Mechanisms Directing Adherens Junctions and Actin Network Interactions

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是必不可少的，并且对于某些病理生理条件（例如伤口愈合）也是必需的。相反，粘附连接的丧失是癌症的标志，导致不受限制的细胞增殖和转移。细胞-细胞粘附连接需要在浆细胞膜上正确组装多蛋白复合物。在这里，单跨膜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。它们的胞质尾部结构域与？连环蛋白，它反过来又结合到？连环蛋白似乎通过抑制板状足的产生来指导粘附连接的形成。然而，这种三元钙粘蛋白：？？- catenin：？？-连环蛋白复合物不直接与肌动蛋白网络结合，而肌动蛋白网络是稳定这些连接和组织稳态所必需的。一种观点是，局部浓度的增加？-在这些复合物中的连环蛋白有利于？连环蛋白同源二聚体，然后通过其C-末端的结构域直接结合肌动蛋白来稳定这些复合物。通过从晶体结构转移到生物化学，然后转移到生物学，拟议的研究将定义粘附连接是如何稳定的，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丢失奠定基础，并可能为治疗干预提供新的途径。 公共卫生相关性：后生动物的发育和体内平衡需要细胞与它们的邻居形成稳定的接触，即创造的粘附连接。粘附连接是由跨膜钙粘蛋白受体的胞外结构域的同型相互作用指导的多蛋白复合物，该受体结合？连环蛋白通过它们的细胞内尾部结构域;连环蛋白然后结合到？？-连环蛋白和这种三元复合物似乎指导粘附连接的形成。我们的研究计划将确定这些连接是如何稳定和控制肌动蛋白网络。

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.