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Isolation of novel proteins that regulate the Wnt signaling pathway

调节 Wnt 信号通路的新型蛋白质的分离

基本信息

批准号：
12558080
负责人：
KIKUCHI Akira
金额：
$ 8.45万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12558080/
关键词：
Wnt signaling Axin β-catenin Axam Duplin Idax genetic diagnosis SUMO化核移行 APC β-catenin GSK-3β リン酸化

项目摘要

We have identified three novel proteins that regulate the Wnt signaling pathway in this project. They are Axin-binding, Dvl-binding, and β-catenin-binding proteins, and we designated them Axam, Idax, and Duplin, respectively. Axam has nuclear localization signal (NLS) at the N-terminus and Axin-binding domain in its central region. Furthermore, Axam shares high homology with the catalytic domain of Senp1, which is a SUMO specific protease. Indeed, Axam showed an desumoylation activity. Axam stimulated degradation of β-catenin in mammalian cells and inhibited axis formation in Xenopus embryos. Catalyticaly inactive mutant of Axam reduced these activity. Therefore, sumoylation may be involved in the Wnt signaling pathway. Idax does not share any homology with other proteins. Idax suppressed Wnt dependent β-catenin accumulation and axis formation by inhibiting the binding of Dvl to Axin. Duplin has NLS and β-catenin-binding domain in its C-treminus. Although Duplin inhibited β-catenin-dependent Tcf activation and axis formation, the Duplin mutant that lacks NLS lost these activities, suggesting that Duplin must be in the nucleus to exert its functions. Taken together, Axam, Idax, and Duplin act as a negative regulator of the Wnt signaling pathway. Screening of mutations of these novel molecules in human cancers remains to be clarified.

在这个项目中，我们已经确定了三个调节Wnt信号通路的新蛋白。它们是轴蛋白结合蛋白、dvl结合蛋白和β-catenin结合蛋白，我们分别将它们命名为Axam、Idax和Duplin。Axam在其n端具有核定位信号（NLS），在其中心区域具有轴蛋白结合域。此外，Axam与SUMO特异性蛋白酶Senp1的催化结构域具有高度同源性。事实上，Axam显示出去氧基化活性。Axam刺激哺乳动物细胞中β-连环蛋白的降解，抑制爪蟾胚胎中轴的形成。催化失活突变体Axam降低了这些活性。因此，sumoylation可能参与了Wnt信号通路。Idax与其他蛋白质没有同源性。Idax通过抑制Dvl与Axin的结合抑制Wnt依赖性β-连环蛋白的积累和轴的形成。Duplin在其c -末端具有NLS和β-catenin结合域。虽然Duplin抑制β-catenin依赖性Tcf激活和轴形成，但缺乏NLS的Duplin突变体失去了这些活性，这表明Duplin必须在细胞核中才能发挥其功能。综上所述，Axam， Idax和Duplin作为Wnt信号通路的负调控因子。在人类癌症中筛选这些新分子的突变仍有待澄清。