Wnts synergize to activate β-catenin signaling

Abstract

Wnt ligands regulate diverse signaling pathways during development, maintenance of tissue homeostasis, and in various disease states. While signaling regulated by individual Wnts has been extensively studied, Wnts are rarely expressed alone, and the consequences of Wnt gene co-expression are not well understood. We studied the effect of co-expression of Wnts on the β-catenin signaling pathway. While some Wnts are deemed ‘non-canonical’ due to their limited ability to activate β-catenin when expressed alone, unexpectedly, we find that multiple Wnt combinations can synergistically activate β-catenin signaling in multiple cell types. WNT1 and WNT7B mediated synergistic Wnt signaling requires FZD5, FZD8, LRP6, as well as the WNT7B co-receptors GPR124 and RECK. Unexpectedly, this synergistic signaling occurs downstream of β-catenin stabilization, and is correlated with increased lysine acetylation of β-catenin. Wnt synergy provides a general mechanism to confer increased combinatorial control over this important regulatory pathway.