Cross-talk between the TGFβ and Wnt signaling pathways in murine embryonic maxillary mesenchymal cells

The transforming growth factor beta (TGF beta) and Writ signaling pathways play central roles regulating embryogenesis and maintaining adult tissue homeostasis. TGF beta 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 TGF beta 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 TGF beta leads to enhanced reporter activity from TOPflash, a Wnt-responsive reporter plasmid. Transcriptional cooperation between TGF beta and Wnt did not require the presence of a Smad binding element, nor did it occur when a TGF beta-responsive reporter plasmid (p3TP-lux) was transfected. Overexpression of Smad 3 further enhanced the cooperation between Wnt and TGF beta while overexpression of dominant-negative Smads 2 and 3 inhibited this effect. Co-stimulation with TGF beta led to greater nuclear translocation of P-catenin, providing explanation for the effect of TGF beta on Wnt-3a reporter activity. Wnt-3a exerted antiproliferative activity in MEMM cells, similar to that exerted by TGF beta. In addition, Wnt-3a and TGF beta in combination led to synergistic decreases in MEMM cell proliferation. These data demonstrate a functional interaction between the TGF beta and Wnt signaling pathways and suggest that Wnt activation of the canonical pathway is an important mediator of MEMM cell growth. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.