The very first description of Hippo signaling in mammals a little more than 10 years ago showed a striking phenotype in the liver, linking the role of this signaling pathway to organ size control and carcinogenesis

The very first description of Hippo signaling in mammals a little more than 10 years ago showed a striking phenotype in the liver, linking the role of this signaling pathway to organ size control and carcinogenesis. functions. We format open questions and future study directions that will help to improve our understanding of this important pathway in liver disease. and mammals, the importance of Hippo signaling in the liver became evident having a impressive phenotype: overexpression of YAP or manifestation of triggered YAP resulted in dramatic overgrowth of the liver, identifying Hippo signaling as an important determinant TAK-778 in organ size control (Camargo et al., 2007; Dong et al., 2007). Quick development of hepatocellular carcinoma (HCC) upon YAP overexpression further confirmed a potent oncogenic role of this protein (Dong et al., 2007). More recently, the investigation of Hippo signaling in non-parenchymal liver cells, including hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) has brought insight into the complex interplay between different hepatic cell types with serious impact on the pathophysiology of liver disease. Here, we provide an overview of Hippo signaling in the liver including recent improvements and open questions along with long term directions in the field. Hippo Regulators Restrict Proliferation and Maintain Differentiation in Hepatocytes Soon after the finding of YAP function in murine liver, MST1 and MST2 protein kinases were confirmed as upstream Hippo pathway regulators that restrict YAP activation, tissue overgrowth, and carcinogenesis (Figure 1; Zhou et al., 2009; Lu et al., 2010; Song et al., 2010). In the same line, hepatic inactivation of the MST1/2-adaptor protein SAV1/WW45 resulted in YAP-associated cell proliferation and mutant mice ultimately developed tumors with characteristics of HCC and intrahepatic cholangiocarcinomas (ICC) (Lee et al., 2010; Lu et al., 2010). The conditional knock-out of Hippo pathway is TAK-778 conserved in mammals (Figure 1). Open in a separate window FIGURE 1 Key components of the Hippo pathway in Drosophila and mammals. In all of these models, conditional inactivation of Hippo pathway genes was achieved by using either transgenic mice (Zhou et al., 2009; Song et al., 2010) or an (Benhamouche et al., 2010; Lu et al., 2010; Zhang et al., 2010), which is also active in fetal hepatoblasts that give rise to bile duct cells. Mutant mice showed varying degrees of hepatocyte proliferation but also exhibited proliferation and expansion of a hepatic cell population with small nuclei around the portal triad, so-called oval cells. These cells were long considered to function as bipotent liver progenitor cells that can differentiate into hepatocytes and bile duct cells under certain conditions such as severe hepatocyte damage C a hypothesis that has been challenged by recent research (Tanimizu and Mitaka, 2014). The expansion of oval cells and the development of both HCC and ICC initially led to the speculation that tumors in Hippo pathway-inactivated models arise from these potential bipotent progenitor cells. However, recent studies suggest that these phenotypes arise from trans-differentiation of mutant hepatocytes and deregulated biliary morphogenesis (Yimlamai et al., 2014; Benhamouche-Trouillet et al., 2018). Several TAK-778 hepatocyte-specific transfection models can trigger the development of tumors with mixed differentiation: overexpression of YAP as well as inactivation of TAK-778 the upstream Hippo regulator Nf2 mediated by AAV-Cre induces de-differentiation of hepatocytes toward a progenitor-like phenotype (Yimlamai et al., 2014). Additionally, hydrodynamic tail vein injection of transposon-based expression constructs for constitutively active YAP and PIK3CA C the catalytic subunit of PI3K C resulted in formation of liver tumors with hepatocellular, cholangiocellular, or mixed HCC/ICC CDKN2AIP differentiation. In this model, tumors were characterized by activation of mTORC1/2, ERK/MAPK, and Notch pathways (Li et al., 2015). To date, the molecular basis for the cooperation between PI3K and YAP signaling in liver cancer is not well understood, but could TAK-778 be mediated be PI3K-induced upregulation of CD166, a cell surface protein that has been shown to positively regulate YAP activity (Ma et al., 2014). On the other hand, data from breast epithelial cells and colon cancer cells indicate that PI3K/PDK1/AKT signaling promotes YAP activity via LATS-dependent and -independent systems (Zhao et al., 2018). Nevertheless, if this system can be conserved in liver organ cancer and exactly how it pertains to mobile differentiation remains to become investigated. From what’s known to day, YAP C and perhaps additional oncogenic pathways such as for example PI3K signaling C not merely appear to promote proliferation and tumorigenesis generally, but oncogenic plasticity of hepatocytes with trans-differentiation also.