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Genes & Dev. 24 (22): 2517-2530

Copyright © 2010 by Cold Spring Harbor Laboratory Press.

Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors

Luca Grumolato1, Guizhong Liu1, Phyllus Mong1, Raksha Mudbhary1, Romi Biswas1, Randy Arroyave1, Sapna Vijayakumar1, Aris N. Economides2,, and Stuart A. Aaronson1,3

1 Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA;
2 Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, USA

Abstract: Wnt ligands signal through β-catenin and are critically involved in cell fate determination and stem/progenitor self-renewal. Wnts also signal through β-catenin-independent or noncanonical pathways that regulate crucial events during embryonic development. The mechanism of noncanonical receptor activation and how Wnts trigger canonical as opposed to noncanonical signaling have yet to be elucidated. We demonstrate here that prototype canonical Wnt3a and noncanonical Wnt5a ligands specifically trigger completely unrelated endogenous coreceptors—LRP5/6 and Ror1/2, respectively—through a common mechanism that involves their Wnt-dependent coupling to the Frizzled (Fzd) coreceptor and recruitment of shared components, including dishevelled (Dvl), axin, and glycogen synthase kinase 3 (GSK3). We identify Ror2 Ser 864 as a critical residue phosphorylated by GSK3 and required for noncanonical receptor activation by Wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (LRP6) in response to Wnt3a. Furthermore, this mechanism is independent of Ror2 receptor Tyr kinase functions. Consistent with this model of Wnt receptor activation, we provide evidence that canonical and noncanonical Wnts exert reciprocal pathway inhibition at the cell surface by competition for Fzd binding. Thus, different Wnts, through their specific coupling and phosphorylation of unrelated coreceptors, activate completely distinct signaling pathways.

Key Words: Ror1/2 • LRP5/6 • Wnt3a • Wnt5a • receptor activation • noncanonical Wnt signaling

Received for publication June 8, 2010. Accepted for publication September 20, 2010.

3 Corresponding author.

E-MAIL stuart.aaronson{at}mssm.edu; FAX (212) 987-2240.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1957710.

Supplemental material is available at http://www.genesdev.org.

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