Abstract
In a recent issue of Nature, Hao et al. report an unexpected link between the secreted stem cell factor/Wnt agonist R-spondin and Wnt receptors through the transmembrane ZNRF3 protein, a RING finger ubiquitin ligase. ZNRF3 acts to turn over Frizzled and LRP6 receptors. R-spondin binds to ZNRF3, in addition to transmembrane LGR4/5 receptors, to antagonize degradation of the Wnt receptors by ZNRF3, thereby resulting in increased Frizzled and LRP6 levels and a greater Wnt response.