Mechanisms directing adherens junctions and actin network interactions

指导粘附连接和肌动蛋白网络相互作用的机制

基本信息

批准号：
9913186
负责人：
TINA IZARD
金额：
$ 9.53万
依托单位：
SCRIPPS FLORIDA
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 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913186
关键词：
3-Dimensional Actins Adherens Junction Adhesions Binding Biochemical Biochemistry Biological Biology Bundling Cadherins Calcium Binding Cell Adhesion Cell Adhesion Molecules Cell Proliferation Cell membrane Cell-Cell Adhesion Cells Cellular biology Coin Collaborations Complex Cryoelectron Microscopy Crystallization Cytoplasmic Tail Cytoskeletal Proteins Cytoskeleton Cytosol Development Disease Disseminated Malignant Neoplasm Distant E-Cadherin Epithelial Equilibrium Eukaryota Extracellular Domain F-Actin F-actin-binding proteins Fluorescence Resonance Energy Transfer Foundations Funding Genetic Transcription Homeostasis Human Immunoglobulins Interdisciplinary Study Length Ligands Link Lipids Malignant Neoplasms Mechanics Mediating Membrane Molecular Molecular Conformation Morphogenesis Morphology Multiprotein Complexes Neoplasm Metastasis Neoplasms Neurons Organ Organogenesis Pathologic Phosphatidylinositol 4,5-Diphosphate Photobleaching Plasma Cells Play Process Production Proteins Protomer Regulation Research Research Project Grants Role Simple Epithelium Site Structure Tail Therapeutic Intervention Tissues Transmembrane Domain Vinculin Wound Healing X-Ray Crystallography afadin alpha catenin beta catenin cell growth cell motility crosslink dimer experimental study extracellular in vivo innovation insight mechanical load migration monomer multidisciplinary programs receptor reconstruction tumor progression tumorigenesis

项目摘要

Program summary The balance between cell migration and cell–cell adhesion is crucial during development and is altered in disease states such as metastatic cancers. Cells migrate during development to specific sites when upon contact with other cells; they become stationary and differentiate into tissues. Thus, strong cell–cell adhesion is necessary in maintaining tissue integrity. Changes in cell–cell adhesion reinitiate cell migration during cell turnover or wound healing or allow metastatic cells to scatter to distant organs. The formation and stabilization of cell-cell adhesion complexes (adherens junctions) is essential for metazoan development, organogenesis, and tissue homeostasis, and it also necessary for some pathophysiological conditions, such as wound healing. In contrast, loss of adherens junctions is a hallmark of cancer, leading to unrestricted cell proliferation and metastasis. Cell-cell adherens junctions require the proper assembly of multi-protein complexes at the plasma cell membrane. Here, homotypic interactions between the calcium-binding ectodomains of single transmembrane pass cadherin receptors allow neighboring cells to bind to one another. The interactions of their cytoplasmic tail domains with β-catenin, which in turn binds to α-catenin, appear to direct the formation of adherens junctions, by inhibiting the production of lamellopodia. However, without tension, this ternary cadherin/β-catenin/α-catenin complex does not bind directly to the actin network, which is necessary for stabilizing these junctions and for tissue homeostasis. In the first 3 years of funding by GM094483, we determined the crystal structure of dimeric full-length human α-catenin and of vinculin-bound α-catenin, and these structures and our biochemical and biological studies defined the roles of the vinculin-α-catenin interaction in the formation and stabilization of adherens junctions. By moving from crystal structures and 3D reconstructions to biochemistry and then to biology, the proposed studies will define how adherens junctions are stabilized and control the organization of the actin cytoskeleton. Collectively, our proposed studies will significantly increase our understanding of α-catenin monomer-dimer transitions and their effects on membrane dynamics, migration, and cell adhesion. Importantly, our multi-disciplinary studies will also lay the foundation for understanding how these controls are lost during tumor progression and may suggest new avenues for therapeutic intervention.

节目概要细胞迁移和细胞间粘附之间的平衡在发育过程中至关重要，疾病状态发生改变，例如转移性癌症，细胞在发育过程中迁移到特定的区域。当与其他细胞接触时，它们变得静止并分化成组织。强的细胞间粘附对于维持组织完整性是必要的。细胞间粘附的变化。在细胞更新或伤口愈合过程中重新启动细胞迁移或允许转移细胞分散到远处的器官。细胞与细胞粘附复合物（粘附连接）的形成和稳定对于后生动物发育、器官发生和组织稳态，对于某些动物来说也是必要的病理生理状况，例如伤口愈合，相反，粘附连接的丧失是一个原因。癌症的标志，导致不受限制的细胞增殖和细胞粘附。连接需要在浆细胞膜上正确组装多蛋白复合物。单次跨膜通道的钙结合胞外域之间的同型相互作用钙粘蛋白受体允许相邻细胞相互结合。具有 β-连环蛋白的细胞质尾部结构域，进而与 α-连环蛋白结合，似乎可以指导粘附连接的形成，通过抑制板状伪足的产生。张力，这种三元钙粘蛋白/β-连环蛋白/α-连环蛋白复合物不直接与肌动蛋白网络结合，这对于稳定这些连接和组织稳态是必要的。在GM094483资助的前3年里，我们确定了二聚体全长的晶体结构人类 α-连环蛋白和纽蛋白结合的 α-连环蛋白，以及这些结构和我们的生化和生物学研究定义了纽蛋白-α-连环蛋白相互作用在形成和通过从晶体结构和 3D 重建转向稳定粘附连接。生物化学，然后是生物学，拟议的研究将定义粘附连接是如何进行的总的来说，我们提出的研究将稳定并控制肌动蛋白细胞骨架的组织。显着增加我们对 α-连环蛋白单体-二聚体转变及其影响的理解重要的是，我们的多学科研究也将。为了解这些控制在肿瘤进展过程中如何丧失奠定基础，并可能提出治疗干预的新途径。