Mechanisms of Armadillo/Beta-catenin degradation

描述(申请人提供)：不适当地激活Wingless(Wg)/Wnt信号通路经常导致人类癌症，如结肠癌。WG信号通过调节关键效应蛋白β-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，ARM受到一种针对ARM降解的多蛋白复合体(破坏复合体)的负调控。然而，关于销毁综合体如何运作的几个基本问题仍然存在。特别是，APC蛋白在破坏复合体中的作用尚不清楚。为了探讨APC在销毁复合体中的作用，将以果蝇APC2作为人APC的模型进行结构/功能分析，并将从这一分析中获得的信息将用于评估销毁复合体中APC的几个模型。其次，将确定降解ARM的E3泛素连接酶的分子组成，特别是评估ROC蛋白在ARM降解中的重要性。最后，对APC蛋白在将手臂从破坏复合体转移到E3泛素连接酶中具有第二功能的假设进行了研究。

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.