gsk3β is involved in jnk2-mediated β-catenin inhibitiongsk3β参与jnk2-mediatedβ-catenin抑制.pdfVIP

GSK3b Is Involved in JNK2-Mediated b-Catenin Inhibition 1 1 1 2 1 Dong Hu , Xiuli Bi , Wenfeng Fang , Anjia Han , Wancai Yang * 1 Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America, 2 Department of Pathology, the First Affiliated Hospital and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China Abstract Background: We have recently reported that mitogen-activated protein kinase (MAPK) JNK1 downregulates b-catenin signaling and plays a critical role in regulating intestinal homeostasis and in suppressing tumor formation. This study was designed to determine whether JNK2, another MAPK, has similar and/or different functions in the regulation of b-catenin signaling. Methodology and Principal Findings: We used an in vitro system with manipulation of JNK2 and b-catenin expression and found that activated JNK2 increased GSK3b activity and inhibited b-catenin expression and transcriptional activity. However, JNK2-mediated downregulation of b-catenin was blocked by the proteasome inhibitor MG132 and GSK3b inhibitor lithium chloride. Moreover, targeted mutations at GSK3b phosphorylation sites (Ser33 and Ser37) of b-catenin abrogated JNK2- mediated suppression of b-catenin. In vivo studies further revealed that JNK2 deficiency led to upregulation of b-catenin and increase of GSK3-b phosphorylation in JNK2-/- mouse intestinal epithelial cells. Additionally, physical interaction and co- localization among JNK2, b-catenin and GSK3b were observed by immunoprecipitation, mammalian two-hybridization assay and confocal microscopy, respectively. Conclusion and Significance: In general, our data suggested that JNK2, like JNK1, interacts with and s