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The Hippo pathway and its downstream effectors, the transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), regulate organ growth and cell plasticity during animal development and regeneration. Remarkably, experimental activation of YAP/TAZ in the mouse can promote regeneration in organs with poor or compromised regenerative capacity, such as the adult heart and the liver and intestine of old or diseased mice. However, therapeutic YAP/TAZ activation may cause serious side effects. Most notably, YAP/TAZ are hyperactivated in human cancers, and prolonged activation of YAP/TAZ triggers cancer development in mice. Thus, can the power of YAP/TAZ to promote regeneration be harnessed in a safe way? Here, we review the role of Hippo signalling in animal regeneration, examine the promises and risks of YAP/TAZ activation for regenerative medicine and discuss strategies to activate YAP/TAZ for regenerative therapy while minimizing adverse side effects. ispartof: NATURE REVIEWS MOLECULAR CELL BIOLOGY vol:20 issue:4 pages:211-226 ispartof: location:England status: published

Mixed signals at tumor margins The Hippo signaling pathway has been implicated in tumor growth, sparking interest in the pathway as a potential therapeutic target. In a study of liver cancer in genetically manipulated mice, Moya et al. discovered that the role of this pathway in tumorigenesis is more complex than previously appreciated. They confirmed that activation of the Hippo pathway within tumor cells drives tumor growth; however, they also found that activation of the pathway in adjacent healthy cells has the opposite effect, suppressing tumor growth. Whether tumor cells survive or are eliminated thus appears to depend on competing signals produced by the tumor and surrounding tissue. Science , this issue p. 1029

Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19+), hepatocellular carcinoma keratin 19 negative (HCC K19&minus, ), combined hepatocellular&ndash, cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19&minus, HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19&minus, HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics.

The Hippo-pathway effectors Yap/Taz are assumed to be master regulators of organ regeneration. In the mouse liver, loss of Yap indeed affects the regeneration potential of hepatocytes. However, we found that this is not due to a requirement for Yap in hepatocytes to drive proliferation and regeneration, but is rather due to non-cell autonomous effects of the bile duct defects that develop in the absence of Yap. Developmental deletion of Yap and Taz in liver progenitors, which develop into hepatocytes and bile epithelial cells (BECs), impaired liver regeneration after toxin-induced injury. However, hepatocyte-specific deletion of Yap/Taz in adult mice revealed that Yap/Taz are dispensable in hepatocytes for liver regeneration. In contrast, deletion of Yap/Taz in mature BECs recapitulated the liver regeneration defects that were observed after knockout in liver progenitor cells. Notably, loss of Yap/Taz in BECs impaired bile duct integrity over time, induced a cholestatic liver phenotype, and increased apoptosis in wild-type hepatocytes after toxic liver injury. Our data show that Yap and Taz are required to maintain bile duct integrity, which is essential to maintain the regenerative capacity of adult hepatocytes. Citation Format: Elisabeth Verboven, Ivan M. Moya, Georg Halder. Yap activity in bile ducts, but not in hepatocytes, is required for normal liver regeneration [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A13.

SummaryThe Drosophila Yorkie (Yki) protein and its mammalian homolog Yes-associated protein (YAP) are potent growth promoters, and YAP overexpression is associated with multiple types of cancer [1, 2]. Yki and YAP are transcriptional coactivators and function as downstream effectors of the Hippo tumor suppressor pathway [1–4]. The regulation of Yki and YAP by the Hippo signaling pathway has been extensively investigated; however, how they regulate gene expression is poorly understood. To identify additional regulators of Yki activity, we performed a genome-wide RNAi screen in Drosophila S2 cells. In this screen, we identified the conserved protein Mask (Multiple ankyrin repeats single KH domain) as a novel promoter of Yki activity in vitro and validated this function in vivo in Drosophila. We found that Mask is required downstream of the Hippo pathway for Yki to induce target-gene expression and that Mask forms complexes with Yki. The human Mask homolog MASK1 complexes with YAP and is required for the full activity of YAP. Additionally, elevated MASK1 expression is associated with worsened outcomes for breast cancer patients. We conclude that Mask is a novel cofactor for Yki/YAP required for optimal Yki/YAP activity during development and oncogenesis.

We have a limited ability to stimulate cells in damaged tissues to regenerate properly patterned and functional organs. Excitingly, however, recent work shows that experimental modulation of the Hippo pathway can promote the regeneration of several organs in mice. The Hippo pathway plays pivotal and specific roles in organ growth, cellular plasticity, and stem cell biology, which are all important for regeneration. In this review we survey and compare the effects of experimental manipulation of Hippo signaling in mouse on the development, homeostasis, and regeneration of the heart, liver, intestine, and other organs. We also discuss the potential of targeting the Hippo pathway as a therapeutic approach for regenerative medicine.

Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical-basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non-cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non-cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.

Vascular endothelial growth factor (VEGF) is a major driver of blood vessel formation. However, the signal transduction pathways culminating in the biological consequences of VEGF signaling are only partially understood. Here, we show that the Hippo pathway effectors YAP and TAZ work as crucial signal transducers to mediate VEGF-VEGFR2 signaling during angiogenesis. We demonstrate that YAP/TAZ are essential for vascular development as endothelium-specific deletion of YAP/TAZ leads to impaired vascularization and embryonic lethality. Mechanistically, we show that VEGF activates YAP/TAZ via its effects on actin cytoskeleton and that activated YAP/TAZ induce a transcriptional program to further control cytoskeleton dynamics and thus establish a feedforward loop that ensures a proper angiogenic response. Lack of YAP/TAZ also results in altered cellular distribution of VEGFR2 due to trafficking defects from the Golgi apparatus to the plasma membrane. Altogether, our study identifies YAP/TAZ as central mediators of VEGF signaling and therefore as important regulators of angiogenesis.

The Hippo pathway is a signal transduction pathway that regulates organ growth, stem cell biology, regeneration and cancer. Three recent proteomic studies with Hippo pathway components uncovered extensive networks of interacting proteins revealing novel connections to cell-cell junctions, regulation by vesicle trafficking, and phosphorylation-dependent remodeling of the interactome, and provide a rich landscape of novel interactors ripe for mechanistic studies.