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Science 316 (5831): 1619-1622

Copyright © 2007 by the American Association for the Advancement of Science

Wnt Induces LRP6 Signalosomes and Promotes Dishevelled-Dependent LRP6 Phosphorylation

Josipa Bilic,1 Ya-Lin Huang,1 Gary Davidson,1 Timo Zimmermann,2 Cristina-Maria Cruciat,1 Mariann Bienz,3 Christof Niehrs1*

Abstract: Multiple signaling pathways, including Wnt signaling, participate in animal development, stem cell biology, and human cancer. Although many components of the Wnt pathway have been identified, unresolved questions remain as to the mechanism by which Wnt binding to its receptors Frizzled and Low-density lipoprotein receptor–related protein 6 (LRP6) triggers downstream signaling events. With live imaging of vertebrate cells, we show that Wnt treatment quickly induces plasma membrane–associated LRP6 aggregates. LRP6 aggregates are phosphorylated and can be detergent-solubilized as ribosome-sized multiprotein complexes. Phospho-LRP6 aggregates contain Wnt-pathway components but no common vesicular traffic markers except caveolin. The scaffold protein Dishevelled (Dvl) is required for LRP6 phosphorylation and aggregation. We propose that Wnts induce coclustering of receptors and Dvl in LRP6-signalosomes, which in turn triggers LRP6 phosphorylation to promote Axin recruitment and ß-catenin stabilization.

1 Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
2 Advanced Light Microscopy Facility, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
3 MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.

* To whom correspondence should be addressed. E-mail: Niehrs{at}DKFZ-Heidelberg.DE


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LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of {beta}-catenin.
C. S. Cselenyi, K. K. Jernigan, E. Tahinci, C. A. Thorne, L. A. Lee, and E. Lee (2008)
PNAS 105, 8032-8037
   Abstract »    Full Text »    PDF »
Wnt Signal Amplification via Activity, Cooperativity, and Regulation of Multiple Intracellular PPPSP Motifs in the Wnt Co-receptor LRP6.
B. T. MacDonald, C. Yokota, K. Tamai, X. Zeng, and X. He (2008)
J. Biol. Chem. 283, 16115-16123
   Abstract »    Full Text »    PDF »
Plasma membrane recruitment of dephosphorylated {beta}-catenin upon activation of the Wnt pathway.
J. Hendriksen, M. Jansen, C. M. Brown, H. van der Velde, M. van Ham, N. Galjart, G. J. Offerhaus, F. Fagotto, and M. Fornerod (2008)
J. Cell Sci. 121, 1793-1802
   Abstract »    Full Text »    PDF »
Wnt signalling in development and disease: Max Delbruck Center for Molecular Medicine meeting on Wnt Signaling in Development and Disease.
C. Fuerer, R. Nusse, and D. ten Berge (2008)
EMBO Rep. 9, 134-138
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Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions.
X. Zeng, H. Huang, K. Tamai, X. Zhang, Y. Harada, C. Yokota, K. Almeida, J. Wang, B. Doble, J. Woodgett, et al. (2008)
Development 135, 367-375
   Abstract »    Full Text »    PDF »

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