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 {beta}-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 {beta}-catenin/Arm. Here, we define a small conserved N-terminal Arm/{beta}-catenin (Arm34-87) peptide, which binds IFT140, as a dominant interference tool to attenuate Wg/Wnt-signaling in vivo. Expression of Arm34-87 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 Arm34-87 effect being enhanced or suppressed, respectively. Arm34-87 thus inhibits Wg/Wnt-signaling by interfering with the nuclear translocation of endogenous Arm/{beta}-catenin. Importantly, this mechanism is conserved in mammals with the equivalent {beta}-catenin34-87 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/{beta}-catenin, and thus this might serve as an entry point for potential therapeutic applications to attenuate Wnt/{beta}-catenin signaling.