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）的形成和稳定是后生动物发育、器官发生和组织稳态所必需的，也是一些病理生理条件所必需的，例如伤口愈合。相反，粘附连接的丧失是癌症的一个标志，导致无限制的细胞增殖和转移。细胞-细胞黏附连接需要多蛋白复合物在质细胞膜上的适当组装。在这里，钙结合外结构域之间的同型相互作用允许相邻细胞相互结合。它们的细胞质尾部结构域与？-catenin，然后结合？-catenin，似乎通过抑制板足的产生来指导粘附连接的形成。然而，这个三元系钙粘蛋白：？？ ？-catenin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。一种想法是局部浓度的增加？-连环蛋白在这些复合物中有利于？-连环蛋白同型二聚体，然后通过c末端的结构域直接与肌动蛋白结合，从而稳定这些复合物。通过从晶体结构到生物化学再到生物学，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，我们的研究还将为理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。

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.