A conserved MST1/2–YAP axis mediates Hippo signaling during lung growth

Abstract

Hippo signaling is a critical player in controlling the growth of several tissues and organs in diverse species. The current model of Hippo signaling postulates a cascade of kinase activity initiated by the MST1/2 kinases in response to external stimuli. This leads to inactivation of the transcriptional coactivators, YAP/TAZ, due to their cytoplasmic retention and degradation that is correlated with YAP/TAZ phosphorylation. In most tissues examined, YAP plays a more dominant role than TAZ. Whether a conserved Hippo pathway is utilized during lung growth and development is unclear. In particular, the regulatory relationship between MST1/2 and YAP/TAZ in the lung remains controversial. By employing the Shh-Cre mouse line to efficiently inactivate genes in the lung epithelium, we show that loss of MST1/2 kinases in the epithelium can lead to neonatal lethality caused by lung defects. This is manifested by perturbation of lung epithelial cell proliferation and differentiation. These phenotypes are more severe than those produced by Nkx2.1-Cre, highlighting the effects of differential Cre activity on phenotypic outcomes. Importantly, expression of YAP targets is upregulated and the ratio of phospho-YAP to total YAP protein levels is reduced in Mst1/2-deficient lungs, all of which are consistent with a negative role of MST1/2 in controlling YAP function. This model gains further support from both in vivo and in vitro studies. Genetic removal of one allele of Yap or one copy of both Yap and Taz rescues neonatal lethality and lung phenotypes due to loss of Mst1/2. Moreover, knockdown of Yap in lung epithelial cell lines restores diminished alveolar marker expression caused by Mst1/2 inactivation. These results demonstrate that MST1/2 inhibit YAP/TAZ activity and establish a conserved MST1/2-YAP axis in coordinating lung growth during development.

Crumbs3-Mediated Polarity Directs Airway Epithelial Cell Fate through the Hippo Pathway Effector Yap

“…The Hippo pathway has emerged as a major regulator of Yap localization, with the core pathway kinases, Lats1 and Lats2 (Lats1/2), promoting the direct phosphorylation of Yap on conserved serine residues, which induce cytoplasmic sequestration and degradation of Yap (Dong et al, 2007; Zhao et al, 2010). These modifications have been implicated in the regulation of Yap activity in the lung (Lange et al, 2014; Lin et al, 2015; Mahoney et al, 2014; Zhao et al, 2014). However, how these kinases are regulated with respect to organ morphogenesis and patterning is unclear.…”

HMGCR positively regulated the growth and migration of glioblastoma cells

“…TAZ has been reported to regulate multiple physiological processes, including lung differentiation (Lin et al, 2015), adipogenesis and osteogenesis (He et al 2012,;Tang et al, 2013). In the progression of tumorigenesis, TAZ was found to be up-regulated in various types of cancer and regulated the proliferation, migration as well as the epithelial-mesenchymal transition (EMT) (Liu et al, 2010;Pan, 2010).…”

Hippo pathway in lung development

“…One study demonstrated Mst1/2 regulated lung development through Foxa2 independently of Yap/Taz signaling (12). However, the other studies indicated that Hippo components Mst1/2 and Mob1 regulated lung development through Hippo effector Yap/Taz, which means a canonical Hippo-Yap signaling pathway was involved (13,15,16). Whether Foxa2 mediates some aspects of Mst1/2 function in the lung is unclear.…”

“…Whether Foxa2 mediates some aspects of Mst1/2 function in the lung is unclear. The discrepancy of Mst1/2 studies of regulatory relationship between Mst1/2 and Yap in the lung may be due to variable efficiencies of the mouse Cre lines to remove Mst1/2 in different mouse models (15).…”