Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 321 (5894): 1350-1353

Copyright © 2008 by the American Association for the Advancement of Science

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}

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 (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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Glypican-3 binds to Frizzled and plays a direct role in the stimulation of canonical Wnt signaling.
M. Capurro, T. Martin, W. Shi, and J. Filmus (2014)
J. Cell Sci. 127, 1565-1575
   Abstract »    Full Text »    PDF »
{beta}-Arrestin Promotes Wnt-induced Low Density Lipoprotein Receptor-related Protein 6 (Lrp6) Phosphorylation via Increased Membrane Recruitment of Amer1 Protein.
V. Kriz, V. Pospichalova, J. Masek, M. B. C. Kilander, J. Slavik, K. Tanneberger, G. Schulte, M. Machala, A. Kozubik, J. Behrens, et al. (2014)
J. Biol. Chem. 289, 1128-1141
   Abstract »    Full Text »    PDF »
Is Wilms Tumor a Candidate Neoplasia for Treatment with WNT/{beta}-Catenin Pathway Modulators?--A Report from the Renal Tumors Biology-Driven Drug Development Workshop.
D. Perotti, P. Hohenstein, I. Bongarzone, M. Maschietto, M. Weeks, P. Radice, and K. Pritchard-Jones (2013)
Mol. Cancer Ther. 12, 2619-2627
   Abstract »    Full Text »    PDF »
Smurf1-Mediated Lys29-Linked Nonproteolytic Polyubiquitination of Axin Negatively Regulates Wnt/{beta}-Catenin Signaling.
C. Fei, Z. Li, C. Li, Y. Chen, Z. Chen, X. He, L. Mao, X. Wang, R. Zeng, and L. Li (2013)
Mol. Cell. Biol. 33, 4095-4105
   Abstract »    Full Text »    PDF »
Modulation of Lipid Kinase PI4KII{alpha} Activity and Lipid Raft Association of Presenilin 1 Underlies {gamma}-Secretase Inhibition by Ginsenoside (20S)-Rg3.
M. S. Kang, S.-H. Baek, Y. S. Chun, A. Z. Moore, N. Landman, D. Berman, H. O. Yang, M. Morishima-Kawashima, S. Osawa, S. Funamoto, et al. (2013)
J. Biol. Chem. 288, 20868-20882
   Abstract »    Full Text »    PDF »
Clathrin and AP2 are required for PtdIns(4,5)P2-mediated formation of LRP6 signalosomes.
I. Kim, W. Pan, S. A. Jones, Y. Zhang, X. Zhuang, and D. Wu (2013)
J. Cell Biol. 200, 419-428
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 4-kinase II{alpha} function at endosomes is regulated by the ubiquitin ligase Itch.
J. Mossinger, M. Wieffer, E. Krause, C. Freund, F. Gerth, M. Krauss, and V. Haucke (2012)
EMBO Rep. 13, 1087-1094
   Abstract »    Full Text »    PDF »
Frizzled and LRP5/6 Receptors for Wnt/{beta}-Catenin Signaling.
B. T. MacDonald and X. He (2012)
Cold Spring Harb Perspect Biol 4, a007880
   Abstract »    Full Text »    PDF »
LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
D. C. Berwick and K. Harvey (2012)
Hum. Mol. Genet. 21, 4966-4979
   Abstract »    Full Text »    PDF »
The E3 Ubiquitin Ligase ITCH Negatively Regulates Canonical Wnt Signaling by Targeting Dishevelled Protein.
W. Wei, M. Li, J. Wang, F. Nie, and L. Li (2012)
Mol. Cell. Biol. 32, 3903-3912
   Abstract »    Full Text »    PDF »
CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis.
W. Pan, V. N. Pham, A. N. Stratman, D. Castranova, M. Kamei, K. R. Kidd, B. D. Lo, K. M. Shaw, J. Torres-Vazquez, C. M. Mikelis, et al. (2012)
Blood 120, 489-498
   Abstract »    Full Text »    PDF »
Disabled-2 (Dab2) inhibits Wnt/{beta}-catenin signalling by binding LRP6 and promoting its internalization through clathrin.
Y. Jiang, X. He, and P. H. Howe (2012)
EMBO J. 31, 2336-2349
   Abstract »    Full Text »    PDF »
Wnt3a-stimulated LRP6 phosphorylation is dependent upon arginine methylation of G3BP2.
R. K. Bikkavilli and C. C. Malbon (2012)
J. Cell Sci. 125, 2446-2456
   Abstract »    Full Text »    PDF »
Inhibition of GSK3 by Wnt signalling - two contrasting models.
C. Metcalfe and M. Bienz (2011)
J. Cell Sci. 124, 3537-3544
   Abstract »    Full Text »    PDF »
Transmembrane Protein 198 Promotes LRP6 Phosphorylation and Wnt Signaling Activation.
J. Liang, Y. Fu, C.-M. Cruciat, S. Jia, Y. Wang, Z. Tong, Q. Tao, D. Ingelfinger, M. Boutros, A. Meng, et al. (2011)
