Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer

Abstract

SUMMARY The Hippo pathway and its regulatory target, YAP, has recently emerged as an important biochemical signaling pathway that tightly governs epithelial tissue growth. Initially defined in Drosophilia, this pathway has shown remarkable conservation in vertebrate systems with many components of the Hippo/YAP pathway showing biochemical and functional conservation. The liver is particularly sensitive to changes in Hippo/YAP signaling with rapid increases in liver size becoming manifest on the order of days to weeks after perturbation. The first identified direct targets of Hippo/YAP signaling were pro-proliferative and anti-apoptotic gene programs, but recent work has now implicated this pathway in cell fate choice, stem cell maintenance/renewal, epithelial to mesenchymal transition, and oncogenesis. The mechanisms by which Hippo/YAP signaling is changed endogenously are beginning to come to light as well as how this pathway interacts with other signaling pathways, and important details for designing new therapeutic interventions. This review focuses on the known roles for Hippo/YAP signaling in the liver and promising avenues for future study.

Mechanisms of Hippo pathway regulation

“…Studies of Drosophila and mouse models have established the role of YAP/Yki in regulating tissue progenitor cell self-renewal and expansion, especially in gastrointestinal tissues Barry et al 2013;Gregorieff et al 2015;Imajo et al 2015;Taniguchi et al 2015;Yimlamai et al 2015). Although earlier transgenic mouse studies have shown striking phenotypes and established a role of the Hippo pathway in development and carcinogenesis (Morin-Kensicki et al 2006;Camargo et al 2007;Dong et al 2007;Yabuta et al 2007), many more refined transgenic mouse models with tissue-specific deletion and inducible overexpression have been generated in the last few years.…”

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

“…The Hippo pathway is the major regulator of YAP activity (60,61). Upstream signals that activate Hippo (and inactivate YAP) include extracellular soluble factors via G protein-coupled receptors, mechanotransduction, cell-cell contact, and polarity (28,62), including apical polarity complexes such as Crb3 (63).…”

Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis

“…HCC is the fifth most common cancer and second leading cause of cancer deaths in the world (6,7). It is imperative to understand how these signaling pathways interact with each other when causing HCC, as the same mutations in one signaling pathway are likely to have distinct effects on the disease, depending on the genetic status of its interacting pathways (2,8).…”