Upstream regulation of the Hippo signaling pathway

Hippo 信号通路的上游调控

• 批准号: 10589105
• 负责人: Jianzhong Yu
• 金额: $ 33.81万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589105
• 关键词: Actins; Animals; Apical; Apoptosis; Binding; Biochemical; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Charcot-Marie-Tooth Disease; Cytoskeleton; Defect; Development; Disease; Drosophila genus; Exhibits; F-Actin; Family; Genes; Genetic; Genetic Transcription; Goals; Growth; Homeostasis; Human; Lipids; Malignant Neoplasms; Mediating; Membrane; Membrane Lipids; Mutation; Neurofibromin 2; Oncoproteins; Organ Size; Pathway interactions; Phenotype; Phosphatidylinositols; Phospholipids; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Production; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Testing; Tissues; Tumor Suppressor Proteins; Work; fly; imaginal disc; inorganic phosphate; insight; member; mutant; myotubularin; novel; overexpression; phosphatidylinositol 3-phosphate

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.

项目概要 Hippo 途径是一种进化上保守的发育途径，控制器官大小和组织 所有后生动物的体内平衡。失调的 Hippo 通路与多种疾病有关 人类疾病，包括癌症。尽管 Hippo 通路核心信号级联已经很完善， Hippo 通路的上游调控尚不清楚。在这里我们鉴定了果蝇肌管蛋白 (Mtm) 作为 Hippo 通路的新型上游调节因子。 mtm 缺失导致组织过度生长 diap1 的表达升高并扩展了两个最著名的 Hippo 通路靶基因。 mtm突变体 果蝇还表现出鼓间细胞增多和后滤泡细胞分化异常， 增殖，河马信号缺陷的标志。 Mtm 是肌管蛋白家族的成员 磷酸肌醇脂质磷酸酶具有控制膜磷脂动力学的已知功能。 我们一致发现 Mtm 与膜相关并与多种膜脂结合。我们的 初步研究还揭示了 mtm 突变细胞中顶端 F-肌动蛋白的强烈积累。我们因此 假设 Mtm 是 Hippo 通路的一种新型上游调节因子，可调节膜 磷脂动力学和肌动蛋白细胞骨架重塑。该项目的目标是了解 Hippo 中 Mtm 介导的磷脂动力学和肌动蛋白细胞骨架重塑的功能相关性 通路上游调控。本研究的目的是阐明两者之间的调节关系 Mtm 和 Hippo 途径已知成分（目标 1），以确定 Mtm 对膜的作用 磷脂动力学及其在 Hippo 通路中的功能相关性（目标 2），并定义下游 Mtm 在 Hippo 通路调节中的细胞功能（目标 3）。这项研究的完成将为 对 Hippo 通路上游信号如何协调的机制理解。