Upstream regulation of the Hippo signaling pathway

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PROJECT SUMMARY The Hippo pathway is an evolutionarily conserved developmental pathway that controls organ size and tissue homeostasis in all metazoan animals. Dysregulated Hippo pathway has been implicated in a wide range of human disorders, including cancer. Despite the well-established Hippo pathway core signaling cascade, the upstream regulation of the Hippo pathway is less understood. Here we identified Drosophila Myotubularin ( Mtm) as a novel upstream regulator of the Hippo pathway. Loss-of-mtm caused tissue overgrowth with elevated expression of diap1 and expanded, two most well-known Hippo pathway target genes. mtm mutant flies also exhibited increased interommatidial cells and aberrant posterior follicle cell differentiation and proliferation, hallmarks of Hippo signaling defects. Mtm is a member of the myotubularin family of phosphoinositide lipid phosphatases with known function in controlling membrane phospholipid dynamics. Consistently, we found that Mtm is membrane associated and binds to multiple membrane lipids. Our preliminary studies also revealed a strong apical F-actin accumulation in mtm mutant cells. We therefore hypothesize that Mtm is a novel upstream regulator of the Hippo pathway that regulates membrane phospholipid dynamics and actin cytoskeleton remodeling. The goal of this project is to understand the functional relevance of Mtm-mediated phospholipid dynamics and actin cytoskeleton remodeling in Hippo pathway upstream regulation. The objective of this study is to elucidate the regulatory relationship between Mtm and the Hippo pathway known components (Aim 1), to determine the role of Mtm on membrane phospholipid dynamics and its functional relevance in Hippo pathway (Aim 2), and to define the downstream cellular function of Mtm in Hippo pathway regulation (Aim 3). Accomplishment of this study will provide novel mechanistic understanding of how Hippo pathway upstream signals are coordinated.