Wnt–β-catenin signaling

Abstract

After stabilization, β-catenin translocates across the nuclear pore complex to the nucleoplasm. It is thought that this is an intrinsic property of β-catenin, although there are several factors that can influence its nuclear import or export. Once in the nucleus, β-catenin can act as a transcriptional co-regulator, binding to specific DNA-binding transcription factors. Although the list of proteins known to recruit β-catenin to target genes is growing — Foxo, PitX2, SOX9 and SOX17, for example — most cases of Wnt-mediated transcriptional regulation involve members of the TCF protein family.While the interaction of β-catenin and TCF is critical for activation of Wnt targets, it is also critical that these targets are not activated inappropriately by small amounts of nuclear β-catenin. Several different factors have been identified that act as nuclear β-catenin buffers — they compete with the β-catenin–TCF interaction by binding to either factor. ICAT, Chibby, Sox9 and CtBP-APC are among the factors that bind to β-catenin and inhibit it binding to TCF. Members of the TLE/Gro family do the same for TCFs (Figure 3Figure 3A). These nuclear factors raise the threshold of nuclear β-catenin required for its recruitment to Wnt targets via binding to TCF.Figure 3The TCF transcriptional switch mediating activation of Wnt targets.In the absence of signaling (A), TCF represses Wnt targets by recruiting co-repressors such as TLE/Gro. Other repressive complexes also contribute to this silencing. In addition, there are several factors that act as ‘nuclear β-catenin buffers’ which prevent β-catenin–TCF interaction when β-catenin is present at low concentrations. On Wnt signaling (B), the high level of nuclear β-catenin overcomes these buffers, and β-catenin displaces the repressors from the target gene chromatin. β-catenin dependent recruitment of a variety of co-activators allows transcription to proceed.View Large Image | View Hi-Res Image | Download PowerPoint SlideIn the absence of signaling, many Wnt targets are silenced by TCF-mediated repression. This occurs in part through TCF binding to TLE/Gro, which in turn recruits histone deacetylases (Figure 3Figure 3A). Other factors have also been implicated in silencing Wnt targets — for example, Kaiso and the chromatin remodeling complex ACF — though these act in parallel to TCF–TLE/Gro and do not function on all targets.When β-catenin reaches levels sufficient to bind to TCF, this interaction displaces TLE/Gro from Wnt target genes, relieving repression. In addition, β-catenin serves as a landing platform for a variety of transcriptional co-activators. These include Legless/Bcl9 and Pygopus (Pygo) which bind to the amino-terminal half of β-catenin, while the histone acetyl transferase CBP and Parafibromin/Hyrax bind to the carboxy-terminal portion. There are many other co-activators that bind to β-catenin and promote its ability to activate Wnt target genes; however, many of these factors are likely to be gene, cell-type or species-specific. Indeed, while pygo is essential for Wnt regulation of targets in flies, mice lacking both pygo genes have a much more modest reduction in Wnt target gene expression. At the general level, however, the idea that β-catenin switches a TCF from a transcriptional repressor to an activator is a useful way to think of Wnt-mediated regulation of many target genes. While invertebrate TCFs clearly contain both the repressive and activating activities — essential in flies and worms which only have one TCF each — it appears that some vertebrate TCFs have become more specialized, with TCF3 possessing mainly silencing activity and LEF1 functioning in the activation portion of the transcriptional switch.It should be noted that there are many genes that are downregulated in response to Wnt signaling, and in some cases it has been confirmed that a TCF–β-catenin complex directly mediates this repression. How many of the genes downregulated by Wnt–β-catenin signaling are directly repressed remains an important unanswered question. The mechanism of TCF–β-catenin repression has not been worked out in detail, and it appears to be different among the few genes studied in detail. The diversity of mechanisms by which β-catenin can regulate gene expression likely explains how this pathway can perform so many essential functions throughout the animal kingdom.