulation of the Hippo pathway kinases (Hpo and Wts) or upstream regulators (Ex, Mer, Kibra, Ft, etc.) promotes Yki-induced cell proliferation and leads to tissue/organs overgrowth [16, 25, 26, 28]
Summary
The Hippo pathway was originally identified by genetic screens of tumor suppressors for tissue growth control in Drosophila melanogaster. Hippo pathway regulates stem cell self-renewal and expansion and tissue regeneration [30,31,32]. E-cadherin inhibits YAP/TAZ activation without involving the upstream signals of the Hippo pathway.
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