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

Abstract

Wnt ligands signal through b-catenin and are critically involved in cell fate determination and stem/progenitor self-renewal. Wnts also signal through b-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.[Keywords: Ror1/2; LRP5/6; Wnt3a; Wnt5a; receptor activation; noncanonical Wnt signaling] Supplemental material is available at http://www.genesdev.org.

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Although several Wnts preferentially activate either β-catenin-dependent (Wnt-1/3a) or β-catenin-independent (Wnt-5a/11) pathways, the activity of many Wnts is influenced by cellular context and the receptors available (LRPs versus RORs, for example) [31]. Traditionally FZD-LRP receptor-coreceptor combinations have been considered to be canonical, while RORs, RYK, PTK7 and VANGLs alone or in combination with FZDs have been associated with noncanonical Wnt signaling [31].…”

“…Traditionally FZD-LRP receptor-coreceptor combinations have been considered to be canonical, while RORs, RYK, PTK7 and VANGLs alone or in combination with FZDs have been associated with noncanonical Wnt signaling [31]. However, there are more than 15 different Wnt receptors and co-receptors, and the particular combination of these, together with a given Wnt, can affect subsequent signaling events [3].…”

Wnt4 antagonises Wnt3a mediated increases in growth and glucose stimulated insulin secretion in the pancreatic beta-cell line, INS-1

“…Downstream signalling from these receptors appears to follow distinct pathways [16,17]. The best characterised of these is the "canonical pathway" which regulates gene transcription by controlling the protein levels and cellular localisation of β-catenin [18].…”

Epithelial Wnt Ligands Regulate Pulmonary Vasculature Development

“…There are complex interactions between canonical Wnts and non-canonical Wnts as well. It was proposed that canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors [23]. Non-canonical Wnt5a could even activate canonical Wnt signaling at the presence of Frizzled4 (Fz4) and Lrp5 (not Lrp6), which is similar to how Norrin (another Wnt-like protein/ligand) stabilizes β-catenin, and so does noncanonical Wnt11 [24][25][26].…”