Wnt3a-Mediated Formation of Phosphatidylinositol 4,5-Bisphosphate Regulates LRP6 Phosphorylation

Abstract

The canonical Wnt–β-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 α and phosphatidylinositol-4-phosphate 5-kinase type I (PIP5KI) as required for Wnt3a-induced LRP6 phosphorylation at Ser ¹⁴⁹⁰ 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.