Receptor heterodimerization as a novel mechanism for regulation of Wnt/β-catenin signaling

The Wnt pathway plays important roles in multiple physiological and pathophysiological processes. Here we report a novel mechanism regulating the Wnt pathway through heterodimerization of lipoprotein receptor-related protein (LRP6), a Wnt co-receptor and very low-density lipoprotein receptor (VLDLR), which is in the same family as LRP6 and was originally known as a receptor for lipoproteins. Knockdown of Vldlr expression elevated LRP6 levels and activated Wnt/β-catenin signaling, whereas over-expression of Vldlr suppressed Wnt signaling. Moreover, we demonstrated that the VLDLR ectodomain is essential and sufficient for inhibition of Wnt signaling. The VLDLR ectodomain accelerated internalization and degradation of LRP6 through heterodimerization with the LRP6 extracellular domain. Monoclonal antibodies specific for the VLDLR ectodomain blocked VLDLR:LRP6 heterodimerization, resulting in enhanced Wnt/β-catenin signaling in vitro and in vivo. Taken together, these findings suggest that heterodimerization of receptors in the membrane accelerates LRP6 turnover, and represent a new mechanism for regulation of Wnt/β-catenin signaling.