PI-5-P links the Hippo Pathway and PI5P4K signaling [PIP4K2A/B shRNA]

The phosphoinositide PI-5-P is a signaling lipid that mediates cellular responses to oxidative stress and DNA damage, however it is unclear how PI-5-P participates in these processes. Intracellular pools of PI-5-P are regulated by PI5P-Kinases (PI5P4Ks), but how PI5P4K activity is controlled has also remained elusive. Here, we used an unbiased screen to discover the core Hippo pathway kinases MST1/2 phosphorylate and inhibit PI5P4K signaling in vitro and in cells. We further show PI5P4Ks regulate several Hippo/YAP-related phenotypes in human cells, such as the interaction between the key Hippo proteins MOB1-LATS, and the genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we show that MOB1 binds PI-5-P with high specificity and potency, providing a signaling connection between the Hippo Pathway and PI5P4Ks. These discoveries shed new light on how these two important evolutionary conserved signaling pathways are integrated to regulate metazoan development and human disease.