Mechanism of nuclear signaling and cell-cell adhesion by catenins

描述（由申请人提供）：单个细胞粘附和分化成不同组织的能力是多细胞生物体的主要特征。钙粘蛋白/连环蛋白粘附信号系统在协调细胞间粘附和分化方面发挥着核心作用，因为连环蛋白蛋白不仅构成将细胞固定在一起的结构“尼龙搭扣”，而且还指导细胞核中的基因表达。多功能蛋白质，b-连环蛋白，被广泛认为是这种粘附信号的模型。β-连环蛋白通过与T细胞因子（TCF）型DN结合因子相互作用以形成激活基因的二元转录复合物来转导细胞外Wnt信号。在细胞-细胞接触时，b-连环蛋白还将钙粘蛋白型粘附受体的胞质结构域连接到肌动蛋白结合蛋白1-连环蛋白，其允许细胞通过稳健的细胞间粘附连接相互作用。由于β-连环蛋白根据其亚细胞分布和结合伙伴而表现出肿瘤抑制或致癌活性，因此了解β-连环蛋白如何靶向粘附或核信号复合物，对于寻求抑制致癌但保留肿瘤抑制活性的策略是相关的。β-连环蛋白的活性。虽然β-连环蛋白对信号传导和细胞粘附的贡献主要是通过其各自与TCF和钙粘蛋白的结合来确定的，但调节这些相互作用的磷酸化和上游信号仍然不清楚。该提案旨在确定钙粘蛋白（Aim 1）和β-连环蛋白（Aim 2）的磷酸化如何影响β-连环蛋白粘附和核信号传导功能。肌动蛋白结合蛋白，1-连环蛋白，连接2-连环蛋白/钙粘蛋白复合物的基础肌动蛋白细胞骨架，但控制1-连环蛋白结合肌动蛋白的机制仍然不清楚。目的3试图确定1-连环蛋白的磷酸化如何影响细胞-细胞粘附。总而言之，这一提议将导致对基于连环蛋白的粘附和核信号传导功能如何通过磷酸化调节的理解，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。 公共卫生相关性：在许多上皮癌中发现核b-连环蛋白信号的激活，并且是遗传性和散发性形式的结肠癌的主要原因，结肠癌是美国第四大常见癌症。β-连环蛋白也是基于钙粘蛋白的粘附复合物的关键组分，其可用作肿瘤抑制单位。由于β-catenin的定位决定了其同时具有肿瘤抑制和启动子功能，因此了解促进钙粘蛋白/catenin粘附功能和限制β-catenin核信号传导功能的磷酸化事件将进一步抑制β-catenin的致癌活性，同时保留catenin的肿瘤抑制活性。

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. PUBLIC HEALTH RELEVANCE: Activation of nuclear b-catenin signaling is found in numerous epithelial cancers and is the major cause of hereditary and sporadic forms of colon cancer-the 4th most common cancer in the United States. b-catenin is also a critical component of cadherin-based adhesion complexes, which can serve as a tumor suppressive unit. Since b-catenin exhibits both tumor suppressive and promoter functions depending on its localization, understanding the phosphorylation events that promote cadherin/catenin adhesive function and restrict 2-catenin nuclear signaling function will further strategies to inhibit the oncogenic activity of b-catenin, while preserving the tumor suppressive activities of catenins.