Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6

Background: Dickkopf-1 (Dkk-1) is a head inducer secreted from the vertebra te head organizer and induces anterior development by antagonizing Wnt sign aling, Although several families of secreted antagonists have been shown to inhibit Wnt signal transduction by binding to Wnt, the molecular mechanism of Dkk-1 action is unknown. The Wnt family of secreted growth factors init iates signaling via the Frizzled (Fz) receptor and its candidate coreceptor , LDL receptor-related protein 6 (LRP6), presumably through Fz-LRP6 complex formation induced by Wnt. The significance of the Fz-LRP6 complex in signa l transduction remains to be established. Results: We report that Dkk-1 is a high-affinity ligand for LRP6 and inhibi ts Wnt signaling by preventing Fz-LRP6 complex formation induced by Wnt. Dk k-1 binds neither Wnt nor Fz, nor does it affect Wnt-Fz interaction. Dkk-1 function in head induction and Wnt signaling inhibition strictly correlates with its ability to bind LRP6 and to disrupt the Fz-LRP6 association. LRP6 function and Dkk-1 inhibition appear to be specific for the Wnt/Fz beta -c atenin pathway. Conclusions: Our results demonstrate that Dkk-1 is an LRP6 ligand and inhib its Wnt signaling by blocking Wnt-induced Fz-LRP6 complex formation. Our fi ndings thus reveal a novel mechanism for Wnt signal modulation. LRP6 is a W nt coreceptor that appears to specify Wnt/Fz signaling to the beta -catenin pathway, and Dkk-1,distinct from Wnt binding antagonists, may be a specifi c inhibitor for Wnt/beta -catenin signaling. Our findings suggest that Wnt- Fz-LRP6 complex formation, but not Wnt-Fz interaction, triggers Wnt/beta -c atenin signaling. (C) 2001 Elsevier Science Ltd. All rights reserved.