Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP
Lavinia Palamiuc, Jared L. Johnson, Zeinab Haratipour, Ryan M. Loughran, Woong Jae Choi, Gurpreet K. Arora, Vivian Tieu, Kyanh Ly, Alicia Llorente Lope, Sophia Crabtree, Jenny C. Y. Wong, Archna Ravi, Thorsten Wiederhold, Rabi Murad, Raymond D. Blind, Brooke M. Emerling
Abstract
, respectively, are emerging as intracellular metabolic and stress sensors. We performed an unbiased screen to investigate the signals that these kinases relay and the specific upstream regulators controlling this signaling node. We found that the core Hippo pathway kinases MST1/2 phosphorylated PI5P4Ks and inhibited their signaling in vitro and in cells. We further showed that PI5P4K activity regulated several Hippo- and YAP-related phenotypes, specifically decreasing the interaction between the key Hippo proteins MOB1 and LATS and stimulating the YAP-mediated genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we showed that PI5P interacted with MOB1 and enhanced its interaction with LATS, thereby providing a signaling connection between the Hippo pathway and PI5P4Ks. These findings reveal how these two important evolutionarily conserved signaling pathways are integrated to regulate metazoan development and human disease.