Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation

The canonical Wnt-beta-catenin signaling pathway is initiated by inducing phosphorylation of one of the Wnt receptors, low- density lipoprotein receptor- related protein 6 ( LRP6), at threonine residue 1479 ( Thr(1479)) and serine residue 1490 (Ser(1490)). By screening a human kinase small interfering RNA library, we identified phosphatidylinositol 4- kinase type II alpha and phosphatidylinositol- 4- phosphate 5- kinase type I (PIP5KI) as required for Wnt3a-induced LRP6 phosphorylation at Ser1490 in mammalian cells and confirmed that these kinases are important for Wnt signaling in Xenopus embryos. Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [PtdIns (4,5)P-2] through frizzled and dishevelled, the latter of which directly interacted with and activated PIP5KI. In turn, PtdIns (4,5)P-2 regulated phosphorylation of LRP6 at Thr(1479) and Ser(1490). Therefore, our study reveals a signaling mechanism for Wnt to regulate LRP6 phosphorylation.