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信号的调节。 经典的钙粘蛋白是细胞-细胞粘附蛋白，其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，控制细胞与细胞之间的动态相互作用。 细胞尽管对钙粘蛋白介导的粘附的基本功能已经有了很多了解，但对钙粘蛋白介导的粘附的理解还不够。 动态细胞表面调节的潜在机制尚未实现，也不是很好 了解这种调节机制如何控制体内的生理过程。钙粘蛋白也 信号进入细胞以传达关于组织状态的信息。其中一种方法是刺激 Hippo-YAP信号通路介导生长的接触抑制。这一过程被增长所对抗 因子信号传导，通过PI3-激酶（PI3K）信号传导途径，其抑制Hippo途径并刺激 核雅普。我们将研究钙粘蛋白嗜同性粘附的调节机制， 结合在不同的分析水平，从基本的生物化学/生物物理/结构机制，通过细胞 粘附控制的生物学过程（特别是p120-catenin的作用），以评估粘附的作用 调节体内生理过程。我们发现癌症和唇裂相关的E- 钙粘蛋白特异性地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它们在生理控制中的作用， 上皮和内皮的屏障功能，特别是在炎症过程中， 这些功能尤其重要。对内皮连接调节的研究将要求我们发展 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细胞中E-钙粘蛋白的研究进行比较。我们还将调查 钙粘蛋白传递各种信号进入细胞的机制。一个主要的焦点将是监管 通过钙粘蛋白介导的接触和通过Hippo-YAP途径和相关的TEAD转录因子 生长因子和PI3K信号传导。我们的目标是了解它们是如何运作的，并使我们能够 发展遗传学的方法来选择性地干扰这些在体内的相互作用，以评估它们的重要性。河马 将通过形成钙粘蛋白接触的信号传导与通过紧密连接的信号传导以及通过形成钙粘蛋白接触的信号传导进行比较。 由钙粘蛋白的机械张力产生。Hippo-YAP通路可能是一个重要的新的分支 除了众所周知的Akt-TOR途径外，PI3K信号通路还调节组织生长。 这一假设将在体内进行测试，无论是对组织过度生长疾病的研究引起的体细胞镶嵌 组成型活性PI3K突变和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， 膜以及这些过程如何调节体内组织和器官的生理学和生长。

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.