title: Cross-talk between the TGFbeta and Wnt signaling pathways in murine embryonic maxillary mesenchymal cells.
abstract: The transforming growth factor beta (TGFbeta) and Wnt signaling pathways play central roles regulating embryogenesis and maintaining adult tissue homeostasis. TGFbeta mediates its cellular effects through types I and II cell surface receptors coupled to the nucleocytoplasmic Smad proteins. Wnt signals via binding to a cell surface receptor, Frizzled, which in turn activates intracellular Dishevelled, ultimately leading to stabilization and nuclear translocation of beta-catenin. Previous studies have demonstrated several points of cross-talk between the TGFbeta and Wnt signaling pathways. In yeast two-hybrid and GST-pull down assays, Dishevelled-1 and Smad 3 have been shown to physically interact through the C-terminal one-half of Dishevelled-1 and the MH2 domain of Smad 3. The current study demonstrates that co-treatment of murine embryonic maxillary mesenchyme (MEMM) cells with Wnt-3a and TGFbeta leads to enhanced reporter activity from TOPflash, a Wnt-responsive reporter plasmid. Transcriptional cooperation between TGFbeta and Wnt did not require the presence of a Smad binding element, nor did it occur when a TGFbeta-responsive reporter plasmid (p3TP-lux) was transfected. Overexpression of Smad 3 further enhanced the cooperation between Wnt and TGFbeta while overexpression of dominant-negative Smads 2 and 3 inhibited this effect. Co-stimulation with TGFbeta led to greater nuclear translocation of beta-catenin, providing explanation for the effect of TGFbeta on Wnt-3a reporter activity. Wnt-3a exerted antiproliferative activity in MEMM cells, similar to that exerted by TGFbeta. In addition, Wnt-3a and TGFbeta in combination led to synergistic decreases in MEMM cell proliferation. These data demonstrate a functional interaction between the TGFbeta and Wnt signaling pathways and suggest that Wnt activation of the canonical pathway is an important mediator of MEMM cell growth.
authors.affiliation: University of Louisville Birth Defects Center, Department of Molecular, Cellular, and Craniofacial Biology, 501 South Preston Street, Suite 301, Louisville, KY 40292, United States. dennis.warner@louisville.edu
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Warner
authors.forename: Robert M
authors.initials: RM
authors.lastname: Greene
authors.forename: M Michele
authors.initials: MM
authors.lastname: Pisano
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D008297:Male; D008437:Maxilla / Q000166:cytology / Q000196:embryology*; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D051900:Smad3 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin
chemical_list: C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin