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 (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.
Pan
Weijun
W
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
Choi
Sun-Cheol
SC
Wang
He
H
Qin
Yuanbo
Y
Volpicelli-Daley
Laura
L
Swan
Laura
L
Lucast
Louise
L
Khoo
Cynthia
C
Zhang
Xiaowu
X
Li
Lin
L
Abrams
Charles S
CS
Sokol
Sergei Y
SY
Wu
Dianqing
D
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D060466:Axin Protein; D002460:Cell Line; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D015778:Minor Histocompatibility Antigens; D008954:Models, Biological; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D014981:Xenopus / Q000196:embryology; D029867:Xenopus Proteins
D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D015778:Minor Histocompatibility Antigens; D019269:Phosphatidylinositol 4,5-Diphosphate; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D012097:Repressor Proteins; C555506:WNT3A protein, Xenopus; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D029867:Xenopus Proteins; D013912:Threonine; D012694:Serine; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase; C020077:1-phosphatidylinositol-4-phosphate 5-kinase
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