Mechanism of nuclear signaling and cell-cell adhesion by catenins

连环蛋白的核信号传导和细胞间粘附机制

• 批准号: 8656125
• 负责人: Cara J Gottardi
• 金额: $ 29.42万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656125
• 关键词: Actin-Binding Protein; Actins; Adherens Junction; Adhesions; Adhesives; Binding; Cadherins; Cell Adhesion; Cell Differentiation process; Cell Nucleus; Cell-Cell Adhesion; Cells; Colon Carcinoma; Complex; Cytoplasmic Tail; Cytoskeleton; Epithelial; Event; Exhibits; Gene Expression; Genes; Genetic Transcription; Glycogen Synthase Kinase 3; Individual; Inherited; Lead; Link; Malignant Neoplasms; Modeling; Normal tissue morphology; Nuclear; Nuclear Import; Oncogenic; Organism; Phosphorylation; Play; Proteins; Research; Role; Signal Transduction; System; TCF Transcription Factor; Tissues; Tumor Biology; United States; adhesion receptor; base; extracellular; promoter; tumor

DESCRIPTION (provided by applicant): The ability of individual cells to adhere and differentiate into distinct tissues is a major feature of multicellular organisms. The cadherin/catenin adhesion signaling system plays a central role in coordinating cell-cell adhesion and differentiation, as catenin proteins not only comprise the structural "Velcro" that holds cells together, but also direct gene expression in the nucleus. The multifunctional protein, b-catenin, is widely viewed as a model for such adhesion signaling. b-catenin transduces extracellular Wnt signals by interacting with T-cell factor (TCF)-type DN -binding factors to form a binary transcription complex that activates genes. At cell-cell contacts, b-catenin also links the cytoplasmic domain of cadherin-type adhesion receptors to the actin-binding protein, 1-catenin, which allows cells to interact through robust intercellular adhering junctions. Since b-catenin exhibits either tumor suppressive or oncogenic activities depending on its subcellular distribution and binding partners, understanding how b-catenin is targeted to adhesive or nuclear signaling complexes is relevant to strategies that seek to inhibit the oncogenic, but spare the tumor suppressive activities of b-catenin. While the contribution of b-catenin to signaling and cell adhesion is largely determined through its respective binding to TCF and cadherin proteins, the phosphorylations and upstream signals that modulate these interactions remain poorly defined. This proposal seeks to determine how phosphorylation of cadherins (Aim 1) and 2-catenin (Aim 2) impact b-catenin adhesive and nuclear signaling functions. The actin binding protein, 1-catenin, links the 2-catenin/cadherin complex to the underlying actin cytoskeleton, but mechanisms that control 1-catenin binding to actin remain poorly defined. Aim 3 seeks to determine how phosphorylation of 1-catenin impacts cell-cell adhesion. Altogether, this proposal will lead to an understanding of how catenin-based adhesive and nuclear signaling functions are regulated by phosphorylation, which are fundamental questions broadly relevant to normal tissue integrity and tumor biology.

描述（由申请人提供）：单个细胞粘附和分化为不同组织的能力是多细胞生物的主要特征。 Cadherin/catenin粘附信号系统在协调细胞 - 细胞粘附和分化方面起着核心作用，因为Catenin蛋白不仅包含将细胞凝聚在一起的结构“维球体”，而且还构成了核中基因表达的结构“ velcro”。多功能蛋白B-catenin被广泛视为这种粘附信号传导的模型。 B-catenin通过与T细胞因子（TCF）-Type DN结合因子相互作用来传递细胞外Wnt信号，形成激活基因的二元转录复合物。在细胞 - 细胞接触处，B-catenin还将钙粘蛋白型粘附受体的细胞质结构域与肌动蛋白结合蛋白1-catenin联系起来，该蛋白1-钙蛋白使细胞可以通过强大的细胞间粘附连接连接。由于B-catenin取决于其亚细胞分布和结合伴侣表现出肿瘤抑制或致癌活性，因此了解B-catenin如何针对粘合剂或核信号传导复合物，与寻求抑制致癌性但要避免B-catenin抑制性抑制活性的策略有关。虽然B-catenin对信号传导和细胞粘附的贡献在很大程度上取决于其与TCF和Cadherin蛋白的各自结合，但调节这些相互作用的磷酸化和上游信号仍然很差。该提案旨在确定钙粘蛋白（AIM 1）和2-catenin（AIM 2）的磷酸化如何影响B-catenin粘合剂和核信号传导功能。肌动蛋白结合蛋白1-catenin将2-catenin/cadherin复合物与潜在的肌动蛋白细胞骨架联系起来，但是控制1-catenin与肌动蛋白结合的机制仍然很差。 AIM 3试图确定1-catenin的磷酸化如何影响细胞细胞粘附。总而言之，该提案将导致对基于Catenin的粘合剂和核信号传导功能的理解，这是磷酸化的调节，这是与正常组织完整性和肿瘤生物学广泛相关的基本问题。