Upstream regulation of the Hippo signaling pathway

项目摘要 河马途径是一种进化上保守的发育途径，控制器官大小和组织 所有后生动物体内的平衡。Hippo通路的失调涉及广泛的 包括癌症在内的人类疾病尽管Hippo通路的核心信号级联已经建立， 对Hippo通路的上游调控了解较少。在这里我们鉴定了果蝇肌管蛋白 （Mtm）作为Hippo途径的新型上游调节剂。MTM缺失导致组织过度生长， diap 1和扩展的表达升高，这是两个最知名的Hippo途径靶基因。mtm突变体 果蝇还表现出增加的卵间细胞和异常的后卵泡细胞分化， 这是河马信号缺陷的标志MTM是肌管蛋白家族的一员， 已知在控制膜磷脂动力学中具有功能的磷酸肌醇脂质磷酸酶。 因此，我们发现Mtm是膜相关的，并结合到多个膜脂质。我们 初步研究还揭示了在mtm突变细胞中的强顶端F-肌动蛋白积累。因此我们 假设Mtm是Hippo通路调节膜的一种新的上游调节因子 磷脂动力学和肌动蛋白细胞骨架重塑。本项目的目标是了解 Mtm介导的磷脂动力学与海马肌动蛋白细胞骨架重塑的功能相关性 上游调控途径。本研究的目的是阐明调节之间的关系， Mtm和Hippo通路的已知组分（Aim 1），以确定Mtm对膜的作用 磷脂动力学及其在Hippo途径中的功能相关性（目的2），并确定下游 Mtm在Hippo通路调节中的细胞功能（Aim 3）。这项研究的完成将提供新的 对Hippo通路上游信号如何协调的机械理解。

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.