Inhibition of the Wnt Signaling Pathway by Idax, a Novel Dvl-Binding Protein

In attempting to clarify the roles of Dvl in the Wnt signaling pathway, we identified a novel protein which binds to the PDZ domain of Dvl and named it Idax (for inhibition of the Dvl and Axin complex). Idax and Axin competed with each other for the binding to Dvl. Immunocytochemical analyses showed that Idax was localized to the same place as Dvl in cells and that expression of Axin inhibited the colocalization of Dvl and Idax. Further, Wnt-induced accumulation of β-catenin and activation of T-cell factor in mammalian cells were suppressed by expression of Idax. Expression of Idax in Xenopus embryos induced ventralization with a reduction in the expression of siamois, a Wnt-inducible gene. Idax inhibited Wnt- and Dvl- but not β-catenin-induced axis duplication. It is known that Dvl is a positive regulator in the Wnt signaling pathway and that the PDZ domain is important for this activity. Therefore, these results suggest that Idax functions as a negative regulator of the Wnt signaling pathway by directly binding to the PDZ domain of Dvl.

为阐明Dvl（Dishevelled）在Wnt信号通路（Wnt signaling pathway）中的作用，我们鉴定出一种可结合Dvl的PDZ结构域（PDZ domain）的新型蛋白质，并将其命名为Idax（即Dvl与Axin复合物抑制剂）。Idax与轴蛋白（Axin）可竞争性结合Dvl。免疫细胞化学分析显示，Idax与Dvl在细胞内定位于同一区域；而轴蛋白的表达会抑制Dvl与Idax的共定位。进一步实验表明，Idax的表达可抑制哺乳动物细胞中Wnt诱导的β-连环蛋白（β-catenin）积累以及T细胞因子（T-cell factor）的激活。在非洲爪蟾（Xenopus）胚胎中表达Idax，可诱导腹侧化表型，并降低Wnt诱导基因siamois的表达水平。Idax能够抑制Wnt与Dvl介导的轴重复，但对β-连环蛋白诱导的轴重复无影响。已知Dvl是Wnt信号通路的正向调控因子，且其PDZ结构域对该调控活性至关重要。综上，上述结果表明Idax可通过直接结合Dvl的PDZ结构域，作为Wnt信号通路的负向调控因子发挥功能。