Ajuba negatively regulates the Wnt signaling pathway by promoting GSK-3β-mediated phosphorylation of β-catenin
Ajuba negatively regulates the Wnt signaling pathway by promoting GSK-3β-mediated phosphorylation of β-catenin
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DOI：
10.1038/sj.onc.1210644
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发表时间：
2008-01-10
期刊：
影响因子：
8
通讯作者：
Yamamoto, T.
中科院分区：
文献类型：
--
作者：
Haraguchi, K.;Ohsugi, M.;Yamamoto, T.
Wnt信号通路对胚胎发育和癌变至关重要。在Wnt刺激下，β -连环蛋白稳定并与t细胞因子或淋巴细胞增强因子结合，从而激活靶基因的转录。在没有Wnt刺激的情况下，β -连环蛋白的水平通过糖原合成酶激酶(GSK)- β -b介导的磷酸化和随后的蛋白酶体依赖性降解而降低。在这里，我们报告了Ajuba作为Wnt信号通路的负调节因子的鉴定。Ajuba是LIM结构域蛋白的一员，参与决定细胞命运和调节细胞增殖和分化。我们发现，强制表达Ajuba会破坏β -连环蛋白的稳定，抑制靶基因的表达。阿朱巴通过加强β -连环蛋白和GSK-3 β之间的关联，促进GSK-3 β介导的β -连环蛋白磷酸化。此外，Wnt刺激诱导β -连环蛋白的积累和阿朱巴的不稳定。我们的研究结果表明，Ajuba对Wnt信号通路的调节很重要。
The Wnt signaling pathway is essential for embryonic development and carcinogenesis. Upon Wnt stimulation, beta-catenin is stabilized and associates with T-cell factor or lymphoid enhancing factor, thereby activating transcription of target genes. In the absence of Wnt stimulation, the level of beta-catenin is reduced via glycogen synthase kinase (GSK)-beta b-mediated phosphorylation and subsequent proteasome-dependent degradation. Here, we report the identification of Ajuba as a negative regulator of the Wnt signaling pathway. Ajuba is a member of LIM domain-containing proteins that contribute to cell fate determination and regulate cell proliferation and differentiation. We found that enforced expression of Ajuba destabilized beta-catenin and suppressed target gene expression. Ajuba promoted GSK-3 beta-mediated phosphorylation of beta-catenin by reinforcing the association between beta-catenin and GSK-3 beta. Furthermore, Wnt stimulation induced both accumulation of beta-catenin and destabilization of Ajuba. Our findings suggest that Ajuba is important for regulation of the Wnt signaling pathway.