title: Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors.
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.
authors.affiliation: Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Grumolato
authors.forename: Guizhong
authors.initials: G
authors.lastname: Liu
authors.forename: Phyllus
authors.initials: P
authors.lastname: Mong
authors.forename: Raksha
authors.initials: R
authors.lastname: Mudbhary
authors.forename: Romi
authors.initials: R
authors.lastname: Biswas
authors.forename: Randy
authors.initials: R
authors.lastname: Arroyave
authors.forename: Sapna
authors.initials: S
authors.lastname: Vijayakumar
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D051157:Frizzled Receptors / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D010766:Phosphorylation; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D051157:Frizzled Receptors; C489739:Fzd1 protein, mouse; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D043562:Receptors, G-Protein-Coupled; C555510:WNT3A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C438615:Wnt5a protein, mouse; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse