Regulator of G-Protein Signaling 3 Isoform 1 (PDZ-RGS3) Enhances Canonical Wnt Signaling and Promotes Epithelial Mesenchymal Transition

• Published in: The Journal of biological chemistry 2012-09, Vol.287 (40), p.33480-33487
• Main Authors: Shi, Chong-Shan, Huang, Ning-Na, Kehrl, John H.
• Format: Article
• Language: English
• Subjects: Actins - chemistry; Animals; beta Catenin - metabolism; Catalytic Domain; Catenin; Cell Line; Dogs; Epithelial to Mesenchymal Transition; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Glycogen Synthase Kinase 3; GTP-Binding Proteins - metabolism; GTPase-Activating Proteins - metabolism; HEK293 Cells; Humans; Models, Biological; Protein Structure, Tertiary; Proto-Oncogene Proteins c-myc - metabolism; RGS Proteins; RNA, Small Interfering - metabolism; Signal Transduction; Snail Family Transcription Factors; Transcription Factors - metabolism; Wnt Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.361873

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. Background: Wnt signaling is subject to regulation by regulator of G-protein signaling domain-containing proteins. Results: PDZ-RGS3 binds GSK3β and inhibits its activity. Conclusion: PDZ-RGS3 enhances canonical Wnt signaling. Significance: PDZ-RGS3 expression may promote epithelial to mesenchymal transition.