Wg/Wnt-signaling induced nuclear translocation of β-catenin is attenuated by a β-catenin peptide through its interaction with IFT-A in development and cancer cells

ABSTRACT Wnt/Wingless (Wg) signaling is critical for many developmental patterning processes and linked to diseases, including cancer. Canonical Wnt-signaling is mediated by β-catenin, Armadillo/Arm in Drosophila transducing signal activation to a nuclear response. The IFT-A/Kinesin-2 complex is required to promote the nuclear translocation of β-catenin/Arm. Here, we define a small conserved N-terminal Arm/β-catenin (Arm 34–87 ) peptide, which binds IFT140, as a dominant interference tool to attenuate Wg/Wnt-signaling in vivo . Expression of Arm 34–87 is sufficient to antagonize endogenous Wnt/Wg-signaling activation resulting in marked reduction of Wg-signaling target gene expression. This effect is modulated by endogenous levels of Arm and IFT140, with the Arm 34–87 effect being enhanced or suppressed, respectively. Arm 34–87 thus inhibits Wg/Wnt-signaling by interfering with the nuclear translocation of endogenous Arm/β-catenin. Importantly, this mechanism is conserved in mammals with the equivalent β-catenin 34–87 peptide blocking nuclear translocation and pathway activation, including in cancer cells. Our work indicates that Wnt-signaling can be regulated by a defined N-terminal peptide of Arm/β-catenin, and thus this might serve as an entry point for potential therapeutic applications to attenuate Wnt/β-catenin signaling.