Mechanisms Directing Adherens Junctions and Actin Network Interactions

描述(由申请人提供)：细胞-细胞黏附复合体(黏附连接)的形成和稳定对于后生动物的发育、器官的发生和组织的动态平衡是必不可少的，也是一些病理生理条件所必需的，例如伤口愈合。相比之下，黏附连接的丧失是癌症的一个标志，导致细胞不受限制地增殖和转移。细胞-细胞黏附连接需要在质细胞膜上适当地组装多蛋白复合体。在这里，单个跨膜通过钙粘附素受体的钙结合外区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β-连环蛋白的相互作用，进而与？-连环蛋白结合，似乎通过抑制板孔的产生来指导粘连连接的形成。然而，这种三元钙粘蛋白：？？-连环蛋白：？？-连环蛋白复合体并不直接与肌动蛋白网络结合，肌动蛋白网络是稳定这些连接和组织动态平衡所必需的。一种认为，在这些复合体中，β-连环蛋白浓度的局部增加有利于β-连环蛋白同源二聚体的形成，然后通过C-末端的一个结构域直接与肌动蛋白结合来稳定这些复合体。通过从晶体结构到生物化学再到生物学，拟议的研究将定义附着连接是如何稳定的，并控制肌动蛋白细胞骨架的组织。重要的是，我们的研究也将为了解这些控制如何在肿瘤进展过程中丢失奠定基础，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.