A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells

Nat Cell Biol. 2006 Dec;8(12):1398-406. doi: 10.1038/ncb1508. Epub 2006 Oct 29.


Accumulating evidence indicates that hyperactive Wnt signalling occurs in association with the development and progression of human breast cancer. As a consequence of engaging the canonical Wnt pathway, a beta-catenin-T-cell factor (TCF) transcriptional complex is generated, which has been postulated to trigger the epithelial-mesenchymal transition (EMT) that characterizes the tissue-invasive phenotype. However, the molecular mechanisms by which the beta-catenin-TCF complex induces EMT-like programmes remain undefined. Here, we demonstrate that canonical Wnt signalling engages tumour cell dedifferentiation and tissue-invasive activity through an Axin2-dependent pathway that stabilizes the Snail1 zinc-transcription factor, a key regulator of normal and neoplastic EMT programmes. Axin2 regulates EMT by acting as a nucleocytoplasmic chaperone for GSK3beta, the dominant kinase responsible for controlling Snail1 protein turnover and activity. As dysregulated Wnt signalling marks a diverse array of cancerous tissue types, the identification of a beta-catenin-TCF-regulated Axin2-GSK3beta-Snail1 axis provides new mechanistic insights into cancer-associated EMT programmes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Axin Protein
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cell Nucleus / metabolism
  • Chick Embryo
  • Cytoplasm / metabolism
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / metabolism*
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Neoplastic
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Mesoderm / pathology
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Nuclear Export Signals
  • Protein Transport
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Snail Family Transcription Factors
  • TCF Transcription Factors / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism


  • AXIN2 protein, human
  • Axin Protein
  • Cytoskeletal Proteins
  • Nuclear Export Signals
  • RNA, Messenger
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • TCF Transcription Factors
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3