A Wnt-Axin2-GSK3β cascade regulates Snail1 activity in breast cancer cells

Jong In Yook, Xiao Yan Li, Ichiro Ota, Casey Hu, Hyun Sil Kim, Nam Hee Kim, So Young Cha, Joo Kyung Ryu, Yoon Jung Choi, Jin Kim, Eric R. Fearon, Stephen J. Weiss

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Abstract

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 β-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 β-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 GSK3β, 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 β-catenin-TCF-regulated Axin2-GSK3β-Snail1 axis provides new mechanistic insights into cancer-associated EMT programmes.

Original languageEnglish
Pages (from-to)1398-1406
Number of pages9
JournalNature Cell Biology
Volume8
Issue number12
DOIs
Publication statusPublished - 2006 Dec 1

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All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Yook, J. I., Li, X. Y., Ota, I., Hu, C., Kim, H. S., Kim, N. H., Cha, S. Y., Ryu, J. K., Choi, Y. J., Kim, J., Fearon, E. R., & Weiss, S. J. (2006). A Wnt-Axin2-GSK3β cascade regulates Snail1 activity in breast cancer cells. Nature Cell Biology, 8(12), 1398-1406. https://doi.org/10.1038/ncb1508