A model for signaling specificity of Wnt/Frizzled combinations through co‐receptor recruitment

Wnts control mammalian developmental morphogenesis and are critical for adult stem cell maintenance. Wnts initiate several intracellular signaling cascades, such as Wnt/β‐catenin‐, Wnt/Ca 2+ ‐ and Wnt/ROR2‐signaling. Signaling preference of Wnts for these various pathways is thought to depend on the repertoire of receptors present on recipient cells. Here, we propose a further refinement of this receptor model and hypothesize that Wnt signaling specificity depends on co‐receptor recruitment upon binding of Wnt to Frizzled receptor molecules. In this model, recruitment of LRP5/6 leads to activation of Wnt/β‐catenin signaling, whereas signaling through other pathways is mediated by recruiting ROR2.