The Role of b-catenin in EGFR-Related Tumor Development

描述(由申请人提供)：EGF诱导的信号和增加的β-连环蛋白反式激活已分别被报道与肿瘤的形成和发展相关。然而，EGF诱导的信号和增加的β-连环蛋白反式激活之间的确切关系尚不清楚。我们的初步数据显示，EGF治疗破坏了过度表达EGFR的肿瘤细胞的细胞间连接，并增加了β-连环素的反式激活。此外，EGF诱导的β-连环蛋白反式激活是通过小窝蛋白-1和Ras/Raf/ERK依赖的途径来调节的。ERK MAP激酶与β-连环蛋白结合，使我们探索了EGF诱导的β-连环蛋白反式激活的机制，以及它在异常过度表达EGFR的人类癌症发展中的作用。在目标1中，我们将分析ERK和β-连环蛋白在EGF治疗中的关系，以及这种关系在β-连环蛋白核转位和反式激活中的作用。目的2重点了解ERK非依赖性但小窝蛋白1依赖的β-连环蛋白反式激活调控机制，以及EGF刺激下β-连环蛋白内吞作用的机制。在目标3中，我们计划确定β-连环蛋白反式激活在EGFR相关肿瘤生长和转移中的作用。了解EGFR和Wnt信号成分之间的相互作用将为理解肿瘤细胞的侵袭和转移提供重要的基础，这可能为开发更有效的癌症治疗提供新的靶点和途径。

DESCRIPTION (provided by applicant): EGF-induced signaling and increased beta-catenin transactivation have been reported separately to correlate with tumor formation and development. However, the exact relationship between EGF-induced signaling and increased beta-catenin transactivation is not clear. Our preliminary data show that EGF treatment disrupts cell-cell junctions of tumor cells overexpressing EGFR and increases beta-catenin transactivation. Moreover, EGF-induced beta-catenin transactivation is regulated through caveolin-1- and Ras/Raf/ERK-dependent pathways. ERK MAP kinase binds to beta-catenin, leading to our exploration into the mechanism of EGF-induced beta-catenin transactivation and its role in the development of human cancers that have aberrantly overexpress EGFR. In Aim 1, we will analyze the relationship between ERK and beta-catenin in response to EGF treatment and the role of this relationship in beta-catenin nuclear translocation and transactivation. Aim 2 focuses on understanding the mechanism of ERK-independent but caveolin-1-dependent regulation of beta-catenin transactivation and the mechanism of beta-catenin endocytosis in response to EGF stimulation. In Aim 3, we plan to determine the role of beta-catenin transactivation in EGFR-related tumor growth and metastasis. Understanding the interplay between EGFR and Wnt signaling components will provide an important basis for understanding tumor cell invasion and metastasis, which may provide novel targets and approaches for developing more effective cancer therapies.