Transcriptional regulation by Smads: Crosstalk between the TGF-beta and Wnt pathways

Background: Several studies have shown that cooperation between transformin g growth factor beta (TGF-beta) and Wnt/wingless signaling pathways plays a role in controlling certain developmental events. These factors elicit the ir biological effects through distinct pathways in which TGF-beta and Wnt s ignaling induce activation of the transcriptional regulators Smads and lymp hoid enhancer binding factor/T-cell-specific factor (LEF/TCF), respectively . To understand the mechanism for cooperativity between these pathways, we have investigated the molecular mechanism for this synergistic effect. Methods: Transcriptional assays were conducted by transient transfection of HepG2 cells with use of luciferase reporter constructs. Protein/protein in teraction studies were conducted in vitro with the use of glutathione-S-tra nsferase pull-down assays and in intact cells by immunoprecipitation and im munoblotting. Results: We show that Smads physically interact with LEF1/TCF transcription factors and that specific DNA binding sites in the Xenopus twin promoter a re required for synergistic activation by TGF-beta and Wnt pathways. in add ition, we demonstrate that TGF-beta -dependent activation of LEF1/TCF targe t genes can occur independently of beta -catenin, an essential component of the Wnt signaling pathway. Conclusions: TGF-beta and Wnt signaling pathways can independently or coope ratively regulate LEF1/TCF target genes. This suggests that the cooperation between these pathways may be important for the specification of cell fate s during development.