Wnt-4 activates the canonical β-catenin-mediated Wnt pathway and binds Frizzled-6 CRD: functional implications of Wnt/β-catenin activity in kidney epithelial cells

摘要: The Wnt signaling pathway is central to the development of all animals and cancer progression, yet largely unknown are pairings secreted ligands their respective Frizzled transmembrane receptors or, in many cases, relative contributions canonical (beta-catenin/LEF/TCF) versus noncanonical signals. Specifically, kidney where Wnt-4 essential for mesenchymal epithelial transition that generates tissue's collecting tubules, corresponding receptor(s) downstream mechanism(s) unclear. In this report, we addressed these issues using Madin-Darby Canine Kidney (MDCK) cells, which competent form tubules vitro. Employing established reporter constructs Wnt/beta-catenin activity, have determined MDCK cells highly responsive Wnt-4, -1, -3A, but not Wnt-5A control conditions, precisely reflecting functional findings from null mesenchyme ex vivo rescue studies. We confirmed Wnt-4's activity mediated by effectors beta-Engrailed dnTCF-4 suppress pathway. further found express Frizzled-6 receptor forms a biochemical complex with CRD. Since did appear transduce signal, data supported recently Golan et al., there presumably exists another as mediating activation beta-catenin/LEF/TCF. Finally, report signals help maintain cell growth survival do contribute standard HGF-induced (nonphysiologic) tubule formation. Our results combination work Xenopus laevis (not shown) lead us believe binds both receptors, thereby activating pathways may each tubulogenesis.