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Molecular and Cellular Biology, June 2004, p. 4757-4768, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4757-4768.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Wnt Proteins Induce Dishevelled Phosphorylation via an LRP5/6- Independent Mechanism, Irrespective of Their Ability To Stabilize ß-Catenin

José M. González-Sancho,{dagger} Keith R. Brennan,{ddagger} Leslie A. Castelo-Soccio, and Anthony M. C. Brown*

Department of Cell and Developmental Biology, Weill Medical College of Cornell University, and Strang Cancer Research Laboratory at The Rockefeller University, New York, New York 10021

Received 16 November 2003/ Returned for modification 8 December 2003/ Accepted 4 March 2004

Wnt glycoproteins play essential roles in the development of metazoan organisms. Many Wnt proteins, such as Wnt1, activate the well-conserved canonical Wnt signaling pathway, which results in accumulation of ß-catenin in the cytosol and nucleus. Other Wnts, such as Wnt5a, activate signaling mechanisms which do not involve ß-catenin and are less well characterized. Dishevelled (Dvl) is a key component of Wnt/ß-catenin signaling and becomes phosphorylated upon activation of this pathway. In addition to Wnt1, we show that several Wnt proteins, including Wnt5a, trigger phosphorylation of mammalian Dvl proteins and that this occurs within 20 to 30 min. Unlike the effects of Wnt1, phosphorylation of Dvl in response to Wnt5a is not concomitant with ß-catenin stabilization, indicating that Dvl phosphorylation is not sufficient to activate canonical Wnt/ß-catenin signaling. Moreover, neither Dickkopf1, which inhibits Wnt/ß-catenin signaling by binding the Wnt coreceptors LRP5 and -6, nor dominant-negative LRP5/6 constructs could block Wnt-mediated Dvl phosphorylation. We conclude that Wnt-induced phosphorylation of Dvl is independent of LRP5/6 receptors and that canonical Wnts can elicit both LRP-dependent (to ß-catenin) and LRP-independent (to Dvl) signals. Our data also present Dvl phosphorylation as a general biochemical assay for Wnt protein function, including those Wnts that do not activate the Wnt/ß-catenin pathway.

* Corresponding author. Mailing address: Strang Cancer Research Laboratory at The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: (212) 734-0567, ext. 232. Fax: (212) 472-9471. E-mail: amcbrown{at}med.cornell.edu.

{dagger} Present address: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, E-28029 Madrid, Spain.

{ddagger} Present address: School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.

Molecular and Cellular Biology, June 2004, p. 4757-4768, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.4757-4768.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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