Mechanosensitive cadherin adhesion and its regulation

机械敏感钙粘蛋白粘附及其调控

• 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
• 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

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.

摘要 在组织形成、组织再生和癌症转移过程中，细胞重排通过 细胞群的耦合运动，这一现象称为集体细胞迁移。一种关键蛋白质 E-钙粘蛋白(E-cadherin，ECAD)参与了上皮细胞的集体迁移，是一种重要的细胞-细胞黏附蛋白。 ECAD黏附受到仔细的调节，以协调细胞单层的复杂运动和 粘连是某些癌症的特征。然而，人们对ECAD的结构和粘附性知之甚少 以及这如何在集体细胞迁移中表现出来。 ECAD的胞外区介导黏附，而它的胞内区与调节区结合 P120-连环蛋白、α-连环蛋白和纽蛋白等蛋白质，它们将ECAD与肌动蛋白细胞骨架联系起来。我们假设 α-连环蛋白、纽蛋白和p120-连环蛋白通过变构控制 ECAD胞外区。我们还提出，一些ECAD癌症突变阻碍了由内而外的调控 ECAD构象和了解它们的作用机制将提供对 肿瘤发生中的黏附调节。 在本提案的目标1中，我们将在α-连环蛋白、p120-连环蛋白和纽蛋白结合蛋白中分配不同的角色 调节ECAD构象并测量癌症突变如何阻碍由内而外的黏附调节。在……里面 目的2，我们将确定细胞质蛋白如何通过以下方式改变ECAD胞外区的构象 建立细胞间连接的详细结构模型，有无ECAD癌症突变。最后，在 目的3，我们将解决不同的ECAD构象和癌症突变体在肿瘤细胞迁移模式中的作用 上皮细胞。 我们提出的研究将提供对ECAD介导的粘连的详细机制的理解 并解决在上皮组织形成、伤口愈合和癌症中重要的粘连状态。这 知识将能够选择性地靶向和抑制特定的ECAD结构，这可能会损害 癌症进展。