Mutual antagonism between dickkopf1 and dickkopf2 regulates Wnt/beta-catenin signalling

Wnts are secreted glycoproteins implicated in diverse processes during embr yonic patterning in metazoans. They signal through seven-transmembrane rece ptors of the Frizzled (Fz) family [1] to stabilise beta -catenin [2]. Wnts are antagonised by several extracellular inhibitors including the product o f the dickkopf1 (dkk1) gene, which was identified in Xenopus embryos and is a member of a multigene family. The dkk1 gene acts upstream of the Wnt pat hway component dishevelled but its mechanism of action is unknown [3]. Alth ough the function of Dkk1 as a Wnt inhibitor in vertebrates is well establi shed [3-6], the effect of other Dkks on the wnt/beta -catenin pathway is un clear. Here, we report that a related family member, Dkk2, activates rather than inhibits the wnt/beta -catenin signalling pathway in Xenopus embryos. Dkk2 strongly synergised with Wnt receptors of the Fz family to induce Wnt signalling responses. The study identifies Dkk2 as a secreted molecule tha t is able to activate wnt/beta -catenin signalling. The results suggest tha t a coordinated interplay between inhibiting dkk1 and activating dkk2 can m odulate Fz signalling.