Molecular Mechanisms of Cell Adhesion

细胞粘附的分子机制

• 批准号: 10604429
• 负责人: TINA IZARD
• 金额: $ 35.78万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604429
• 关键词: Molecular; Mechanisms; Cell; Adhesion

Program Summary This Maximizing Investigators’ Research Award (MIRA) proposal is directly relevant to the long-range plans of the National Institute of General Medical Sciences (NIGMS). Our laboratory received continuous NIGMS funding since 2004 that allowed us to make substantial advances in our understanding of the mechanisms of the dynamic contacts between neighboring cells (adherens junctions), as well as between cells and the extracellular matrix (focal adhesions structures). These cell junctions, in addition of holding animal cells together, communicate signals and control the stress placed upon cells. Over the past 16 years, we contributed important mechanistic discoveries towards an understanding of · how the cell-cell junctions connect cells in tissues to regulate tissue homeostasis that are crucial to provide the tissue barrier of epithelia, as well as cell migration and proliferation; and · how cell junctions initiate and maintain cell adhesion while regulating the organization of the underlying actin cytoskeleton by establishing a center for cell signaling and gene transcript regulation. Such processes are highly dynamic and tightly regulated. Our laboratory focused on defining the activation mechanisms of key regulators of these cell junctions that we studied biochemically and in live cells. Our discoveries were accelerated by our development of new techniques that overcame significant structural biology hurdles that stalled the field and that are applicable to many other structural biology studies. We discovered how talin activates vinculin, two ubiquitously expressed, actin-binding proteins, to stabilizes focal adhesions and thereby suppressing cell migration. Our high-resolution vinculin crystal structures, that we confirmed biochemically and in live cells, showed the auto-inhibitory intramolecular interactions that inactivate vinculin and thereby prevent vinculin from binding to the actin cytoskeleton. On the other hand, our high-resolution crystal structures of a-catenin, a crucial mediator of intercellular adhesions, revealed the mechanistic roles that its quaternary structures play in cell-cell adhesion and in the formation of the dynamic link to the actin cytoskeleton. Significantly, our discoveries led to mechano- transduction studies of cell-cell and cell-matrix junctions on how cells sense and transmit forces. More recently, we discovered how lipid binding to vinculin, to its cardiac isoform metavinculin, and to talin regulates focal adhesion turnover. This knowledge and expertise are the foundation for further discoveries that will additionally focus on the understudied role that the plasma membrane plays in cell adhesion. In the long run, we hope to gain a complete understanding of cell adhesion by attaining a near atomic structure of a “synthetic” cell junction. The regulation and dysregulation of cell junctions are fundamental to many biological processes such as development and cancer, and our proposed studies have therefore both basic and potentially translational significance.

计划概要 这项最大化研究者研究奖（MIRA）提案与长期研究直接相关。 国家普通医学科学研究所 (NIGMS) 的计划。我们实验室连续收到 自 2004 年以来 NIGMS 的资助使我们在对这一问题的理解上取得了实质性进展 相邻细胞之间（粘附连接）以及之间的动态接触机制 细胞和细胞外基质（粘着斑结构）。这些细胞连接除了保持 动物细胞聚集在一起，传递信号并控制施加在细胞上的压力。 在过去的 16 年里，我们为理解 · 细胞与细胞的连接如何连接组织中的细胞以调节对生命至关重要的组织稳态 提供上皮细胞的组织屏障以及细胞迁移和增殖；和 · 细胞连接如何启动和维持细胞粘附，同时调节底层组织 通过建立细胞信号传导和基因转录调控中心来构建肌动蛋白细胞骨架。 这些过程是高度动态且受到严格监管的。我们的实验室专注于定义激活 我们通过生化和活细胞研究了这些细胞连接的关键调节因子的机制。我们的 我们开发的新技术克服了重大的结构性问题，加速了发现 阻碍该领域发展的生物学障碍也适用于许多其他结构生物学研究。 我们发现了talin如何激活纽蛋白（两种普遍表达的肌动蛋白结合蛋白）以稳定 粘着斑，从而抑制细胞迁移。我们的高分辨率纽蛋白晶体结构， 我们通过生化和活细胞证实了自抑制分子内相互作用 使纽蛋白失活，从而阻止纽蛋白与肌动蛋白细胞骨架结合。 另一方面，我们的 a-连环蛋白（细胞间质的重要介质）的高分辨率晶体结构 粘附，揭示了其四级结构在细胞间粘附和细胞粘附中发挥的机制作用 与肌动蛋白细胞骨架的动态连接的形成。值得注意的是，我们的发现导致了机械- 关于细胞如何感知和传递力的细胞-细胞和细胞-基质连接的转导研究。 最近，我们发现脂质如何与纽蛋白、其心脏异构体元纽蛋白和踝蛋白结合 调节粘着斑周转。这些知识和专业知识是进一步发现的基础 此外，该研究还将重点关注质膜在细胞粘附中所起的尚未被研究的作用。 从长远来看，我们希望通过获得近原子水平来获得对细胞粘附的完整理解。 “合成”细胞连接的结构。细胞连接的调节和失调是细胞连接的基础 许多生物过程，例如发育和癌症，因此我们提出的研究 具有基本意义和潜在的转化意义。