Type I gamma phosphatidylinositol phosphate kinase i5 suppresses YAP1 signaling

Dysregulation of the Hippo/Yes-associated protein (YAP) signaling pathway has been associated with several diseases, including cancer, neurological disorders, and cardiovascular conditions. However, the precise molecular mechanisms governing Hippo/YAP signaling are not fully understood, and additional regulators of this pathway need to be identified. Our research has identified type I gamma phosphatidylinositol phosphate kinase i5 (PIPKIγi5) as a regulator of Hippo/YAP signaling. PIPKIγi5 is a kinase responsible for synthesizing phosphatidylinositol-4,5-bisphosphate (PI4,5P₂). By directly interacting with YAP1, PIPKIγi5 prevents the nuclear translocation of YAP1, thereby suppressing YAP1-mediated gene transcription. Thus, PIPKIγi5 functions as a suppressor of YAP1-mediated signaling. The kinase activity of PIPKIγi5, which generates PI4,5P₂, is essential for controlling YAP1 function. PI4,5P₂ promotes the interaction of YAP1 with the 14-3-3 protein, which retains YAP1 in the cytosol. Given the role of YAP1 signaling in cancer cell stemness, depletion of PIPKIγi5 enhances YAP1 signaling and promotes tumorsphere formation in head and neck squamous cell carcinoma. These findings highlight a PI4,5P₂-modulated signaling nexus that exerts specific control over Hippo/YAP signaling and its biological functions.