CATENIN AND CADHERIN SIGNALING IN DEVELOPMENT AND CANCER

P-连环蛋白是钙粘附素黏附蛋白复合体的组成部分，是一种细胞内信号转导系统。 在Wnt途径中，p-catenin受ARC肿瘤抑制蛋白的调节，并且两者的突变 P-连环蛋白和E-钙粘蛋白与多种形式的癌症有关。该项目的两个总体目标是 确定p-连环蛋白信号的细胞质调控机制，并确定 钙粘附素如何影响p-连环蛋白信号、细胞分化和肿瘤细胞生长。 P-catenin的核输入对信号转导很重要，并通过一种新的机制发生，涉及其 与核孔的相互作用。β-连环蛋白的核孔对接机制及其调节作用 WNT信号通路将被研究，p-连环蛋白信号是由一个非常大的蛋白质复合体调节的 包括ARC、Axin和激酶GSKSp。完整的复合体的性质将用In 体外p-连环蛋白信号分析、磷酸化分析和对-连环蛋白相互作用的分析。情结 还将进行纯化，以确定关键的蛋白质组分。此外，最近发现的一个角色 第二个ARC蛋白，APC-2，在p-catenin信号通路中的早期非洲爪哇胚胎将被评估。 钙粘附素的表达通过将其结合在质膜上来拮抗p-catenin信号转导，从而提供一种 潜在的机制将细胞黏附的变化与基因表达的调节结合起来。有没有可能 钙粘附素对β-连环蛋白信号转导的调节在脑内神经脊的发育中起重要作用 非洲爪哇胚胎，一种上皮向间质的转变，将被探索。同样，将进行实验，以 确定调节P-连环蛋白信号或增强细胞对肿瘤黏附的相对作用 E-钙粘附素的抑制功能。还将进行实验，以确定E-钙粘素是否可以 直接产生信号，介导接触抑制细胞生长。 这些实验应该有助于我们理解p-连环蛋白介导的信号转导和 深入了解细胞黏附、组织形态发生和肿瘤生长之间的关系。

P-catenin is a component of the cadherin adhesion protein complex and an intracellular signal transducing protein in the Wnt pathway, p-catenin is regulated by the ARC tumor suppressor protein, and mutations in both p-catenin and E-cadherin are implicated in many forms of cancer. The two overall objectives of the project are to determine the mechanism underlying the cytoplasmic regulation of p-catenin signaling, and to determine how cadherins affect p-catenin signaling, cell differentiation, and tumor cell growth. Nuclear import of p-catenin is important for signaling and occurs by a novel mechanism involving its interaction with the nuclear pore. The mechanism of p-catenin nuclear pore docking and its regulation by the Wnt signaling pathway will be studied, p-catenin signaling is regulated by a very large protein complex that includes ARC, axin, and the kinase GSKSp. The properties of the intact complex will be studied using an in vitro p-catenin signaling assay, phosphorylation assays, and analyses of p-catenin interactions. The complex will also be purified in order to identify key protein components. Furthermore, the role of a recently identified second ARC protein, APC-2, in p-catenin signaling in the early Xenopus embryo will be evaluated. Cadherin expression antagonizes p-catenin signaling by binding it up at the plasma membrane, providing a potential mechanism to couple changes in cell adhesion to regulation of gene expression. The possibility that cadherin regulation of p-catenin signaling plays an important role in development of the neural crest in the Xenopus embryo, an epithelial-mesenchymal transition, will be explored. Similarly, experiments will be done to determine the relative contributions of regulating P-cateninsignaling or enhancing cell adhesion to the tumor suppressor function of E-cadherin. Experiments will also be performed to determine whether E-cadherin can directly generate signals that mediate contact inhibition of cell growth. These experiments should help us understand the mechanisms of p-catenin-mediated signaling and provide insights into the relationships between cell adhesion, tissue morphogenesis, and tumor growth.