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. 2024 Jun 25;43(6):114362. doi: 10.1016/j.celrep.2024.114362. Epub 2024 Jun 13.

Abstract

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 Arm34-87/β-catenin peptide binds to IFT140, acting as a dominant interference tool to attenuate Wg/Wnt signaling in vivo. Arm34-87 expression antagonizes endogenous Wnt/Wg signaling, resulting in the reduction of its target expression. Arm34-87 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 Arm34-87 effect being enhanced or suppressed. Importantly, this mechanism is conserved in mammals with the equivalent β-catenin24-79 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.

Keywords: CP: Developmental biology; Wnt signaling; cancer; developmental patterning; nuclear translocation; β-catenin.

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Animals
  • Armadillo Domain Proteins* / genetics
  • Armadillo Domain Proteins* / metabolism
  • Cell Nucleus* / metabolism
  • Drosophila Proteins* / metabolism
  • Drosophila melanogaster / metabolism
  • Humans
  • Peptides / metabolism
  • Peptides / pharmacology
  • Protein Binding
  • Transcription Factors
  • Wnt Signaling Pathway*
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism
  • beta Catenin* / metabolism

Substances

  • beta Catenin
  • Drosophila Proteins
  • Armadillo Domain Proteins
  • Wnt1 Protein
  • wg protein, Drosophila
  • ARM protein, Drosophila
  • Peptides
  • Transcription Factors