Mechanosensitive cadherin adhesion and its regulation

机械敏感钙粘蛋白粘附及其调控

基本信息

批准号：
10553124
负责人：
Sanjeevi Sivasankar
金额：
$ 37.44万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553124
关键词：
3-Dimensional Actins Adhesions Adhesives Binding Binding Proteins Biomechanics Cadherins Cancer Cluster Cell Adhesion Molecules Cell physiology Cell-Cell Adhesion Cells Characteristics Complex Coupled Cytoplasmic Protein Cytoplasmic Tail Cytoskeleton Data Dissociation E-Cadherin Epithelial Cells Epithelium Exhibits Functional disorder Intercellular Junctions Invaded Knowledge Laboratories Link Malignant Neoplasms Measures Mediating Membrane Modeling Molecular Molecular Conformation Movement Mutation Natural regeneration Neoplasm Metastasis Pattern Property Proteins Regulation Research Role Structural Models Structure Time Tissues Vertebral column Vinculin alpha catenin cancer cell cell motility extracellular genetic regulatory protein insight migration monolayer mutant single molecule tissue regeneration tumor progression tumorigenesis wound closure wound healing

项目摘要

ABSTRACT Cellular rearrangements during tissue formation, tissue regeneration and cancer metastasis occur via the coupled movement of groups of cells, a phenomenon known as collective cell migration. A key protein involved in the collective migration of epithelial cells is E-cadherin (Ecad), an essential cell-cell adhesion protein. Ecad adhesion is carefully regulated to orchestrate complex movement of cell monolayers and dysregulation of adhesion is a characteristic of certain cancers. However, little is known about how Ecad structure and adhesion are regulated and how this manifests in collective cell migration. The extracellular region of Ecad mediates adhesion, while its intracellular domain binds to regulatory proteins such as p120-catenin, α-catenin and vinculin, which link Ecad to the actin cytoskeleton. We hypothesize that α-catenin, vinculin and p120-catenin regulate adhesion by allosterically controlling the conformation of the Ecad extracellular region. We also propose that some Ecad cancer mutations impede the inside-out regulation of Ecad conformation and that understanding their mechanism of action will provide molecular insights into adhesion regulation in tumorigenesis. In aim 1 of this proposal, we will assign distinct roles to α-catenin, p120-catenin, and vinculin binding in modulating Ecad conformation and measure how cancer mutations impede inside-out regulation of adhesion. In aim 2, we will establish how cytoplasmic proteins alter the conformation of the Ecad extracellular region by building detailed structural models for intercellular junctions, with and without Ecad cancer mutations. Finally, in aim 3, we will resolve the role of different Ecad conformations and cancer mutants on the migratory patterns of epithelial cells. Our proposed research will provide a detailed mechanistic understanding of Ecad mediated adhesion and resolve adhesive states that are important in epithelial tissue formation, wound healing, and cancer. This knowledge will enable selective targeting and inhibition of specific Ecad structures, which can compromise cancer progression.

抽象的组织形成期间的细胞重排，组织再生和癌症转移通过细胞组的政变运动，一种被称为集体细胞迁移的现象参与上皮细胞集体迁移的是E-钙粘蛋白（ECAD），一种必需的细胞粘附蛋白。 ECAD粘附是经过仔细的定制的，以编排细胞单层的复杂运动和失调的失调粘附是某些癌症的特征。是规范的，以及这如何在集体细胞迁移中表现出来。 ECAD的细胞外区域介导粘附，而其细胞内结构域则介导蛋白质，例如P120-catenin，α-catenin和vinculin，它们将ECAD与肌动蛋白细胞骨架联系起来 α-钙蛋白，杂种蛋白和p120-catenin通过变构控制该构象来调节粘附。 ECAD细胞外区域。 ECAD构象和将其作用机理缠绕的构型将提供分子int象肿瘤发生中的粘附调节。在提案的目标1中，我们将为α-catenin，p120-catenin和vinculin结合分配不同的作用。调节ECAD构象并测量癌症突变如何阻碍粘附的内部调节 AIM 2, We Will Estoplasmic Proteins Alter the Conforation of the ECAD EXTRACELLRRRRRRRRRRRRR 构建详细的结构模型，以进行细胞间连接，并没有ECAD癌症 AIM 3，我们将解决不同ECAD构象和癌症突变体在迁移模式中的作用上皮细胞。我们的支撑研究提供了对ECAD介导的粘附的详细机械理解并解决在上皮，伤口愈合和癌症中很重要的粘合剂知识将使特定的ECAD结构的选择性定位和不可自行性，这可能会损害癌症进展。