Protein phosphorylation and growth factor function

Project Summary/Abstract
The emerging Hippo pathway plays a major role in development, cell growth, tissue homeostasis, and
organ size. Dysregulation of Hippo pathway contributes to human diseases, most notably cancer. TCGA study
with analysis of over nine thousand human tumor samples has revealed that Hippo is one of the nine signals
pathways that are frequently altered and contributes to human cancer. The Hippo pathway consists a kinase
cascade that phosphorylates and inhibits the downstream transcription module of YAP/TAZ. A wide range of
signals have been discovered to modulate the Hippo pathway. However, the precise mechanism of Hippo
pathway regulation, particularly how upstream signals feed into the Hippo kinase cascade, is largely unknown.
The major goal of this proposal is to understand the fundamental mechanism of Hippo pathway regulation. By
screening for natural compounds to modulate the Hippo pathway, we have discovered that microcolin B (MCB)
potently activates the Hippo kinases. Our preliminary study indicates that MCB directly targets
phosphatidylinositol transfer protein (PITP) to activate the Hippo pathway. PITP functions to transfer
phosphatidylinositol from ER, the site of synthesis, to other compartment membranes, particularly plasma
membrane, in the cell. Our preliminary data suggest an exciting and novel model that phosphatidylinositol
metabolites play a key role in Hippo regulation. We further propose that NF2, which is a key upstream regulator
of the Hippo pathway and can bind phosphatidylinositol phosphates (PIPs), may mediate the PIP signal to Hippo
regulation. This proposal aims to demonstrate the function and mechanism of phosphatidylinositol and its
metabolites in Hippo regulation and how PIPs mediate upstream signals to Hippo. Further, completion of this
project will provide exciting scientific basis of using small molecules to target the Hippo pathway for YAP
dependent cancer.

Grant Number: 5R01GM051586-29
NIH Institute/Center: NIH
Principal Investigator: JOAN BROWN