Mechanisms of Armadillo/Beta-catenin degradation

描述（由申请人提供）：无翼(Wg)/Wnt信号通路的不当激活经常导致人类癌症，如结肠癌。Wg信号通过调节关键效应蛋白-连环蛋白（在果蝇中称为Armadillo (Arm)）的细胞内水平而发生。大量实验证据表明，针对Arm进行降解的多蛋白复合物（破坏复合物）对Arm进行负调控。然而，关于破坏复合体如何起作用的几个基本问题仍然存在。特别是，蛋白质APC在破坏复合体中的作用仍然未知。为了研究APC在破坏复合体中的作用，我们将果蝇APC2作为人类APC的模型，进行结构/功能分析，并通过分析获得的信息来评估APC在破坏复合体中的几种功能模型。其次，将定义降解Arm的E3泛素连接酶的分子组成，具体评估Roc蛋白在Arm降解中的重要性。最后，我们将研究APC蛋白在将Arm从破坏复合体转移到E3泛素连接酶中具有第二种功能的假设。

DESCRIPTION (provided by applicant): Inappropriate activation of the Wingless (Wg)/Wnt signaling pathway frequently results in human cancers, such as colon cancer. Wg signaling occurs by regulating the intracellular levels of the key effector protein, beta-catenin (called Armadillo (Arm) in Drosophila). Substantial experimental evidence suggests that Arm is negatively regulated by a multi-protein complex (the destruction complex) that targets Arm for degradation. Several fundamental questions still remain, however, concerning how the destruction complex functions. In particular, the role of the protein APC in the destruction complex remains unknown. To address the role of APC in the destruction complex, a structure/function analysis will be performed using Drosophila APC2 as a model for human APC, and the information gained from this analysis will be used to evaluate several models of APC function in the destruction complex. Secondly, the molecular composition of the E3 ubiquitin ligase that degrades Arm will be defined, specifically evaluating the importance of Roc proteins in Arm degradation. Finally, the hypothesis that APC proteins have a second function in transferring Arm from the destruction complex to E3 ubiquitin ligases will be investigated.