Cadherin Clusters and actin filaments

钙粘蛋白簇和肌动蛋白丝

• 批准号: 10579179
• 负责人: Sergey M Troyanovsky
• 金额: $ 46.23万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579179
• 关键词: Actins; Adaptor Signaling Protein; Adherens Junction; Adhesions; Adhesives; Amaze; Binding; Binding Proteins; Cadherins; Cell Polarity; Cell-Cell Adhesion; Cells; Complex; Coupled; Cytoskeletal Modeling; Cytoskeleton; Data; Development; Event; F-Actin; Foundations; Generations; Individual; Lateral; Link; Liquid substance; Mediating; Medicine; Microfilaments; Molecular; Morphogenesis; Play; Process; Proliferating; Proteins; Radial; Reaction; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Protein; Stratification; Structure; Testing; Time; Tissues; Vertebrates; Work; alpha catenin; cell motility; design; experimental study; extracellular; flexibility; fortification; in vitro Model; in vivo; intercalation; mutant; nanocluster; novel; pharmacologic; practical application; recruit; scaffold; segregation; solid state

Cadherin clustering is a unique molecular process that mediates and controls cell-cell adhesion. In addition, it also regulates the actin cytoskeleton, polarity, proliferation, and apparently other structures and signaling pathways. Cadherin clusters reinforce weak individual adhesive bonds and generate functional cell-cell adhesion links. By connecting to F-actin, they determine the overall organization and dynamics of the actin cytoskeleton. Finally, they provide specific structural scaffolds for various signaling pathways. Despite such incredibly important functions, which obviously play out in nearly every aspect of tissue morphogenesis, the molecular mechanisms and regulation of cadherin clustering remains to be studied. This proposal will shed light on how cadherin clusters form and how they participate in such diverse array of cellular mechanisms. The work done under this proposal in previous years showed that adherens junctions (AJs), the major cell-cell adhesion structures in vertebrates, consist of numerous transient but highly adhesive cadherin nanoclusters. The short lifetime of each cluster makes AJs adhesive and flexible at the same time. The continuous generation of these clusters is apparently based on a remarkable reaction – cooperative binding of the cadherin-associated protein α-catenin to actin filaments. The assembly- disassembly cycles of both cadherin clusters and associated F-actin are tightly coupled thereby synchronizing cadherin and actin dynamics in adjacent cells. Finally, we found that cadherin clusters could be structurally diversified by cadherin/catenin-bound proteins. Diversification of cadherin clustering is based on the fact that each of these proteins provides specific modes of lateral cadherin- cadherin interactions. A variety of these interactions results in formation of an array of distinct clusters each of which might have particular functions. The advances in understanding cadherin clustering allow us to come up with this proposal, which includes: (i) the role of cadherin in clustering and function of two proteins, signaling protein Erbin, and adaptor protein PLEKHA5; (ii) molecular mechanisms interconnecting extracellular cadherin binding events with α-catenin-binding to F-actin; and (iii) the role of cadherin clustering in some examples of tissue morphogenesis.

钙粘蛋白成簇是介导和控制细胞间粘附的独特分子过程。在 此外，它还调节肌动蛋白细胞骨架，极性，增殖和其他明显的结构 和信号通路。钙粘蛋白簇增强弱的单个粘附键， 功能性细胞-细胞粘附连接。通过连接到F-肌动蛋白，它们决定了整个组织 和肌动蛋白细胞骨架的动力学。最后，它们为各种不同的细胞提供了特定的结构支架。 信号通路尽管如此令人难以置信的重要功能，显然发挥了近 组织形态发生的各个方面，钙粘蛋白的分子机制和调节 聚类仍有待研究。这项提议将阐明钙粘蛋白簇是如何形成的， 它们参与了多种多样的细胞机制。 根据这一建议在前几年所做的工作表明，粘附连接（AJs），主要是 脊椎动物中的细胞间粘附结构，由许多短暂但高度粘附的 钙粘蛋白纳米簇。每个簇的短寿命使得AJs同时具有粘合性和柔性 时间这些星系团的连续产生显然是基于一个显着的反应- 钙粘蛋白相关蛋白α-连环蛋白与肌动蛋白丝的协同结合。大会─ 钙粘蛋白簇和相关的F-肌动蛋白的拆卸周期紧密耦合， 使相邻细胞中的钙粘蛋白和肌动蛋白动力学同步。最后，我们发现钙粘蛋白簇 可以通过钙粘蛋白/连环蛋白结合蛋白在结构上多样化。钙粘蛋白的多样性 聚类是基于这样的事实，即这些蛋白质中的每一种都提供了特定的侧向钙粘蛋白模式， 钙粘蛋白相互作用各种各样的这些相互作用的结果形成一个阵列的不同集群 每一个都可能具有特定的功能。钙粘蛋白成簇的研究进展 允许我们提出这个建议，其中包括：（i）钙粘蛋白在聚类中的作用， 两种蛋白质，信号蛋白Erbin和衔接蛋白PLEKHA 5的功能;（ii）分子 细胞外钙粘蛋白结合事件与α-连环蛋白结合F-肌动蛋白的相互作用机制; 和（iii）钙粘蛋白簇在组织形态发生的一些例子中的作用。