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Molecular and Cellular Biology, August 2003, p. 5825-5835, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5825-5835.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Novel Mechanism for Wnt Activation of Canonical Signaling through the LRP6 Receptor

Guizhong Liu, Anna Bafico, Violaine K. Harris, and Stuart A. Aaronson*

Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029

Received 10 February 2003/ Returned for modification 12 March 2003/ Accepted 20 May 2003

LDL receptor-related protein 6 (LRP6) is a Wnt coreceptor in the canonical signaling pathway, which plays essential roles in embryonic development. We demonstrate here that wild-type LRP6 forms an inactive dimer through interactions mediated by epidermal growth factor repeat regions within the extracellular domain. A truncated LRP6 comprising its transmembrane and cytoplasmic domains is expressed as a constitutively active monomer whose signaling ability is inhibited by forced dimerization. Conversely, Wnts are shown to activate canonical signaling through LRP6 by inducing an intracellular conformational switch which relieves allosteric inhibition imposed on the intracellular domains. Thus, Wnt canonical signaling through LRP6 establishes a novel mechanism for receptor activation which is opposite to the general paradigm of ligand-induced receptor oligomerization.

* Corresponding author. Mailing address: Derald H. Ruttenberg Cancer Center, 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, August 2003, p. 5825-5835, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5825-5835.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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