A new cog in a critical signaling machine

The Wnt signaling pathway is pivotal to the regulation of embryogenesis, metabolism and tumorigenesis. Lin Li and colleagues at the Shanghai Institutes for Biological Sciences, China, now add a previously uncharacterized component to this intricate pathway.

Wnt is a secretory protein that binds to two receptors — Frizzled and LRP5/6 — on target cells, which results in the recruitment of the protein Axin to LRP5/6 and hence activates the signaling protein β-catenin to regulate gene transcription. LRP5/6 is known to be regulated by binding to a number of other proteins and by phosphorylation.

In characterizing proteins that bind to LRP5, Li and colleagues identified Caprin-2, a little-studied protein¹. They demonstrated that the binding is direct and functionally important: Caprin-2 over-expression stabilizes β-catenin and enhances Wnt-dependent gene expression, while its ablation has the opposite effect. Furthermore, in the model organism zebrafish, in which Wnt signaling controls development, Caprin-2 ablation blocks Wnt signaling and results in developmental abnormalities.

In terms of molecular mechanism, Li and colleagues show that Caprin-2 functions through regulation of LRP5/6 phosphorylation, which is required for the LRP5/6-Axin interaction. Some evidence also points to a second role in binding Axin, which the researchers are now examining in detail.