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，这两个进程相互交叉，但它们相互依存的程度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信号传导之间的两个潜在的关键联系。这些连接之一是含有E-钙粘蛋白和γ-分泌酶的复合物，γ-分泌酶是产生Notch衍生信号的酶。这些蛋白质通过p120- catenin相互连接，p120- catenin是基于钙粘蛋白的粘附的关键调节剂。在第二种复合物中，E-钙粘蛋白与Notch配体Dll 1或Jag 2相互作用。这一建议涉及四个问题：㈠这两个综合体的详细结构是什么，它们是如何组装的？(ii)钙粘蛋白在它们的细胞表面动力学，特别是在它们的内吞作用中起什么作用？(iii)它们在Notch信号中的作用是什么？(iv)它们在角质形成细胞分化中的作用是什么？我们建议，钙粘蛋白促进Notch信号转导共集群Notch信号成分内细胞连接和/或内吞结构。此外，这些簇的钙粘蛋白驱动的内吞作用可以产生Notch构象的转变，从而启动Notch信号级联。这一建议将有助于阐明在正常稳态和炎症性皮肤疾病中协调角质形成细胞的形态发生、增殖和分化程序的机制。

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.