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

机译:#beta#-Trcp偶联#beta#-catenin磷酸化降解并调节非洲爪蟾轴的形成

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摘要

Regulation of #beta#-catenin stability is essential for Wnt signal transduction during development and tumor- igenesis. 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 cancers. How #beta#-catenin phos- phorylation 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 Skpl, 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 imbryo.
机译:#β#-catenin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,Axin-糖原合酶激酶(GSK)-3#beta#复合物通过#beta#-catenin的丝氨酸磷酸化将#beta#-catenin靶向泛素化降解,并且关键磷酸丝氨酸残基处的突变稳定了#beta。 #-catenin并引起人类癌症。 #beta#-catenin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#beta#-连环蛋白被#beta#-Trcp特异性识别,这是一种F-box / WD40重复蛋白,也与Skpl(泛素化装置的重要组成部分)相关联。在关键的磷酸丝氨酸残基上带有突变的#beta#-catenin逃脱了#beta#-Trcp的识别,因此为这些突变导致#beta#-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#beta#-Trcp功能可稳定#beta#-catenin,激活Wnt /#beta#-catenin信号传导并诱导非洲爪蟾胚胎中的轴形成。因此,#beta#-Trcp在募集磷酸化的#beta#-catenin进行降解和非洲爪蟾胚胎的背腹模式中起着核心作用。

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