B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 2012 Sep 28;287(40):33480-7. doi: 10.1074/jbc.M112.361873. Epub 2012 Aug 2.
The Wnt β-catenin pathway controls numerous cellular processes including cell differentiation and cell-fate decisions. Wnt ligands engage Frizzled receptors and the low-density-lipoprotein-related protein 5/6 (LRP5/6) receptor complex leading to the recruitment of Dishevelled (Dvl) and Axin1 to the plasma membrane. Axin1 has a regulator of G-protein signaling (RGS) domain that binds adenomatous polyposis coli and Gα subunits, thereby providing a mechanism by which Gα subunits can affect β-catenin levels. Here we show that Wnt signaling enhances the expression of another RGS domain-containing protein, PDZ-RGS3. Reducing PDZ-RGS3 levels impaired Wnt3a-induced activation of the canonical pathway. PDZ-RGS3 bound GSK3β and decreased its catalytic activity toward β-catenin. PDZ-RGS3 overexpression enhanced Snail1 and led to morphological and biochemical changes reminiscent of epithelial mesenchymal transition (EMT). These results indicate that PDZ-RGS3 can enhance signals generated by the Wnt canonical pathway and that plays a pivotal role in EMT.
Wnt β-连环蛋白通路控制着众多细胞过程，包括细胞分化和细胞命运决定。Wnt 配体与 Frizzled 受体和低密度脂蛋白相关蛋白 5/6（LRP5/6）受体复合物结合，导致 Dishevelled（Dvl）和 Axin1 被招募到质膜。Axin1 具有 G 蛋白信号调节因子（RGS）结构域，可与腺瘤性结肠息肉病基因和 Gα 亚基结合，从而提供了 Gα 亚基影响β-连环蛋白水平的机制。在这里，我们表明 Wnt 信号增强了另一种含有 PDZ-RGS3 结构域的蛋白质的表达。降低 PDZ-RGS3 水平会损害 Wnt3a 诱导的经典途径的激活。PDZ-RGS3 与 GSK3β 结合并降低其对β-连环蛋白的催化活性。PDZ-RGS3 的过表达增强了 Snail1，并导致形态和生化变化，类似于上皮间质转化（EMT）。这些结果表明，PDZ-RGS3 可以增强经典 Wnt 通路产生的信号，并在 EMT 中发挥关键作用。
