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Science 5 September 2008:
Vol. 321. no. 5894, pp. 1350 - 1353
DOI: 10.1126/science.1160741
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Reports

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

Weijun Pan,1* Sun-Cheol Choi,2* He Wang,3* Yuanbo Qin,3 Laura Volpicelli-Daley,4 Laura Swan,4 Louise Lucast,4 Cynthia Khoo,5 Xiaowu Zhang,6 Lin Li,3 Charles S. Abrams,5 Sergei Y. Sokol,2 Dianqing Wu1{dagger}

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 (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.

1 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
2 Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
3 State Key Laboratory of Molecular Biology and Center of Cell Signaling, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
4 Department of Cell Biology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
5 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
6 Cell Signaling Technology, Danvers, MA 01923, USA.

* These authors contribute equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: dan.wu{at}yale.edu

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