Lrp5/6 are crucial co-receptors for Wnt/beta-catenin signaling, a pathway biochemically distinct from non-canonical Wnt signaling pathways.Here we examined the possible participation of Lrp5/6 in non-canonical Wnt signaling.We found that Lrp6 physically interacts with Wnt5a, but that this does not lead to phosphorylation of Lrp6 or activation of the Wnt/β-catenin pathway.Overexpression of Lrp6 blocks activation of the Wnt5a downstream target Racl, and this effect is dependent on intact Lrp6 extracellular domains.