CATENIN AND CADHERIN SIGNALING IN DEVELOPMENT AND CANCER

发育和癌症中的连环蛋白和钙粘蛋白信号传导

• 批准号: 7163488
• 负责人: BARRY M. GUMBINER
• 金额: $ 52.43万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163488
• 关键词: Accounting; Adenomatous Polyposis Coli Protein; Adhesions; Adhesives; Affect; Axin protein; Binding; Biochemical; Biological; Biological Assay; Cadherins; Cell Adhesion; Cell Communication; Cell Differentiation process; Cell Fraction; Cell Nucleus; Cell membrane; Cell-Cell Adhesion; Cells; Complex; Contact Inhibition; Depth; Development; Docking; E-Cadherin; Embryo; Epithelial; Event; Gene Expression Regulation; Human; In Vitro; Ligation; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Mesenchymal; Morphogenesis; Mutation; Neural Crest; Nuclear; Nuclear Import; Nuclear Pore; Object Attachment; Particulate; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Property; Proteins; Regulation; Relative (related person); Research Personnel; Role; Signal Pathway; Signal Transduction; Structure; Testing; Tissues; Tumor Cell Line; Tumor Suppressor Proteins; Xenopus; alpha Karyopherins; cell growth; in vitro Assay; insight; neoplastic cell; novel; programs; research study; response; tumor growth

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.

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。