Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides

The Hippo pathway plays a key role in development, organ size control and tissue homeostasis, and its dysregulation contributes to cancer. The LATS tumor suppressor kinases phosphorylate and inhibit the YAP/TAZ transcriptional co-activators to suppress gene expression and cell growth. Through a screen of marine natural products, we identified microcolin B (MCB) as a Hippo activator that preferentially kills YAP-dependent cancer cells. Structure-activity optimization yielded more potent MCB analogs, which led to the identification of phosphatidylinositol transfer proteins alpha and beta (PITP alpha/beta) as the direct molecular targets. We established a critical role of PITP alpha/beta in regulating LATS and YAP. Moreover, we showed that PITP alpha/beta influence the Hippo pathway via plasma membrane phosphatidylinositol-4-phosphate. This study uncovers a previously unrecognized role of PITP alpha/beta in Hippo pathway regulation and as potential cancer therapeutic targets.

Automated summary

The Hippo pathway is crucial for development, organ size control, and tissue homeostasis, and its dysregulation is linked to cancer. In this study, a marine natural product called microcolin B (MCB) was identified as a Hippo activator that selectively kills YAP-dependent cancer cells. Structural optimization led to the discovery that phosphatidylinositol transfer proteins alpha and beta (PITP alpha/beta) are the direct molecular targets of MCB. The study reveals a previously unknown role of PITP alpha/beta in regulating the Hippo pathway and suggests them as potential therapeutic targets for cancer.