Upstream regulation of the Hippo signaling pathway

Hippo 信号通路的上游调控

• 批准号: 10373014
• 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/10373014
• 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; 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; 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.

项目总结 河马途径是一种进化保守的发育途径，控制着器官的大小和组织 所有后生动物的动态平衡。河马信号转导通路失调涉及范围很广 包括癌症在内的人类疾病。尽管河马通路的核心信号级联很好地建立了，但 对河马途径的上游调控知之甚少。在这里，我们鉴定了果蝇肌管蛋白 (MTM)作为河马途径的一种新的上游调节因子。MTM丢失导致组织过度生长 最广为人知的两个河马途径靶基因diap1和Expanded的表达上调。MTM突变体 苍蝇还表现出眼间细胞增多和后毛囊细胞分化异常。 增殖，河马信号缺陷的特征。MTM是肌管蛋白家族的一员。 已知在控制膜磷脂动力学中功能的磷脂酰肌醇脂磷酸酶。 我们一致地发现，MTM是膜相关的，并与多种膜脂结合。我们的 初步研究还显示，MTM突变细胞中有很强的顶端F-肌动蛋白积聚。因此，我们 假设MTM是河马途径的一种新的上游调节因子，它调节细胞膜 磷脂动力学与肌动蛋白细胞骨架重构。本项目的目标是了解 MTM介导的河马磷脂动力学与肌动蛋白细胞骨架重构的功能相关性 上游调节途径。本研究的目的是阐明两者之间的调控关系。 MTM和河马途径已知成分(目标1)，以确定MTM在膜上的作用 河马途径的磷脂动力学及其功能相关性(目标2)，并确定下游 MTM在河马途径调控中的细胞功能(目标3)。这项研究的完成将为我们提供新的 对河马途径上游信号如何协调的机械性理解。