CATENIN AND CADHERIN SIGNALING IN DEVELOPMENT AND CANCER

β-连环蛋白是钙粘蛋白粘附蛋白复合物的一个组成部分，是细胞内信号转导的一个重要途径。 β-连环蛋白是Wnt通路中的蛋白，β-连环蛋白受ARC肿瘤抑制蛋白的调节，两者的突变 β-连环蛋白和E-钙粘蛋白与许多形式的癌症有关。该项目的两个总体目标是 确定β-连环蛋白信号转导的细胞质调节机制，并确定 钙粘蛋白如何影响β-连环蛋白信号传导、细胞分化和肿瘤细胞生长。 β-连环蛋白的核输入对于信号传导是重要的，并通过一种新的机制发生， 与核孔的相互作用。β-catenin核孔对接机制及其调控 Wnt信号通路将被研究，β-连环蛋白信号是由一个非常大的蛋白质复合物， 包括ARC、轴蛋白和激酶GSKSp。完整的复合物的性质将研究使用在 体外β-连环蛋白信号传导测定、磷酸化测定和β-连环蛋白相互作用的分析。复杂 也将被纯化以鉴定关键蛋白质组分。此外，最近确定的一个 将评价第二种ARC蛋白APC-2在早期非洲爪蟾胚胎中β-连环蛋白信号传导中的作用。 钙粘蛋白的表达通过将β-连环蛋白结合在质膜上来拮抗β-连环蛋白信号传导， 将细胞粘附的变化与基因表达的调节偶联的潜在机制。的可能性 钙粘蛋白对β-连环蛋白信号的调节在神经嵴的发育中起着重要的作用。 非洲爪蟾胚胎，上皮-间充质转化，将探讨。同样，将进行实验， 确定调节β-连环蛋白信号传导或增强细胞粘附于肿瘤的相对贡献 E-cadherin的抑制功能。还将进行实验以确定E-钙粘蛋白是否可以 直接产生介导细胞生长的接触抑制的信号。 这些实验应该有助于我们理解β-连环蛋白介导的信号转导机制， 提供了深入了解细胞粘附，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.