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 (Thr1479) and serine residue 1490 (Ser1490). 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)P2] through frizzled and dishevelled, the latter of which directly interacted with and activated PIP5KI. In turn, PtdIns (4,5)P2 regulated phosphorylation of LRP6 at Thr1479 and Ser1490. Therefore, our study reveals a signaling mechanism for Wnt to regulate LRP6 phosphorylation.
PubMed ID: 18772438
PMC ID: PMC2532521
Article link: Science.
Grant support: AR051476 NIAMS NIH HHS , CA132317 NCI NIH HHS , DA018343 NIDA NIH HHS , HL080706 NHLBI NIH HHS , NS36251 NINDS NIH HHS , R01 AR051476-01A1 NIAMS NIH HHS , R01 AR051476-02 NIAMS NIH HHS , R01 AR051476-03 NIAMS NIH HHS , R01 CA132317-01A2 NCI NIH HHS , R01 CA132317 NCI NIH HHS , R01 CA139395 NCI NIH HHS , P30 DA018343 NIDA NIH HHS , R01 AR051476 NIAMS NIH HHS
Genes referenced: dvl2 lrp6 wnt3a