The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-β-catenin pathway by targeting Dishevelled for degradation
The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-β-catenin pathway by targeting Dishevelled for degradation
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DOI：
10.1038/ncb1381
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发表时间：
2006-04-01
影响因子：
21.3
通讯作者：
Moon, RT
中科院分区：
文献类型：
--
作者：
Angers, S;Thorpe, CJ;Moon, RT
disheveled是一种保守蛋白，它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技术，我们已经鉴定了与Dishevelled相关的蛋白质，包括Cullin-3泛素连接酶复合物，该复合物含有Broad复合物、Tramtrack和Bric a Brac （BTB）蛋白kelch样12 （KLHL12）。这种E3泛素连接酶复合物以wnt依赖的方式被招募到disheveled，促进其多泛素化和降解。功能分析表明，在培养细胞以及爪蟾和斑马鱼胚胎中，这种泛素连接酶对Dishevelled的调控可以拮抗wnt - β -连环蛋白通路。考虑到基于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Dishevelled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 -连环蛋白途径。
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.