Mol. Cell. Biol. 31, 2577-2590
   Abstract »    Full Text »    PDF »
Wnt signalling: What The X@# is WTX?.
Y. Regimbald-Dumas and X. He (2011)
EMBO J. 30, 1415-1417
   Abstract »    Full Text »    PDF »
Amer1/WTX couples Wnt-induced formation of PtdIns(4,5)P2 to LRP6 phosphorylation.
K. Tanneberger, A. S. Pfister, K. Brauburger, J. Schneikert, M. V. Hadjihannas, V. Kriz, G. Schulte, V. Bryja, and J. Behrens (2011)
EMBO J. 30, 1433-1443
   Abstract »    Full Text »    PDF »
LRP6 Mediates cAMP Generation by G Protein-Coupled Receptors Through Regulating the Membrane Targeting of G{alpha}s.
M. Wan, J. Li, K. Herbst, J. Zhang, B. Yu, X. Wu, T. Qiu, W. Lei, C. Lindvall, B. O. Williams, et al. (2011)
Science Signaling 4, ra15
   Abstract »    Full Text »    PDF »
Molecular Basis of Wnt Activation via the DIX Domain Protein Ccd1.
Y.-T. Liu, Q.-J. Dan, J. Wang, Y. Feng, L. Chen, J. Liang, Q. Li, S.-C. Lin, Z.-X. Wang, and J.-W. Wu (2011)
J. Biol. Chem. 286, 8597-8608
   Abstract »    Full Text »    PDF »
PIPKI{gamma} Regulates {beta}-Catenin Transcriptional Activity Downstream of Growth Factor Receptor Signaling.
M. Schramp, N. Thapa, J. Heck, and R. Anderson (2011)
Cancer Res. 71, 1282-1291
   Abstract »    Full Text »    PDF »
Identification of Transmembrane Protein 88 (TMEM88) as a Dishevelled-binding Protein.
H.-J. Lee, D. Finkelstein, X. Li, D. Wu, D.-L. Shi, and J. J. Zheng (2010)
J. Biol. Chem. 285, 41549-41556
   Abstract »    Full Text »    PDF »
Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members.
J. Y. Hong, J.-i. Park, K. Cho, D. Gu, H. Ji, S. E. Artandi, and P. D. McCrea (2010)
J. Cell Sci. 123, 4351-4365
   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors.
G. Schulte (2010)
Pharmacol. Rev. 62, 632-667
   Abstract »    Full Text »    PDF »
Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors.
L. Grumolato, G. Liu, P. Mong, R. Mudbhary, R. Biswas, R. Arroyave, S. Vijayakumar, A. N. Economides, and S. A. Aaronson (2010)
Genes & Dev. 24, 2517-2530
   Abstract »    Full Text »    PDF »
Inference for the Initial Stage of Domain Shuffling: Tracing the Evolutionary Fate of the PIPSL Retrogene in Hominoids.
K. Ohshima and K. Igarashi (2010)
Mol. Biol. Evol. 27, 2522-2533
   Abstract »    Full Text »    PDF »
Phosphatidylinositol-4-Phosphate 5-Kinases and Phosphatidylinositol 4,5-Bisphosphate Synthesis in the Brain.
L. A. Volpicelli-Daley, L. Lucast, L.-W. Gong, L. Liu, J. Sasaki, T. Sasaki, C. S. Abrams, Y. Kanaho, and P. De Camilli (2010)
J. Biol. Chem. 285, 28708-28714
   Abstract »    Full Text »    PDF »
An isoform-specific PDZ-binding motif targets type I PIP5 kinase beta to the uropod and controls polarization of neutrophil-like HL60 cells.
S. Manes, G. Fuentes, R. M. Peregil, A. M. Rojas, and R. A. Lacalle (2010)
FASEB J 24, 3381-3392
   Abstract »    Full Text »    PDF »
An Updated Overview on Wnt Signaling Pathways: A Prelude for More.
T. P. Rao and M. Kuhl (2010)
Circ. Res. 106, 1798-1806
   Abstract »    Full Text »    PDF »
Wnt5a regulates distinct signalling pathways by binding to Frizzled2.
A. Sato, H. Yamamoto, H. Sakane, H. Koyama, and A. Kikuchi (2010)
EMBO J. 29, 41-54
   Abstract »    Full Text »    PDF »
PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions.
I. van den Bout and N. Divecha (2009)
J. Cell Sci. 122, 3837-3850
   Abstract »    Full Text »    PDF »
Regulation of Phosphatidylinositol Kinases and Metabolism by Wnt3a and Dvl.
Y. Qin, L. Li, W. Pan, and D. Wu (2009)
J. Biol. Chem. 284, 22544-22548
   Abstract »    Full Text »    PDF »
Loss of phosphatidylinositol 4-kinase 2{alpha} activity causes late onset degeneration of spinal cord axons.
J. P. Simons, R. Al-Shawi, S. Minogue, M. G. Waugh, C. Wiedemann, S. Evangelou, A. Loesch, T. S. Sihra, R. King, T. T. Warner, et al. (2009)
PNAS 106, 11535-11539
   Abstract »    Full Text »    PDF »
Wnt signaling pathways meet Rho GTPases.
K. Schlessinger, A. Hall, and N. Tolwinski (2009)
Genes & Dev. 23, 265-277
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882