UC San Diego

We herein describe a PITP/-PI4KIII-MAP4K signaling axis that modulates the Hippo pathway in response to plasma membrane PI4P levels. Our study highlights a novel role for PITP/ in regulating the Hippo kinase cascade through the identification of VT01454, a small-molecule inhibitor and Microcolin B analog that induces YAP phosphorylation. We characterize VT01454 as both a potent and specific YAP inhibitor, use bio-orthogonal methods to identify PITP/ as the unequivocal targets of VT01454, and functionally validate the role of PITP/ in Hippo signaling by genetic deletion in HEK293A cells. Finally, we demonstrate that VT01454 inhibition of PITP/ regulates the Hippo pathway by modulation of a plasma membrane pool of PI4P, and that MAP4K6/7 are potential PI4P-interacting proteins.