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Molecular and Cellular Biology, May 2005, p. 3475-3482, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3475-3482.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Mechanism of Endogenous Receptor Activation Functionally Distinguishes Prototype Canonical and Noncanonical Wnts

Guizhong Liu, Anna Bafico, and Stuart A. Aaronson*

Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York

Received 15 October 2004/ Returned for modification 10 November 2004/ Accepted 1 February 2005

Wnt glycoproteins are developmentally essential signaling molecules, and lesions afflicting Wnt pathways play important roles in human diseases. Some Wnts signal to the canonical pathway by stabilizing ß-catenin, while others lack this activity. Frizzled serpentine receptors mediate distinct signaling pathways by both classes of Wnts. Here, we tandemly linked noncanonical Wnt5a with the C-terminal half of Dickkopf-2 (Dkk2C), a distinct ligand of the Wnt coreceptor LRP5/6. Whereas Wnt5a, Dkk2C, or both together were incapable of stimulating endogenous canonical signaling, the Wnt5a/Dkk2C chimera efficiently activated this pathway in a manner inhibitable by specific antagonists of either frizzled or LRP receptors. Thus, activation of the canonical pathway requires ligand coupling of an endogenous frizzled/LRP coreceptor complex, rather than Wnt triggering each receptor independently. Moreover, fusion of Wnt5a with Dkk2C unmasked its ability to signal to Dishevelled through multiple frizzleds, indicating that the lack of functional interaction with LRP distinguishes noncanonical Wnt5a from canonical Wnts in mammalian cells. These findings provide a novel mechanism by which the same receptor can be switched between distinct signaling pathways depending on the differential recruitment of a coreceptor by members of the same ligand family.

* Corresponding author. Mailing address: Department of Oncological Sciences, Mount Sinai School of Medicine, Box 1130, One Gustave L. Levy Pl., New York, NY 10029. Phone: (212) 659-5400. Fax: (212) 987-2240. E-mail: stuart.aaronson{at}mssm.edu.

Molecular and Cellular Biology, May 2005, p. 3475-3482, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3475-3482.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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