Wnt signalling is involved in fundamental cellular processes and regulates gene expression through ß-catenin. Mosimann and colleagues now add a piece to the puzzle of Wnt-mediated transcriptional regulation by identifying a novel component of the Wnt pathway that directly associates with ß-catenin to control Wnt target-gene expression.

In the cytoplasm, ß-catenin is constitutively marked for proteasomal degradation. However, upon activation of the Wnt signalling pathway, ß-catenin translocates to the nucleus, where it interacts with the TCF/LEF DNA-binding proteins and induces the transcription of Wnt target genes. Recent studies have revealed some of the nuclear partners of ß-catenin and shed light on the mechanism of Wnt transcriptional regulation. For example, ß-catenin interacts with the BCL9/Legless (LGS; the Drosophilia melanogaster homologue) coactivator, which links ß-catenin to the PhD-finger protein Pygopus (PYGO), to form a complex with TCF/LEF.

Mosimann and colleagues now add a piece to the puzzle of Wnt-mediated transcriptional regulation by identifying a novel component of the Wnt pathway...

In an attempt to identify further factors that mediate the transcriptional output of this complex, Mosimann et al. performed a genetic screen in D. melanogaster and identified a new gene, Hyrax (Hyx), which functions as a positive-regulatory component of the Wnt signalling pathway. Mutational and RNA interference (RNAi) analysis showed that the inactivation of Hyx expression reduces the activity of the Wnt pathway — the reduction of HYX in vivo, as well as the knockdown of HYX in cultured cells, abrogated Armadillo (the D. melanogaster ß-catenin homologue)-mediated transduction of Wnt signals.

Interestingly, HYX and its human orthologue, parafibromin (a known tumour suppressor in parathyroid cancer), are homologous to Saccharomyces cerevisiae Cdc73. Cdc73 is a component of the polymerase-associated factor-1 (PAF1) complex, which is involved in the regulation of transcription initiation and elongation. This finding led the authors to postulate that HYX and parafibromin are nuclear factors of a metazoan PAF1 complex, which mediates Wnt target-gene activation.

But, how does HYX promote Wnt target-gene expression? And could HYX provide the missing link between the ß-catenin complex and trancription initiation and elongation by RNA polymerase II? Mosimann and colleagues showed that a stable complex exists between parafibromin and ß-catenin. Fine-mapping of the regions in parafibromin and ß-catenin that are involved in this direct interaction revealed that the C-terminal domain of ß-catenin interacts with a ß-catenin interaction domain in the N terminus of parafibromin. These results were also confirmed with the D. melanogaster homologues.

As both BCL9/LGS–PYGO and parafibromin are recruited to ß-catenin, the authors reasoned that parafibromin functions in parallel with BCL9/LGS–PYGO. Biochemical analysis showed that the parafibromin–ß-catenin complex also contains BCL9 and PYGO. Therefore, ß-catenin functions as a scaffold protein that assembles a nuclear complex that consists of BCL9/LGS–PYGO and parafibromin.

These findings delineate a new regulatory component of the Wnt signal-transduction pathway. However, many pieces in the puzzle of Wnt signalling-mediated gene expression are still missing, including many transcriptional targets of this complex.