Molecular Mechanisms of Cell Adhesion

细胞粘附的分子机制

• 批准号: 10459227
• 负责人: TINA IZARD
• 金额: $ 48.3万
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10459227
• 关键词: Actin-Binding Protein; Actins; Adherens Junction; Adhesions; Animals; Award; Binding; Biochemical; Biological Process; Cardiac; Cell Adhesion; Cell Proliferation; Cell membrane; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Crystallization; Cytoskeleton; Development; Epithelial; Extracellular Matrix; Focal Adhesions; Foundations; Funding; Genes; Homeostasis; Intercellular Junctions; Knowledge; Laboratories; Link; Lipid Binding; Malignant Neoplasms; Mediator of activation protein; Molecular; National Institute of General Medical Sciences; Play; Process; Protein Isoforms; Regulation; Research; Research Personnel; Resolution; Role; Signal Transduction; Stress; Structure; Talin; Techniques; Tissues; Transcript; Vinculin; alpha catenin; cell motility; mechanotransduction; prevent; programs; structural biology; translational impact; translational potential

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.

程序摘要 这个最大化调查人员的研究奖（MIRA）提案与远程直接相关 国家一般医学科学研究所（NIGMS）的计划。我们的实验室不断收到 自2004年以来的纽格姆斯资金使我们在理解方面取得了重大进步 相邻细胞之间动态接触的机制（粘附连接）以及之间 细胞和细胞外基质（焦点粘合剂结构）。这些细胞连接，除了保持 动物细胞一起传达信号并控制置于细胞上的应力。 在过去的16年中，我们为了解 ·细胞电池连接如何在时间中连接细胞以调节对组织的组织平衡，这对 提供上皮的组织屏障，以及细胞迁移和增殖；和 ·在调节基础组织的同时，细胞连接如何启动和维护细胞粘合剂 肌动蛋白细胞骨架通过建立细胞信号传导和基因转录中心调节中心。 这样的过程是高度动态的，并且受到严格的调节。我们的实验室专注于定义激活 我们在生化和活细胞中研究的这些细胞连接的关键调节剂的机制。我们的 我们开发的新技术克服了重要的结构，从而加速了发现 生物学障碍使该领域停滞不前，并且适用于许多其他结构生物学研究。 我们发现塔林如何激活两个普遍表达的肌动蛋白结合蛋白的vinculin，以稳定 局灶性粘合剂，从而抑制细胞迁移。我们的高分辨率Vinculin晶体结构， 我们在生化细胞和活细胞中证实，显示自身抑制性分子内相互作用表明 灭活杂质蛋白，从而防止源自源自肌动蛋白细胞骨架。 另一方面，我们的高分辨率A-catenin的高分辨率晶体结构，这是一个关键的细胞间介质 粘附，揭示了其四元结构在细胞 - 细胞粘合剂和中发挥的机械作用 与肌动蛋白细胞骨架的动态链接的形成。重要的是，我们的发现导致了机械 细胞细胞和细胞基质连接的转导研究有关细胞如何感知和传递力的转导。 最近，我们发现了脂质如何与Vinculin，其心脏同工型Metavinculin和Talin结合 调节局灶性粘合剂更新。这些知识和专业知识是进一步发现的基础 这还将集中在质膜在细胞粘附中发挥的理解作用。 从长远来看，我们希望通过达到近乎原子能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对 因此，许多生物学过程，例如发育和癌症，我们提出的研究已经 基本和潜在的翻译意义。