Mechanisms of Armadillo/Beta-catenin degradation

犰狳/β-连环蛋白降解机制

• 批准号: 7057063
• 负责人: DAVID M ROBERTS
• 金额: $ 4.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057063
• 关键词: Drosophilidae; Wnt gene /protein; cadherins; enzyme mechanism; phosphorylation; postdoctoral investigator; protein degradation; protein structure function; tumor suppressor proteins; ubiquitin protein ligase

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.

描述（由申请人提供）：无翼（Wg）/Wnt信号通路的不适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受到多蛋白复合物（破坏复合物）的负调控，该复合物靶向Arm进行降解。然而，关于销毁设施如何运作，仍然存在着几个基本问题。特别是，APC蛋白在破坏复合物中的作用仍然未知。为了解决APC在破坏复合体中的作用，将使用果蝇APC 2作为人APC的模型进行结构/功能分析，并且从该分析中获得的信息将用于评估APC在破坏复合体中功能的几种模型。其次，将定义降解Arm的E3泛素连接酶的分子组成，特别是评价Roc蛋白在Arm降解中的重要性。最后，将研究APC蛋白在将臂从破坏复合物转移到E3泛素连接酶中具有第二功能的假设。