Wnt (aka Wingless) signalling plays crucial roles in developmental processes and control of cell proliferation in adult organisms. In the canonical pathway, binding of Wnt to Frizzled receptors leads to the release of β-catenin from a cytoplasmic degradation complex. β-catenin can then translocate to the nucleus, where it cooperates with LEF1/TCF transcription factors to regulate gene expression. Jörg Weiske and Otmar Huber now identify a novel Wnt pathway regulator, the tumour suppressor Hint1 (). The authors show that Hint1 binds to pontin and reptin, two proteins that modulate β-catenin/TCF transcriptional activity. They have mapped the residues responsible and demonstrate that Hint1 associates with the LEF-1/TCF–β-catenin transcription complex through pontin/reptin. Significantly, they go on to demonstrate that Hint1 can negatively regulate β-catenin/TCF transcriptional activity and thereby inhibits expression of the cell-cycle regulator cyclin D1. In addition, Weiske and Huber present evidence that Hint1 acts by disrupting the pontin-reptin complex. They conclude that Hint1 is an important regulator of canonical Wnt signalling. Since this is deregulated in numerous cancers, their findings reveal the basis for the protein's tumour suppressor activity.
