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

• 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
• 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

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， 在转移性癌症等疾病状态下发生改变。细胞在发育过程中迁移到特定的 与其他细胞接触时的位点；它们变得静止并分化成组织。因此， 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，粘附连接的损失是 癌症的标志，导致不受限制的细胞增殖和转移。细胞间粘附 连接需要多蛋白复合物在浆细胞膜上的正确组装。这里， 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彼此结合。他们的互动 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 通过抑制板状伪足的产生来形成粘附连接。然而，如果没有 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 粘附连接的稳定。通过从晶体结构和 3D 重建转向 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 稳定并控制肌动蛋白细胞骨架的组织。总的来说，我们提出的研究将 显着增加我们对 α-连环蛋白单体-二聚体转变及其对 膜动力学、迁移和细胞粘附。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。