Mechanism of nuclear signaling and cell-cell adhesion by catenins

描述（由申请人提供）：单个细胞粘附并分化成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-细胞粘附和分化中起着核心作用，因为catenin蛋白不仅包含将细胞结合在一起的结构“魔术贴”，而且还指导细胞核中的基因表达。多功能蛋白b-连环蛋白被广泛认为是这种粘附信号的模型。b-catenin通过与t细胞因子（TCF）型DN结合因子相互作用，形成激活基因的二元转录复合体，转导细胞外Wnt信号。在细胞间接触时，b-catenin还将钙粘蛋白型粘附受体的细胞质区域与肌动蛋白结合蛋白1-catenin连接，这使得细胞能够通过强大的细胞间粘附连接相互作用。由于b-catenin表现出肿瘤抑制或致癌活性取决于其亚细胞分布和结合伙伴，了解b-catenin如何靶向粘附或核信号复合物，与寻求抑制致癌但不考虑b-catenin的肿瘤抑制活性的策略相关。虽然b-连环蛋白对信号传导和细胞粘附的贡献在很大程度上是通过其各自与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明确。本研究旨在确定cadherins （Aim 1）和2-catenin （Aim 2）的磷酸化如何影响b-catenin粘附和核信号功能。肌动蛋白结合蛋白，1-catenin，将2-catenin/钙粘蛋白复合物连接到潜在的肌动蛋白细胞骨架上，但是控制1-catenin与肌动蛋白结合的机制仍然不清楚。目的3旨在确定1-连环蛋白的磷酸化如何影响细胞-细胞粘附。总之，这一建议将导致理解基于连环蛋白的粘附和核信号功能是如何被磷酸化调节的，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。

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.