When cells cozy up to each other, they tune out Wnt signals, Maher et al. show. The cells dial down their sensitivity by speeding the destruction of β-catenin (β-cat), a key component of the Wnt pathway.
β-cat hooks up with transcription factors to switch on genes in response to Wnt. A phosphodestruction complex, which phosphorylates and then chops up β-cat, provides one control mechanism for dampening the Wnt pathway. Cadherin can also diminish Wnt signaling by capturing β-cat at adherens junctions, suggesting adhesion between cells might alter signal transmission via β-cat.
Maher et al. discovered that the heavily phosphorylated form of β-cat amassed at cell junctions. However, forcing cells apart by altering extracellular calcium levels boosted amounts of a lightly phosphorylated, transcriptionally competent β-cat version. β-cat signaling was also higher when cells lacked neighbors, such as at the edge of a colony or along a scratch in a cell layer.
Driving changes in β-cat levels is the phosphodestruction complex, the researchers suggest. Its components build up at cell junctions. And when cells stick together, the complex's breakdown of β-cat in the cytosol accelerates.
What draws the phosphodestruction complex to cell contacts and controls its activity remains uncertain. But the results suggest that when cells touch, cadherin diminishes their sensitivity to Wnt signals by firing up the phosphodestruction complex, and boosting the demolition of β-cat. If intercellular contacts break, such as during migration, the phosphodestruction complex slows, priming the cell to respond to Wnt signals.
