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：
10352421
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/10352421
关键词：
3-Dimensional Actins Adhesions Adhesives Binding Binding Proteins Biomechanics Cadherins Cancer Cluster Carcinoma Cell Adhesion Molecules Cell physiology Cell-Cell Adhesion Cells Characteristics Complex Coupled Cytoplasmic Protein Cytoplasmic Tail Cytoskeleton Data Dissociation E-Cadherin Epithelial Epithelial Cells Exhibits Functional disorder Intercellular Junctions Invaded Knowledge Laboratories Link Malignant Neoplasms Measures Mediating 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耦合运动，一种被称为集体细胞迁移的现象。关键蛋白参与上皮细胞集体迁移的是E-钙粘蛋白（ECAD），这是一种必需的细胞 - 细胞粘合剂蛋白。 ECAD粘附受到仔细调节，以使细胞单层的复杂运动和失调失调粘附是某些癌症的特征。但是，关于ECAD结构和粘合剂的了解知之甚少受调节以及这在集体细胞迁移中如何表现。 ECAD的细胞外区域介导粘附，而其细胞内结构域与调节结合蛋白质，例如P120-catenin，α-钙蛋白和vinculin，它们将ECAD与肌动蛋白细胞骨架联系起来。我们假设 α-catenin，vinculin和p120-catenin通过变构控制了粘合剂 ECAD细胞外区域。我们还建议某些ECAD癌症突变阻碍了内而外的调节 ECAD的构象和理解其作用机理将提供分子见解肿瘤发生中的粘附调节。在本提案的目标1中，我们将为α-catenin，p120-catenin和vinculin结合分配不同的作用调节ECAD构象和测量癌症突变如何阻碍内而外的粘合剂调节。在 AIM 2，我们将确定细胞质蛋白如何通过建立详细的结构模型，用于具有和没有ECAD癌突变的细胞间连接。最后，在 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。我们提出的研究将对ECAD介导的粘附有详细的机械理解并解决在上皮组织形成，伤口愈合和癌症中很重要的粘合剂状态。知识将使特定ECAD结构的选择性定位和抑制可以妥协癌症进展。