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

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.

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

Figure 1

Functional conservation of the core components of Hippo pathway. The functionally conserved factors of Drosophila melanogaster and mammals are matched by color. This network controls the transcriptional events for regulating cell proliferation, survival, and death.

Figure 2

The mammalian Hippo pathway signaling. Various signal stimulators activate the Hippo pathway, which includes GPCR, cell junction and ECM proteins, and soluble factors. These signals regulate the phosphorylation of MST1/2 and LATS1/2 kinases to further induce YAP/TAZ activation. Without the upstream signals, KIBRA interacts with NF2 to promote the pathway activity. Also, NF2 and MAPK4s directly interact with LAST1/2 and promote LATS1/2 phosphorylation (pLATS1/2). Then, pLATS1/2 phosphorylates YAP/TAZ. And, the phosphorylated YAP/TAZ presents a 14-3-3 biding site and SCFβTrCP specific recognition site, which causes cytoplasmic retention of YAP/TAZ and results in YAP/TAZ degradation. YAP protein is also degraded via autophagy. VGLL4 acts as a transcriptional repressor by competing with YAP/TAZ for binding TEADs. Unphosphorylated YAP/TAZ complex translocates into the nucleus, and acts as transcription coactivators by forming complexes with various transcriptional factors, such as TEADs. Binding of YAP/TAZ with TEAD prevents VGLL4 from associating with the complex, and consequently drives the expression of numerous genes which are related to cell proliferation, survival, and migration. The signaling outcome includes induction of cell cycle regulator cyclin E, cell-death inhibitor Diap1, connective tissue growth factor (CTGF), and fibroblast growth factor (FGF1), and etc.

Figure 3

Regulatory domains of the Hippo pathway effector proteins YAP/TAZ. Prominent regions include the WW domain(s), the coiled-coil (CC) domain, the SH3-binding domain, the TEAD transcription factor-binding domain, the transcriptional activation domain (TAD) and the PDZ-binding motif.

Figure 4

A schematic illustration of YAP/TAZ regulation of TE and ICM specification in preimplantation embryo. During preimplantation, the outer blastomeres of the embryo form an outer epithelial trophoectoderm (TE) that envelopes the remaining blastomere and the inner cell mass (ICM). The Hippo pathway plays a crucial role in the cell fate determination. In the outer cells, nuclear YAP and TEAD4 regulate specification of the TE lineage through activation of the TE-specific genes such as Cdx2 and Gata3. In the inner cells, cell-cell adhesions influence the Hippo signaling. Activated Hippo pathway impairs YAP nuclear localization in the ICM lineage, thereby limiting TEAD4 transcription and abrogating the expression of outer TE-specific genes.

Figure 5

The Hippo signaling in tissue homeostasis, regeneration and cancer. (A) YAP/TAZ activity regulates tissue homeostasis and modulates the cell state. (B) YAP/TAZ activity is declined to a relative low level after birth. The YAP/TAZ activity is reactivated after tissue injuries and constitutively upregulated in cancer.

Figure 6

WWOX controls TGF-β, Hyal-2, and Wnt signaling pathways that cross talks with the Hippo signaling. A panel is shown for the Hippo, Hyal-2/WWOX/Smad4, Wnt and TGF-β signaling pathways. WWOX supports the Hyal-2 and TGF-β signal pathways. However, WWOX blocks the Wnt pathway by binding GSK3β and DvL2. WWOX binds AMOT and probably NF2 in the Hippo pathway, whereas the functional consequence of this binding is unknown.