Mechanism of nuclear signaling and cell-cell adhesion by catenins

描述(申请人提供)：单个细胞黏附和分化成不同组织的能力是多细胞生物体的主要特征。钙粘附素/连接素黏附信号系统在协调细胞间的黏附和分化中起着核心作用，因为连接素蛋白不仅构成了将细胞连接在一起的结构魔术贴，而且还直接在细胞核内表达基因。多功能蛋白质b-catenin被广泛认为是这种黏附信号的模型。B-catenin通过与T细胞因子(Tcf)型dN结合因子相互作用转导细胞外Wnt信号，形成激活基因的二元转录复合体。在细胞与细胞的接触中，b-catenin还将钙粘附素型黏附受体的细胞质结构域连接到肌动蛋白结合蛋白1-catenin，后者允许细胞通过强大的细胞间黏附连接相互作用。由于b-catenin根据其亚细胞分布和结合伙伴的不同表现出肿瘤抑制或致癌活性，了解b-catenin如何靶向于黏附或核信号复合体，对于寻求抑制致癌作用而不是b-catenin的肿瘤抑制活性的策略是相关的。虽然b-catenin对信号和细胞黏附的贡献主要是通过它与TCF和钙粘蛋白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缺乏明确的定义。这项建议试图确定钙粘附素(目标1)和2-连环蛋白(目标2)的磷酸化如何影响b-连环蛋白黏附和核信号功能。肌动蛋白结合蛋白1-连环蛋白将2-连环蛋白/钙粘连蛋白复合体与肌动蛋白细胞骨架连接起来，但控制1-连环蛋白与肌动蛋白结合的机制尚不清楚。目的3试图确定1-连环蛋白的磷酸化如何影响细胞间的黏附。总之，这一建议将导致对连环蛋白粘附剂和核信号功能如何通过磷酸化进行调节的理解，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。

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.