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Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors
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
Wnt ligands signal through β-catenin and are criticallyinvolved in cell fate determination and stem/progenitor self-renewal.Wnts also signal through β-catenin-independent or noncanonicalpathways that regulate crucial events during embryonic development.The mechanism of noncanonical receptor activation and how Wntstrigger canonical as opposed to noncanonical signaling haveyet to be elucidated. We demonstrate here that prototype canonicalWnt3a and noncanonical Wnt5a ligands specifically trigger completelyunrelated endogenous coreceptors—LRP5/6 and Ror1/2, respectively—througha common mechanism that involves their Wnt-dependent couplingto the Frizzled (Fzd) coreceptor and recruitment of shared components,including dishevelled (Dvl), axin, and glycogen synthase kinase3 (GSK3). We identify Ror2 Ser 864 as a critical residue phosphorylatedby GSK3 and required for noncanonical receptor activation byWnt5a, analogous to the priming phosphorylation of low-densityreceptor-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 provideevidence that canonical and noncanonical Wnts exert reciprocalpathway inhibition at the cell surface by competition for Fzdbinding. Thus, different Wnts, through their specific couplingand phosphorylation of unrelated coreceptors, activate completelydistinct signaling pathways.
Characterization of the Interaction of Sclerostin with the Low Density Lipoprotein Receptor-related Protein (LRP) Family of Wnt Co-receptors.
G. Holdsworth, P. Slocombe, C. Doyle, B. Sweeney, V. Veverka, K. Le Riche, R. J. Franklin, J. Compson, D. Brookings, J. Turner, et al. (2012)
J. Biol. Chem.
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