title: Regulator of G-protein signaling 3 isoform 1 (PDZ-RGS3) enhances canonical Wnt signaling and promotes epithelial mesenchymal transition.
abstract: 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.
authors.affiliation: B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Chong-Shan
authors.initials: CS
authors.lastname: Shi
authors.forename: Ning-Na
authors.initials: NN
authors.lastname: Huang
authors.forename: John H
authors.initials: JH
authors.lastname: Kehrl
mesh_terms: D000199:Actins / Q000737:chemistry; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D004285:Dogs; D058750:Epithelial-Mesenchymal Transition; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D020710:RGS Proteins; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000199:Actins; D020690:GTPase-Activating Proteins; D016271:Proto-Oncogene Proteins c-myc; D020710:RGS Proteins; C485898:RGS3 protein, human; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D019204:GTP-Binding Proteins