Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and Wnt pathways

The transforming growth factor-beta (TGF beta) and Wnt/wingless pathways pl ay pivotal roles in tissue specification during development. Activation of Smads, the effecters of TCF beta superfamily signals, results in Smad trans location from the cytoplasm into the nucleus where they act as transcriptio nal comodulators to regulate target gene expression. Wnt/wingless signals a re mediated by the DNA-binding HMG box transcription factors lymphoid enhan cer binding factor 1/T cell-specific factor (LEF1/TCF) and their coactivato r beta-catenin. Herein, we show that Smad3 physically interacts with the HM G box domain of LEF1 and that TGF beta and Wnt pathways synergize to activa te transcription of the Xenopus homeobox gene twin (Xtwn). Disruption of sp ecific Smad and LEF1/TCF DNA-binding sites in the promoter abrogates synerg istic activation of the promoter. Consistent with this observation, introdu ction of Smad sites into a TCF beta-insensitive LEF1/TCF target gene confer s cooperative TCF beta and Wnt responsiveness to the promoter. Furthermore, we demonstrate that TCF beta-dependent activation of LEF1/TCF target genes can occur in the absence of beta-catenin binding to LEF1/TCF and requires both Smad and LEF1/TCF DNA-binding sites in the Xtwn promoter. Thus, our re sults show that TGF beta and Wnt signaling pathways can independently or co operatively regulate LEF1/TCF target genes and suggest a model for how thes e pathways can synergistically activate target genes.