WW and C2 domain–containing proteins regulate hepatic cell differentiation and tumorigenesis through the hippo signaling pathway

Abstract

The Hippo pathway regulates cell differentiation, proliferation, and apoptosis. Upon activation, it inhibits the import of the transcriptional coactivator yes‐associated protein (YAP) into the nucleus, thus suppressing transcription of pro‐proliferative genes. Hence, dynamic and precise control of the Hippo pathway is crucial for organ size control and the prevention of tumor formation. Hippo signaling is controlled by a growing number of upstream regulators, including WW and C2 domain–containing (WWC) proteins, which trigger a serine/threonine kinase pathway. One component of this is the large tumor suppressor (LATS) kinase, which phosphorylates YAP, trapping it in the cytoplasm. WWC proteins have been shown to interact with LATS in vitro and stimulate its kinase activity, thus directly promoting cytoplasmic accumulation of phosphorylated YAP. However, the function of the WWC proteins in the regulation of cell proliferation, organ size control, and tumor prevention in vivo has not yet been determined. Here, we show that loss of hepatic WWC expression in mice leads to tissue overgrowth, inflammation, fibrosis, and formation of liver carcinoma. WWC‐deficient mouse livers display reduced LATS activity, increased YAP‐mediated gene transcription, and enhanced proliferation of hepatic progenitor cells. In addition, loss of WWC expression in the liver accelerates the turnover of angiomotin proteins, which act as negative regulators of YAP activity. Conclusion: Our data define an essential in vivo function for WWC proteins as regulators of canonical and noncanonical Hippo signaling in hepatic cell growth and liver tumorigenesis. Thus, expression of WWC proteins may serve as novel prognostic factors in human liver carcinoma. (Hepatology 2018;67:1546‐1559)

Hippo Signaling in the Liver – A Long and Ever-Expanding Story

“…Given the increase in liver stiffness that occurs in cirrhosis, mechanical inputs are key candidates for oncogenic YAP activation that contributes to fibrosis progression and liver cancer. Mechanistically, several membrane-associated proteins such as Nf2/Merlin, scaffolding proteins of the angiomotin family, and WWC proteins have been shown to positively and – for certain members of the angiomotin family – negatively regulate Hippo signaling (Zhang et al, 2010; Li et al, 2012; Yi et al, 2013; Moleirinho et al, 2017; Hermann et al, 2018) – however, the relevance of these proteins in cirrhosis is unknown to date. Several interacting pathways, including Wnt and Notch signaling, play a role in the control of oncogenic YAP in liver cancer.…”

Distinctive phosphoinositide- and Ca2+-binding properties of normal and cognitive performance–linked variant forms of KIBRA C2 domain

“…1). KIBRA has about 20 reported binding partners (2) and disease links, including dementia (3)(4)(5), kidney disease (6), Tourette disorder (7), and some cancers (8,9). Among its multiple functions, KIBRA is an upstream component of the Hippo pathway (8,10), a central mechanism of organ size control and cellular homeostasis.…”

Decoding WW domain tandem-mediated target recognitions in tissue growth and cell polarity

“…(Hao et al, 2008; Oka et al, 2008; Zhang et al, 2008; Chan et al, 2011; Wang et al, 2011; Zhao et al, 2011; Wang et al, 2012; Huang et al, 2013; Liu et al, 2013; Strano et al, 2001; Alarcón et al, 2009; Yi et al, 2013; Michaloglou et al, 2013). KIBRA WW domains have also been reported to bind to PY-motifs from LATS, AMOTs, and PTPN14 (Baumgartner et al, 2010; Genevet et al, 2010; Yu et al, 2010; Knight et al, 2018; Xiao et al, 2011; Hermann et al, 2018; Wang et al, 2014). The WW domains of SAV1 can bind to PY motifs of LATS (Tapon et al, 2002).…”