Wg/Wnt-signaling-induced nuclear translocation of β-catenin is attenuated by a β-catenin peptide through its interference with the IFT-A complex.

Cell Rep

Department of Cell, Developmental, and Regenerative Biology, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA. Electronic address:

Published: June 2024

Wnt/Wingless (Wg) signaling is critical in development and disease, including cancer. Canonical Wnt signaling is mediated by β-catenin/Armadillo (Arm in Drosophila) transducing signals to the nucleus, with IFT-A/Kinesin 2 complexes promoting nuclear translocation of β-catenin/Arm. Here, we demonstrate that a conserved small N-terminal Arm/β-catenin peptide binds to IFT140, acting as a dominant interference tool to attenuate Wg/Wnt signaling in vivo. Arm expression antagonizes endogenous Wnt/Wg signaling, resulting in the reduction of its target expression. Arm inhibits Wg/Wnt signaling by interfering with nuclear translocation of endogenous Arm/β-catenin, and this can be modulated by levels of wild-type β-catenin or IFT140, with the Arm effect being enhanced or suppressed. Importantly, this mechanism is conserved in mammals with the equivalent β-catenin 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 β-catenin peptide and thus might serve as an entry point for therapeutic applications to attenuate Wnt/β-catenin signaling.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11311196PMC
http://dx.doi.org/10.1016/j.celrep.2024.114362DOI Listing

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