Functional and Structural Links between Cadherin, Gamma-Secretase, and Notch

描述（由申请人提供）：钙粘蛋白介导的粘附和Notch信号通路是多细胞生物进化开始时发展的两个关键过程。第一个过程将大量细胞排列成高度组织化的组织。第二个决定了单个细胞的分化程序。虽然一些间接证据表明这两个过程相互交叉，但它们相互依赖的水平和机制在很大程度上是未知的。我们的初步实验确定了钙粘蛋白介导的粘附和Notch信号之间的两个潜在的关键联系。其中一个链接是含有e -钙粘蛋白和分泌酶的复合物，分泌酶产生notch衍生的信号。这些蛋白通过p120-连环蛋白相互连接，p120-连环蛋白是钙粘蛋白黏附的关键调节因子。在第二个复合体中，e -钙粘蛋白与Notch配体Dll1或Jag2相互作用。这一建议解决了四个问题：(i)这两个建筑群的详细结构是什么，它们是如何组装的？（ii）钙粘蛋白在细胞表面动力学中的作用，特别是在它们的内吞作用中是什么？（iii）它们在Notch信号传导中的作用是什么？（iv）它们在角质形成细胞分化中的作用是什么？我们提出钙粘蛋白通过在细胞-细胞连接处和/或内吞结构内共同聚集Notch信号元件来促进Notch信号转导。此外，钙粘蛋白驱动的这些簇内吞作用可能会引起Notch构象的改变，从而启动Notch信号级联。这一建议将阐明在正常稳态和炎症性皮肤病中角质形成细胞形态发生、增殖和分化程序的协调机制。

DESCRIPTION (provided by applicant): Cadherin-mediated adhesion and the Notch signaling pathway are two critical processes developed at the start of the evolution of multicellular organisms. The first process arranges numerous cells into highly organized tissues. The second determines the differentiation program of individual cells. While some circumstantial evidence suggests that the two processes intersect, the levels and mechanisms of their interdependency are largely unknown. Our preliminary experiments identified two potentially crucial links between cadherin- mediated adhesion and Notch signaling. One of these links is a complex containing E-cadherin and gamma- secretase, the enzyme that generates a Notch-derived signal. The proteins are interconnected via p120- catenin, a critical regulator of cadherin-based adhesion. In a second complex, E-cadherin interacts with Notch ligands, either Dll1 or Jag2. This proposal addresses four questions: (i) What are the detailed structures of both complexes and how are they assembled? (ii) What is the role of cadherin in their cell surface dynamics, and in their endocytosis in particular? (iii) What are their roles in Notch signaling? (iv) What are their roles in keratinocyte differentiation? We propose that cadherin facilitates Notch signal transduction by co-clustering Notch signaling components within cell-cell junctions and/or within the endocytic structures. Furthermore, cadherin-driven endocytosis of these clusters may generate the shift in Notch conformation, thereby initiating a Notch signaling cascade. This proposal will shed light on mechanisms coordinating morphogenetic, proliferation and differentiation programs of keratinocytes during normal homeostasis and inflammatory skin diseases.