TCFs and Wnt/β-catenin signaling: more than one way to throw the switch

Wnts are conserved, secreted signaling proteins that can influence cell behavior by stabilizing β-catenin. Accumulated β-catenin enters the nucleus, where it physically associates with T-cell factor (TCF) family members to regulate target gene expression in many developmental and adult tissues. Recruitment of β-catenin to Wnt response element (WRE) chromatin converts TCFs from transcriptional repressors to activators. This review will outline the complex interplay between factors contributing to TCF repression and coactivators working with β-catenin to regulate Wnt targets. In addition, three variations of the standard transcriptional switch model will be discussed. One is the Wnt/β-catenin symmetry pathway in Caenorhabditis elegans, where Wnt-mediated nuclear efflux of TCF is crucial for activation of targets. Another occurs in vertebrates, where distinct TCF family members are associated with repression and activation, and recent evidence suggests that Wnt signaling facilitates a "TCF exchange" on WRE chromatin. Finally, a "reverse switch" mechanism for target genes that are directly repressed by Wnt/β-catenin signaling occurs in Drosophila cells. The diversity of TCF regulatory mechanisms may help to explain how a small group of transcription factors can function in so many different contexts to regulate target gene expression.