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

钙粘蛋白、γ-分泌酶和 Notch 之间的功能和结构联系

基本信息

批准号：
8469391
负责人：
Sergey M Troyanovsky
金额：
$ 31.29万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8469391
关键词：
Address Adhesions Animal Experiments Binding Biochemical Biological Models Cadherins Cell physiology Cell surface Cells Complex Conflict (Psychology)Data Development Disease E-Cadherin Elements Endocytosis Enzymes Epithelial Cell Proliferation Epithelial Cells Evolution Foundations Homeostasis Human Individual Inflammation Inflammatory Intercellular Junctions Learning Ligands Light Link Maps Mediating Molecular Molecular Conformation Molecular Structure Mutagenesis Notch Signaling Pathway Organism P-Cadherin Participant Pathology Play Process Proteins Reaction Recruitment Activity Reporting Role Signal Pathway Signal Transduction Skin Structure Surface System Techniques Tertiary Protein Structure Tissues Work Wound Healing base carcinogenesis design gamma secretase keratinocyte keratinocyte differentiation mutant notch protein presenilin programs public health relevance research study secretase skin disorder trafficking

项目摘要

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.

描述（由申请人提供）：钙粘蛋白介导的粘附和Notch信号通路是在多细胞生物进化开始时开发的两个关键过程。第一个过程将许多细胞整合到高度组织的组织中。第二个决定了单个细胞的分化程序。尽管一些间接证据表明这两个过程相交，但它们相互依存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信号传导之间的两个潜在至关重要的联系。这些链接之一是一个包含电子钙粘蛋白和γ-泌尿酶的复合物，即产生缺口信号的酶。蛋白质通过P120-Catenin（基于钙粘着蛋白的粘附的关键调节剂）互连。在第二个复合物中，E-钙粘着蛋白与Notch配体相互作用，无论是DLL1还是JAG2。该提案解决了四个问题：（i）两者的详细结构是什么，它们如何组装？（ii）钙粘着蛋白在其细胞表面动力学，尤其是内吞作用中的作用是什么？（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？我们建议钙粘蛋白通过在细胞 - 细胞连接内和/或内吞结构内的共聚类Notch信号分量来促进Notch信号转导。此外，这些簇的钙粘着蛋白驱动的内吞作用可能会产生Notch构象的转移，从而启动Notch信号级联。该提议将阐明在正常稳态和炎症性皮肤疾病期间协调角质形成细胞形态发生，增殖和分化程序的机制。