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

2008; American Association for the Advancement of Science; Volume: 321; Issue: 5894 Linguagem: Inglês

10.1126/science.1160741

1095-9203

Weijun Pan, Sun‐Cheol Choi, He Wang, Yuanbo Qin, Laura A. Volpicelli‐Daley, Laura E. Swan, Louise Lucast, Cynthia Khoo, Xiaowu Zhang, Lin Li, Charles S. Abrams, Sergei Y. Sokol, Dianqing Wu,

Genetics and Neurodevelopmental Disorders

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.