Regulation of cell junctions and cell contact dependent signaling in tissue development and physiology

组织发育和生理学中细胞连接和细胞接触依赖性信号传导的调节

• 批准号: 9900839
• 负责人: BARRY M. GUMBINER
• 金额: $ 78.33万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-04 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900839
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adhesions; Adhesives; Antibodies; Binding; Biochemical; Biological Process; Biophysics; Blood Vessels; Cadherins; Cell Adhesion Molecules; Cell surface; Cell-Cell Adhesion; Cells; Cleft Lip; Contact Inhibition; Development; Disease; E-Cadherin; Endothelium; Epithelial; Epithelium; Goals; Growth; Growth Factor; Growth and Development function; Inflammatory; Intercellular Junctions; Malignant Neoplasms; Mammary Tumorigenesis; Mechanics; Mediating; Membrane; Modeling; Morphogenesis; Mosaicism; Mutation; Nuclear; Organ; Pathway interactions; Permeability; Physiological; Physiological Processes; Physiology; Process; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Protein; Structure; Tight Junctions; Tissues; Work; cadherin 5; genetic approach; in vivo; in vivo evaluation; mouse model; organ growth; tool; transcription factor

Regulation of cell junctions and cell contact dependent signaling in tissue development and physiology. Classical cadherins are cell-cell adhesion proteins that regulate tissue morphogenesis and cell junctions during physiological processes. They are highly regulated at the cell surface, controlling dynamic interactions between cells. Although much is known about the basic functions of cadherin-mediated adhesion, an understanding of the mechanisms underlying dynamic cell surface regulation, has not yet been achieved, nor is it well understood how such regulatory mechanism control physiological processes in vivo. Cadherins also transduce signals into the cell to convey information about the state of the tissue. One way they do is by stimulation of the Hippo-YAP signaling pathway to mediate contact inhibition of growth. This process is antagonized by growth factor signaling, via the PI3-kinase (PI3K) signaling pathway, which inhibits the Hippo pathway and stimulates nuclear YAP. We will investigate the mechanisms underlying the regulation of cadherin homophilic adhesive binding at different levels of analysis, from basic biochemical/biophysical/structural mechanisms, through cell biological process controlling adhesion (especially the role of p120-catenin), to evaluating the roles of adhesion regulation in physiological processes in vivo. We've found that cancer- and cleft lip-associated mutations in E- cadherin specifically interfere with the regulation of adhesion at the cell surface, and these will provide valuable tools for these studies. In vivo studies of cadherin regulation will focus on their roles in physiological control of barrier function in both epithelia and endothelia, especially during inflammatory processes where control of these functions are especially important. Studies on endothelial junctional regulation will require us to develop tools for studying VE-cadherin regulation, including activating antibodies, and models for endothelial barrier function; these will be compared to our studies of E-cadherin in epithelia. We'll also investigate the mechanisms by which cadherins transduce various signals into the cell. A major focus will be on the regulation of the Hippo-YAP pathway and associated TEAD transcription factors by cadherin-mediated contact and by growth factors and PI3K signaling. The goals are both to understand how they function and to enable us to develop genetic approaches to selectively perturb these interactions in vivo to evaluate their importance. Hippo signaling by formation of cadherin contacts will be compared to signaling by tight junctions as well as signals produced by mechanical tension at the cadherins. The Hippo-YAP pathway may be an important new branch of the PI3K signaling pathway that regulates tissue growth in addition to the well-known Akt-TOR pathways. This hypothesis will be tested in vivo both by studies on tissue overgrowth diseases caused by somatic mosaic constitutively active PI3K mutations and by studies of mouse models of mammary tumorigenesis. This project should reveal how cadherins work as bidirectional signaling proteins to transduce changes across the membrane and how these processes regulate the physiology and growth of tissues and organs in vivo.

在组织发育和生理学中调节细胞连接和细胞接触依赖性信号传导。 经典的钙粘蛋白是细胞 - 细胞粘附蛋白，可调节组织形态发生和细胞连接 生理过程。它们在细胞表面受到高度调节，控制着动态相互作用 细胞。尽管对钙粘蛋白介导的粘附的基本功能知之甚少，但对 动态细胞表面调节的基础机制尚未实现，也不是很好 了解这种调节机制如何在体内控制生理过程。钙粘蛋白也会转导 信号进入细胞以传达有关组织状态的信息。他们做的一种方法是刺激 河马信号传导途径介导了接触抑制的生长。这个过程被增长拮抗 因子信号传导，通过PI3-激酶（PI3K）信号通路，该途径抑制河马途径并刺激 核Yap。我们将研究钙粘蛋白均质粘合剂调节的基础机制 从基本的生化/生物物理/结构机制到不同分析水平的结合，到细胞 控制粘附的生物过程（尤其是p120-catenin的作用），以评估粘附的作用 体内生理过程中的调节。我们发现E-中的癌症和唇裂相关突变 钙粘蛋白专门干扰细胞表面的粘附调节，这些将提供有价值的 这些研究的工具。钙粘蛋白调节的体内研究将集中在其在生理控制中的作用 上皮和内皮中的障碍功能，尤其是在炎症过程中 这些功能尤其重要。关于内皮连接法规的研究将需要我们发展 研究VE-钙粘蛋白调节的工具，包括激活抗体和内皮屏障模型 功能;这些将与我们对上皮蛋白的E-钙黏着蛋白的研究进行比较。我们还将调查 钙粘着蛋白将各种信号转向细胞的机制。重点将放在法规上 通过钙粘蛋白介导的接触以及通过 生长因子和PI3K信号传导。目标都是了解它们的运作方式，并使我们能够 开发遗传方法，以选择性地在体内扰动这些相互作用以评估其重要性。河马 通过形成钙粘蛋白接触的信号将与紧密连接的信号和信号进行比较 由钙粘着蛋白的机械张力产生。河马途径可能是一个重要的新分支 除了众所周知的Akt-tor途径外，还调节组织生长的PI3K信号通路。 该假设将在体内通过研究由躯体镶嵌引起的组织过度生长疾病进行研究。 组成性活跃的PI3K突变和通过研究乳腺肿瘤发生的小鼠模型的研究。这个项目 应该揭示钙粘蛋白如何作为双向信号蛋白的作用 膜以及这些过程如何调节体内组织和器官的生理和生长。