β-Trcp couples β-catenin phosphorylation-degradation and regulates Xenopus axis formation
β-Trcp couples β-catenin phosphorylation-degradation and regulates Xenopus axis formation
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DOI：
10.1073/pnas.96.11.6273
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发表时间：
1999-05-25
影响因子：
11.1
通讯作者：
He, X
中科院分区：
文献类型：
--
作者：
Liu, CM;Kato, Y;He, X
β-连环蛋白稳定性的调节对于发育和肿瘤发生过程中的 Wnt 信号转导至关重要。众所周知，轴蛋白-糖原合酶激酶 (GSK)3 β 复合物对 β- 连环蛋白进行丝氨酸磷酸化，以 β-连环蛋白为靶点进行泛素化降解，并且关键磷酸丝氨酸残基的突变可稳定 β-连环蛋白并导致人类慢跑。 β-连环蛋白磷酸化如何导致其降解尚不清楚。在这里，我们证明磷酸化的 β-连环蛋白被 β-Trcp 特异性识别，β-Trcp 是一种 F-box/WD40 重复蛋白，也与泛素化装置的重要组成部分 Skp1 相关。在关键磷酸丝氨酸残基处携带突变的 β-连环蛋白逃避了 β-Trcp 的识别，从而为为什么这些突变导致 β-连环蛋白积累而导致癌症提供了分子解释。显性失活突变体抑制内源性 β-Trcp 功能可稳定 β-catenin，激活 Wnt/β-catenin 信号传导，并诱导非洲爪蟾胚胎中轴的形成。因此，β-Trcp 在募集磷酸化 β-连环蛋白进行降解以及爪蟾胚胎的背腹模式中发挥着核心作用。
Regulation of beta-catenin stability is essential for Wnt signal transduction during development and tumorigenesis. It is well known that serine-phosphorylation of beta-catenin by the Axin-glycogen synthase kinase (GSK)3 beta complex targets beta-catenin for ubiquitination-degradation, and mutations at critical phosphoserine residues stabilize beta-catenin and cause human canters. How beta-catenin phosphorylation results in its degradation is undefined. Here we show that phosphorylated beta-catenin is specifically recognized by beta-Trcp, an F-box/WD40-repeat protein that also associates with Skp1, an essential component of the ubiquitination apparatus. beta-catenin harboring mutations at the critical phosphoserine residues escapes recognition by beta-Trcp, thus providing a molecular explanation for why these mutations cause beta-catenin accumulation that leads to cancer. Inhibition of endogenous beta-Trcp function by a dominant negative mutant stabilizes beta-catenin, activates Wnt/beta-catenin signaling, and induces axis formation in Xenopus embryos. Therefore, beta-Trcp plays a central role in recruiting phosphorylated beta-catenin for degradation and in dorsoventral patterning of the Xenopus embryo.