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FEBS Lett. 2005 Jul 4;579(17):3539-46.

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

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  • 1University 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

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.

PMID:
15955531
[PubMed - indexed for MEDLINE]
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