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: 8107239
• 负责人: TINA IZARD
• 金额: $ 37.62万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107239
• 关键词: Actins; Adherens Junction; Affect; Binding; Binding Sites; Biochemical; Biochemistry; Biological; Biology; C-terminal; Cadherins; Calcium Binding; Cell Proliferation; Cell membrane; Cell-Cell Adhesion; Cells; Chimera organism; Coin; Complex; Cytoplasmic Tail; Cytoskeleton; Data; Data Set; Development; Dimerization; Epithelial Cells; Event; Extracellular Domain; F-Actin; Focal Adhesions; Foundations; Goals; Head; Homeostasis; Human; Length; Link; Malignant Neoplasms; Mediating; Modeling; Molecular Conformation; N-terminal; Neoplasm Metastasis; Organogenesis; Plasma Cells; Play; Production; Research; Role; Site-Directed Mutagenesis; Structural Models; Structure; Tail; Talin; Testing; Therapeutic Intervention; Tissues; Vinculin; Wound Healing; feeding; insight; monomer; mutant; programs; protein complex; receptor; tumor progression

DESCRIPTION (provided by applicant): The formation and stabilization of cell-cell adhesion complexes (adherens junctions) is essential for metazoan development, organogenesis and tissue homeostasis, and is also necessary for some pathophysiological conditions, for example 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 allows neighboring cells to bind to one another. The interactions of their cytoplasmic tail domains with ?-catenin, which in turn binds to ?-catenin, appears to direct the formation of adherens junctions, by inhibiting the production of lamellopodia. However, this ternary cadherin:??-catenin:??-catenin complex does not bind directly to the actin network, which is necessary for stabilizing these junctions and for tissue homeostasis. One thought is that local increases in the concentrations of ?-catenin at these complexes favors the formation of ?-catenin homodimers that then stabilize these complexes by directly binding to actin through a domain in their C-termini. By moving from crystal structures to biochemistry and then to biology, the proposed studies will define how adherens junctions are stabilized and control the organization of the actin cytoskeleton. Importantly, our studies will also lay the foundation for understanding how these controls are lost during tumor progression and may suggest new avenues for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Metazaon development and homeostasis requires that cells from stable contacts, coined adherens junctions, with their neighbors. Adherens junctions are multi- protein complexes that are directed by homotypic interactions of the extracellular domains of transmembrane cadherin receptors, which bind to ?-catenin via their intracellular tail domains; ?-catenin then binds to ??-catenin and this ternary complex appears to direct the formation of adherens junctions. Our research program will define how these junctions are stabilized and control the actin network.

描述（由申请人提供）：细胞-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至关重要，并且对于某些病理生理状况（例如伤口愈合）也是必需的。相反，粘附连接的丧失是癌症的一个标志，导致细胞增殖和转移不受限制。细胞与细胞的粘附连接需要多蛋白复合物在浆细胞膜上的正确组装。在此，单次跨膜通道钙粘蛋白受体的钙结合胞外域之间的同型相互作用允许相邻细胞彼此结合。它们的细胞质尾部结构域与β-连环蛋白的相互作用，进而与β-连环蛋白结合，似乎通过抑制板状伪足的产生来指导粘附连接的形成。然而，这种三元钙粘蛋白：??-连环蛋白：??-连环蛋白复合物并不直接与肌动蛋白网络结合，而肌动蛋白网络对于稳定这些连接和组织稳态是必需的。一种想法是，这些复合物中β-连环蛋白浓度的局部增加有利于形成β-连环蛋白同型二聚体，然后通过其C末端的结构域直接与肌动蛋白结合来稳定这些复合物。通过从晶体结构转向生物化学，然后转向生物学，拟议的研究将定义粘附连接如何稳定并控制肌动蛋白细胞骨架的组织。重要的是，我们的研究还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。 公共健康相关性：Metazaon 的发育和体内平衡需要细胞与邻近细胞形成稳定的接触，形成粘附连接。粘附连接是多蛋白复合物，由跨膜钙粘蛋白受体胞外结构域的同型相互作用引导，跨膜钙粘蛋白受体通过其胞内尾部结构域与β-连环蛋白结合；然后，β-连环蛋白与 β-连环蛋白结合，并且该三元复合物似乎指导粘附连接的形成。我们的研究计划将定义如何稳定这些连接并控制肌动蛋白网络。