Opposing roles of Dkk1 in LRP6 stabilization and Wnt signaling: implication for Wnt ligand-induced LRP6 down-regulation

4385 Classically, ligand-induced cell surface receptor down-regulation has been recognized as a longer-term mechanism for termination of a signaling pathway. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential co-receptor for canonical Wnt signaling. Dickkopf 1 (Dkk1), a major secreted Wnt signaling antagonist, binds to LRP6 with high affinity and prevents the Frizzled-Wnt-LRP5/6 complex formation in response to Wnts. Previous studies have demonstrated that Dkk1 promotes LRP6 internalization and degradation when it forms a ternary complex with the cell surface receptor, Kremen. Intriguingly, in the present study, we found that co-transfection of LRP6 and Dkk1 stabilizes LRP6 at the cell surface while still inhibiting Wnt/LRP6 signaling. This finding was recapitulated with exogenous Dkk1 application suggesting that Dkk1 acts on the cell surface and stabilizes LRP6 at non-functional state. We also found that Kremen coexpression abrogated the effect of Dkk1 on LRP6 expression, suggesting that the effect of Kremen2 is dominant over Dkk1 regulation of LRP6. Furthermore, we demonstrated a Wnt3A-induced LRP6 down-regulation; an effect blocked by Dkk1. Taken together, our results reveal a novel role for Dkk1 on Wnt ligand-induced LRP6 down-regulation and Wnt/LRP6 signaling.