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: 9803476
• 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/9803476
• 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; Motor; Myosin ATPase; Names; Natural regeneration; Nonmuscle Myosin Type IIA; Nuclear; Organ; Organism; Output; Pathway interactions; Phosphotransferases; 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.

项目总结/摘要 组织生长的适当协调在正常发育和发育过程中都是至关重要的。 许多疾病，包括癌症。2000年果蝇和哺乳动物系统的研究 在过去的20年左右，已经确定Hippo途径是组织生长的中心调节器。如同 许多信号通路，Hippo组件包括跨膜蛋白，细胞质激酶 级联，并通过核转录因子介导的输出。然而，Hippo的监管 信号传导异常复杂，涉及机械张力，顶-底极性，反馈回路， 在细胞皮层的空间上不同的区域调节不同通路组分的组装。在 此外，通过平面细胞极性机制的组分施加进一步的途径控制， 特别是通过脂肪/Dachsous信号的输出。脂肪和Dachsous都是大跨膜 原钙粘蛋白，其功能是控制非典型肌球蛋白的丰度和定位， 达克斯Dachs似乎不是一种功能性运动蛋白，而是在细胞皮层起作用， 在激酶级联水平调节途径活性。研究河马途径， 特别是脂肪/Dachsous信号，提供了一个非凡的机会，了解如何多个输入， 感知不同的环境线索，协调控制重要的 发育和疾病相关的生长控制途径。 在这个建议中，我们描述了旨在解开一些复杂的脂肪， Dachsous信号传导，以便我们能够阐明其基本的分子原理， 功能首先，我们提出了蛋白质“核心复合物”的概念，这些蛋白质与Dachs相互作用并招募Dachs。 到细胞皮层，在那里它起着促进生长的作用。在缺乏上游监管的情况下， 蛋白质是最活跃的。我们描述了旨在更好地理解这一点的实验。 复杂的形式和什么因素调节其在细胞皮层组装的能力。第二，我们建议 脂肪和Dachsous共同作用抑制核心复合物的活性，从而 控制组织生长。根据以前发表的数据和我们自己未发表的观察，我们 提出了一个以前未被认识到的作用，Dachsous在消除Dachs从细胞皮层，通过 内吞作用，并描述了一个实验计划，严格测试这一假设。在一起，结果 这些研究有可能从根本上改变我们对生物力学的理解， Hippo组织生长控制途径中的脂肪/Dachsous信号传导。