Mechanisms directing adherens junctions and actin network interactions

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， 在疾病状态如转移性癌症中改变。细胞在发育过程中迁移到特定的 当与其他细胞接触时，它们变得静止并分化成组织。因此，在本发明中， 强的细胞-细胞粘附是维持组织完整性所必需的。细胞-细胞粘附的变化 在细胞更新或伤口愈合期间重新启动细胞迁移，或允许转移细胞分散到 远器官 细胞-细胞粘附复合物（粘附连接）的形成和稳定对于 后生动物的发育，器官发生和组织稳态，它也是必要的一些 病理生理条件，如伤口愈合。相比之下，粘附连接的丧失是一种 癌症的标志，导致不受限制的细胞增殖和转移。细胞-细胞粘附物 连接需要多蛋白复合物在浆细胞膜上的适当组装。在这里， 单次跨膜通过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相互结合。他们之间的互动 β-连环蛋白的胞质尾部结构域与α-连环蛋白结合，似乎可以指导细胞的增殖。 通过抑制板状足的产生形成粘附连接。但如果没有 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结合到肌动蛋白网络， 这对于稳定这些连接和组织内环境稳定是必需的。 在GM 094483资助的前3年，我们确定了二聚体全长的晶体结构， 人α-连环蛋白和长春纽蛋白结合的α-连环蛋白，这些结构和我们的生化和 生物学研究确定了黏着斑蛋白-α-连环蛋白相互作用在形成中的作用， 粘附连接的稳定性。从晶体结构和3D重建， 生物化学，然后生物学，拟议的研究将定义如何粘附连接， 稳定和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 显著增加了我们对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 为理解这些控制在肿瘤进展过程中如何丢失奠定基础， 提出了治疗干预的新途径。

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.