THE KLHL12-CULLIN-3 UBIQUITIN LIGASE NEGATIVELY REGULATES THE WNT-BETA-CATENIN

KLHL12-CULLIN-3 泛素连接酶负向调节 WNT-β-连环蛋白

• 批准号: 7420721
• 负责人: Randall Todd Moon
• 金额: $ 0.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7420721
• 关键词: ligase; proteins; ubiquitin

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dishevelled is a conserved protein that interprets signals received by Frizzled receptors. Using a tandem-affinity purification strategy and mass spectrometry we have identified proteins associated with Dishevelled, including a Cullin-3 ubiquitin ligase complex containing the Broad Complex, Tramtrack and Bric a Brac (BTB) protein Kelch-like 12 (KLHL12). This E3 ubiquitin ligase complex is recruited to Dishevelled in a Wnt-dependent manner that promotes its poly-ubiquitination and degradation. Functional analyses demonstrate that regulation of Dishevelled by this ubiquitin ligase antagonizes the Wnt-beta-catenin pathway in cultured cells, as well as in Xenopus and zebrafish embryos. Considered with evidence that the distinct Cullin-1 based SCF(beta-TrCP)complex regulates beta-catenin stability, our data on the stability of Dishevelled demonstrates that two distinct ubiquitin ligase complexes regulate the Wnt-beta-catenin pathway.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。 Disheveled 是一种保守蛋白，可以解释卷曲受体接收到的信号。使用串联亲和纯化策略和质谱，我们鉴定了与 Dishevelled 相关的蛋白质，包括含有 Broad 复合物、Tramtrack 和 Bric a Brac (BTB) 蛋白 Kelch-like 12 (KLHL12) 的 Cullin-3 泛素连接酶复合物。这种 E3 泛素连接酶复合物以 Wnt 依赖性方式被招募到 Disheveled，促进其多泛素化和降解。功能分析表明，这种泛素连接酶对 Disheveled 的调节会拮抗培养细胞以及爪蟾和斑马鱼胚胎中的 Wnt-β-catenin 通路。考虑到基于不同 Cullin-1 的 SCF(β-TrCP) 复合物调节 β-连环蛋白稳定性的证据，我们关于 Disheveled 稳定性的数据表明，两种不同的泛素连接酶复合物调节 Wnt-β-连环蛋白通路。