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.

项目摘要 河马途径是一种控制器官大小和组织的进化保守的发育途径 所有后生动物中的体内平衡。河马途径失调的范围很广 包括癌症在内的人类疾病。尽管公认的河马途径核心信号级联，但 河马途径的上游调节知之甚少。在这里，我们确定了果蝇肌管蛋白 （MTM）是河马途径的新型上游调节器。 MTM损失导致组织过度生长 DIAP1的表达升高并扩展，这是两个最著名的河马途径靶基因。 mtm突变体 苍蝇还表现出增加的室内细胞和异常的后卵泡细胞分化和 扩散，河马信号缺陷的标志。 MTM是Myoubularin家族的成员 具有已知功能在控制膜磷脂动力学方面的已知功能的磷酸肌醇脂质磷酸酶。 一致地，我们发现MTM与膜相关，并与多种膜脂质结合。我们的 初步研究还揭示了MTM突变细胞中强大的顶端F-肌动蛋白积累。因此，我们 假设MTM是调节膜的河马途径的新型上游调节剂 磷脂动力学和肌动蛋白细胞骨架重塑。该项目的目的是了解 河马中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 途径上游调节。这项研究的目的是阐明 MTM和HIPPO途径已知成分（AIM 1），以确定MTM在膜上的作用 磷脂动力学及其在河马途径中的功能相关性（AIM 2），并定义下游 MTM在河马途径调节中的细胞功能（AIM 3）。这项研究的完成将提供新颖 对河马通路上游信号如何协调的机械理解。