Inter-junctional signaling in epithelial junctional complex

摘要 每个细胞-细胞接触整合了许多功能和结构不同的连接点 类型在形态发生变化过程中，这些连接必须协调重塑。长期 我们项目的目标是确定这种协调的机制。 在我们资助的当前资助周期中，我们研究了粘附性细胞外模块之间的相互作用， 和肌动蛋白结合的粘附连接的细胞内模块（AJs）。这些细胞中的细胞间粘附 连接是由跨膜蛋白，钙粘蛋白，与肌动蛋白细胞骨架相互作用介导的 通过一种叫做连环蛋白的蛋白质。我们发现了一个非凡的结合过程-合作结合 连接蛋白转化为肌动蛋白丝。我们展示了这一过程如何控制钙粘蛋白粘附界面。在 此外，同样的过程将附着在AJs上的肌动蛋白纤维束成束， 另一个连接的组装，称为连接蛋白连接（NJs）。我们的初步数据表明， 组装是基于NJ蛋白对α-连环蛋白组装束的特异性识别， afadin。 在我们的建议中概述的这一数据和其他数据提出了一个新的假设，即肌动蛋白结合蛋白的 NJs、紧密连接和桥粒识别由AJs产生的局部肌动蛋白丝组织 并且这种识别协调细胞-细胞接触中所有连接的组装和动力学。 我们的建议不仅将探索这种概念上的新型细胞信号传导，而且还将奠定 角质形成细胞是了解这种信号在复杂形态发生过程中的作用的基础 分层

Abstract Each cell-cell contact integrates many individual junctions of several functionally and structurally different types. These junctions must be coordinately remodeled during morphogenetic changes. The long-term goal of our project is to define the mechanisms of this coordination. In the current funding cycle of our grant, we study the interplay between adhesive extracellular module and actin-binding intracellular module of adherens junctions (AJs). The cell-cell adhesion in these junctions is mediated by the transmembrane protein, cadherin, that interacts with the actin cytoskeleton through proteins called catenins. We discovered a remarkable binding process – the cooperative binding of α-catenin to actin filaments. We showed how this process controls the cadherin adhesive interface. In addition, the same process bundles actin filaments attached to AJs and the resulting bundles nucleate the assembly of another junctions, called nectin junctions (NJs). Our preliminary data suggests that this assembly is based on the specific recognition of the α-catenin-assembled bundles by the NJ protein, afadin. This and other data, outlined in our proposal, suggest a new hypothesis that the actin-binding proteins of NJs, tight junctions, and desmosomes recognize the local actin filament organization produced by AJs and that this recognition coordinates the assembly and dynamics of all junctions in the cell-cell contacts. Our proposal will not only explore this conceptually new type of cell signaling, but also will lay the foundation for understanding the role of this signaling in a complex morphogenetic process, keratinocyte stratification.