Zhang Wen, Yang Jun, Liu Yajuan, Chen Xi, Yu Tianxin, Jia Jianhang, Liu Chunming
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
J Biol Chem. 2009 Aug 21;284(34):22649-56. doi: 10.1074/jbc.M109.013698. Epub 2009 Jun 25.
A central question in Wnt signaling is the regulation of beta-catenin phosphorylation and degradation. Multiple kinases, including CKI alpha and GSK3, are involved in beta-catenin phosphorylation. Protein phosphatases such as PP2A and PP1 have been implicated in the regulation of beta-catenin. However, which phosphatase dephosphorylates beta-catenin in vivo and how the specificity of beta-catenin dephosphorylation is regulated are not clear. In this study, we show that PP2A regulates beta-catenin phosphorylation and degradation in vivo. We demonstrate that PP2A is required for Wnt/beta-catenin signaling in Drosophila. Moreover, we have identified PR55 alpha as the regulatory subunit of PP2A that controls beta-catenin phosphorylation and degradation. PR55 alpha, but not the catalytic subunit, PP2Ac, directly interacts with beta-catenin. RNA interference knockdown of PR55 alpha elevates beta-catenin phosphorylation and decreases Wnt signaling, whereas overexpressing PR55 alpha enhances Wnt signaling. Taken together, our results suggest that PR55 alpha specifically regulates PP2A-mediated beta-catenin dephosphorylation and plays an essential role in Wnt signaling.
Wnt信号传导中的一个核心问题是β-连环蛋白磷酸化和降解的调控。多种激酶，包括酪蛋白激酶Iα（CKIα）和糖原合成酶激酶3（GSK3），参与β-连环蛋白的磷酸化过程。蛋白磷酸酶如蛋白磷酸酶2A（PP2A）和蛋白磷酸酶1（PP1）也与β-连环蛋白的调控有关。然而，体内哪种磷酸酶使β-连环蛋白去磷酸化，以及β-连环蛋白去磷酸化的特异性是如何调控的尚不清楚。在本研究中，我们发现PP2A在体内调控β-连环蛋白的磷酸化和降解。我们证明PP2A是果蝇中Wnt/β-连环蛋白信号传导所必需的。此外，我们已确定PR55α是PP2A的调节亚基，它控制β-连环蛋白的磷酸化和降解。PR55α而非催化亚基PP2Ac直接与β-连环蛋白相互作用。通过RNA干扰敲低PR55α会提高β-连环蛋白的磷酸化水平并降低Wnt信号传导，而过度表达PR55α则会增强Wnt信号传导。综上所述，我们的结果表明PR55α特异性调节PP2A介导的β-连环蛋白去磷酸化，并在Wnt信号传导中起重要作用。
