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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >β-Trcp couples β-catenin phosphorylation-degradation and regulates Xenopus axis formation
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β-Trcp couples β-catenin phosphorylation-degradation and regulates Xenopus axis formation

机译：β-Trcp偶联β-连环蛋白的磷酸化降解并调节非洲爪蟾轴的形成

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摘要

Regulation of β-catenin stability is essential for Wnt signal transduction during development and tumorigenesis. It is well known that serine-phosphorylation of β-catenin by the Axin-glycogen synthase kinase (GSK)-3β complex targets β-catenin for ubiquitination-degradation, and mutations at critical phosphoserine residues stabilize β-catenin and cause human cancers. How β-catenin phosphorylation results in its degradation is undefined. Here we show that phosphorylated β-catenin is specifically recognized by β-Trcp, an F-box/WD40-repeat protein that also associates with Skp1, an essential component of the ubiquitination apparatus. β-catenin harboring mutations at the critical phosphoserine residues escapes recognition by β-Trcp, thus providing a molecular explanation for why these mutations cause β-catenin accumulation that leads to cancer. Inhibition of endogenous β-Trcp function by a dominant negative mutant stabilizes β-catenin, activates Wnt/β-catenin signaling, and induces axis formation in Xenopus embryos. Therefore, β-Trcp plays a central role in recruiting phosphorylated β-catenin for degradation and in dorsoventral patterning of the Xenopus embryo.
机译：β-catenin稳定性的调节对于发育和肿瘤发生过程中Wnt信号转导至关重要。众所周知，Axin-糖原合酶激酶（GSK）-3β复合物可将β-catenin丝氨酸磷酸化，将β-catenin靶向于泛素化降解，关键磷酸丝氨酸残基处的突变会稳定β-catenin并引起人类癌症。 β-连环蛋白磷酸化如何导致其降解尚不清楚。在这里，我们显示磷酸化的β-catenin被β-Trcp特异性识别，β-Trcp是一种F-box / WD40重复蛋白，也与Skp1相关联，Skp1是泛素化装置的重要组成部分。在关键的磷酸丝氨酸残基上带有β-catenin突变的β-Trcp无法识别，因此为这些突变为何导致β-catenin积聚导致癌症的原因提供了分子解释。显性负突变体抑制内源性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的轴形成。因此，β-Trcp在募集磷酸化的β-连环蛋白用于降解以及非洲爪蟾胚胎的背腹模式中起着核心作用。

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