Regulation of the Dachs core complex in tissue growth control

Dachs 核心复合物在组织生长控制中的调节

• 批准号: 10166884
• 负责人: Richard G Fehon
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166884
• 关键词: Apical; Binding; Biochemical; Biological; Cancer Biology; Cells; Complex; Cues; Cytoplasmic Protein; Data; Development; Disease; Drosophila genus; Endocytosis; Epithelial; F-Actin; Fatty acid glycerol esters; Feedback; Genetic; Goals; Growth; Integral Membrane Protein; Intercellular Junctions; Learning; Ligands; Link; Malignant Neoplasms; Mechanics; Mediating; Molecular; Molecular Genetics; Morphogenesis; Motor; Myosin ATPase; Names; Natural regeneration; Nonmuscle Myosin Type IIA; Nuclear; Organ; Organism; Output; Pathway interactions; Phosphotransferases; Physical activity; Play; Process; Proteins; Publishing; Regulation; Research; Role; SH3 Domains; Signal Pathway; Signal Transduction; Structure; System; Tertiary Protein Structure; Testing; base; cell cortex; design; developmental disease; experimental study; human disease; member; palmitoylation; planar cell polarity; protein complex; protein function; recruit; stem cell biology; tool; transcription factor

Project Summary/Abstract Proper coordination of tissue growth is of fundamental importance both in normal development and in many disease processes, including cancer. Studies in Drosophila and mammalian systems over the past 20 years or so have identified the Hippo pathway as a central regulator of tissue growth. As with many signaling pathways, Hippo components include transmembrane proteins, a cytoplasmic kinase cascade, and output mediated through nuclear transcription factors. However, regulation of Hippo signaling is unusually complex, involving mechanical tension, apical-basal polarity, feedback loops, and regulated assembly of different pathway components at spatially distinct regions of the cell cortex. In addition, further pathway control is exerted by components of the planar cell polarity mechanism, specifically by output from Fat/Dachsous signaling. Fat and Dachsous are both large transmembrane protocadherins that function to control the abundance and localization of an atypical myosin named Dachs. Dachs does not appear be a functional motor protein, but instead functions at the cell cortex to regulate pathway activity at the level of the kinase cascade. Studying the Hippo pathway, and in particular Fat/Dachsous signaling, offers an extraordinary opportunity to learn how multiple inputs that are sensing distinct environmental cues are coordinated to control the output of an important developmental and disease-related growth control pathway. In this proposal, we describe experiments designed to unravel some of the complexity underlying Fat- Dachsous signaling so that we can elucidate the underlying molecular principles essential for its function. First, we propose the notion of a 'core complex' of proteins that interact with and recruit Dachs to the cell cortex where it functions to promote growth. In the absence of upstream regulation, these proteins are maximally active. We describe experiments designed to better understand how this complex forms and what factors regulate its ability to assemble at the cell cortex. Second, we propose the notion that Fat and Dachsous together function to repress activity of the core complex, and thereby control tissue growth. Based on previously published data and our own unpublished observations, we propose a previously unrecognized role for Dachsous in removing Dachs from the cell cortex via endocytosis, and describe an experimental plan to rigorously test this hypothesis. Together, the results of these studies have the potential to fundamentally change our mechanistic understanding of Fat/Dachsous signaling in the Hippo tissue growth control pathway.

项目摘要/摘要 在正常发育和在 许多疾病过程，包括癌症。果蝇和哺乳动物系统的研究 过去20年左右，将河马途径确定为组织生长的中心调节剂。和 许多信号通路，河马成分包括跨膜蛋白，一种细胞质激酶 级联和通过核转录因子介导的输出。但是，河马的调节 信号传导异常复杂，涉及机械张力，顶点极性，反馈回路和 在细胞皮质的空间不同区域的不同途径组件的调节组装。在 此外，通过平面细胞极性机制的组成部分施加了进一步的途径控制， 特别是通过脂肪/二豆信号传导的输出。脂肪和二脑都是大型跨膜 可控制非典型肌球蛋白的丰度和定位的原始蛋白 dachs。 dachs似乎不是功能性运动蛋白，而是在细胞皮质上发挥作用 调节激酶级联水平的途径活性。研究河马途径和 特别的脂肪/二豆信号传导，提供了一个非凡的机会来了解多个输入 感知不同的环境线索是协调的，以控制重要的输出 发育和疾病相关的生长控制途径。 在此提案中，我们描述了旨在阐明脂肪基础的某些复杂性的实验 小采用信号传导，以便我们可以阐明基本的分子原理 功能。首先，我们提出了与dachs相互作用和招募dachs的蛋白质“核心复合物”的概念 到促进生长的功能的细胞皮质。在没有上游调节的情况下，这些 蛋白质具有最大活性。我们描述了旨在更好地理解如何理解的实验 复杂形式以及哪些因素调节其在细胞皮质上组装的能力。其次，我们建议 脂肪和二豆功能抑制核心复合物的活性的观念，从而 控制组织生长。根据先前发布的数据和我们自己未发表的观察结果，我们 提出了先前未认识到的硫s在从细胞皮质中取出dachs的作用 内吞作用，并描述严格检验该假设的实验计划。一起，结果 这些研究有可能从根本上改变我们对 河马组织生长控制途径中的脂肪/二豆信号传导。