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.

项目摘要/摘要 组织生长的适当协调对于正常发育和 许多疾病过程，包括癌症。果蝇和哺乳动物系统的研究进展 在过去的20年左右的时间里，人们已经发现河马途径是组织生长的中心调节因子。和以前一样 许多信号通路中，河马的成分包括跨膜蛋白，一种细胞质激酶 级联，并通过核转录因子介导的输出。然而，对河马的监管 信号异常复杂，涉及机械张力、心尖-基底极性、反馈环和 不同途径组件在细胞皮质空间不同区域的受控组装。在……里面 此外，进一步的通路控制由平面细胞极性机制的组件实施， 特别是通过来自Fat/Dachsous信令的输出。脂肪和腊肠都是大跨膜的 原钙粘附素，功能是控制一种名为的非典型肌球蛋白的丰度和定位 达克斯。DAKS似乎不是一种功能性的运动蛋白，而是在细胞皮质发挥功能，以 在激酶级联的水平上调节通路的活性。研究河马途径，并在 特定的FAT/Dachsous信令，提供了一个非同寻常的机会来了解多个输入如何 是感知到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。 在这项提案中，我们描述了旨在解开肥胖背后的一些复杂性的实验。 Dachsous信号，以便我们能够阐明其基本的分子原理 功能。首先，我们提出了与达赫斯相互作用并招募达赫斯的蛋白质的“核心复合体”的概念。 到细胞皮质，在那里它起到促进生长的作用。在缺乏上游监管的情况下，这些 蛋白质具有最大的活性。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它在细胞皮质组装的能力。第二，我们建议 Fat和Dachsous共同发挥抑制核心复合体活性的概念，从而 控制组织生长。基于之前发表的数据和我们自己未发表的观察结果，我们 提出了Dachsous在通过以下途径将Dachsus从细胞皮质中移除的先前未被认识的作用 内吞作用，并描述了严格检验这一假说的实验计划。总之，结果是 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/Dachsous信号。