Intercadherin Interactions in Epithelial Cells

描述（由申请人提供）：钙粘蛋白介导的粘附是一种重要的形态发生过程，导致形成高度组织化的细胞间连接。 在过去的十年里，我们的实验室一直在研究这一过程背后的分子细节。 我们的实验表明，钙粘蛋白介导的粘附是基于短寿命的钙粘蛋白粘附二聚体的连续形成。这些二聚体的显著特征之一是它们的稳定性：一旦从细胞中提取，二聚体在高达0.2%的SDS浓度下是稳定的。钙是其形成所必需的，但不是其维持所必需的。它们似乎是根据链二聚体模型组织的，链二聚体模型是钙粘蛋白二聚体的众多生物物理模型之一。二聚体的形成和分解都是复杂的细胞调控过程。它们的分解至少部分是由钙粘蛋白内吞作用介导的。这两个过程-钙粘蛋白二聚体的组装和解体-被提出来控制细胞与细胞接触的强度和可塑性。钙粘蛋白粘合剂二聚体，特别是，他们的功能意义和他们的组装分子的原则，是具体目标1的主要课题。此外，位点特异性交联分析将用于定义粘附连接和桥粒中钙粘蛋白-钙粘蛋白相互作用的多样性。调节粘附二聚体的聚集和寿命的细胞内过程是具体目标2的中心主题。本目标还将研究粘附二聚化是否诱导钙粘蛋白和连环蛋白（与钙粘蛋白细胞内区域相关的蛋白质）之间相互作用的任何变化。 这项工作的设计是至关重要的，以了解许多细胞间粘附疾病的分子基础-肿瘤细胞的侵袭和转移，特别是。这项工作也是开发合成粘附调节剂及其在医学中应用的关键一步。

DESCRIPTION (provided by applicant): Cadherin-mediated adhesion is a vital morphogenetic process that results in the formation of highly organized intercellular junctions. For the past decade, our laboratory has been studying the molecular details that underlie the process. Our experiments suggest that cadeherin-mediated adhesion is based on the continuous formation of short-lived cadherin adhesive dimers. One of the notable features of these dimers is their stability: once extracted from cells, the dimers are stable in SDS concentrations as high as 0.2%. Calcium is required for their formation, but not for their maintenance. They appear to be organized according to the strand dimer model, which is one of numerous biophysical models for cadherin dimers. Both the formation and disassembly of the dimers are complex and cell-regulated processes. Their disassembly is mediated, at least in part, by cadherin endocytosis. These two processes-cadherin dimer assembly and disassembly-are proposed to control the strength and plasticity of cell-cell contacts. Cadherin adhesive dimers-specifically, their functional significance and the molecular principles of their assembly-are the main subjects of Specific Aim 1. In addition, site-specific cross-linking analysis will be used to define the diversity of cadherin-cadherin interactions in both adherens junctions and desmosomes. The intracellular processes regulating the clustering and lifetime of adhesive dimers are central subjects of Specific Aim 2. This Aim will also study whether adhesive dimerization induces any changes in the interactions between the cadherin and catenins (proteins that associate with the intracellular region of cadherin). The work designed is critical to understanding the molecular basics of many cell-cell adhesion diseases- tumor cell invasiveness and metastasis, in particular. This work is also a critical step toward the development of synthetic adhesion modulators and their application in medicine.