Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial-mesenchymal transition

Binhua P. Zhou, Jiong Deng, Weiya Xia, Jihong Xu, Yan M. Li, Mehmet Gunduz, Mien Chie Hung

Research output: Contribution to journalArticlepeer-review

1419 Scopus citations

Abstract

The phenotypic changes of increased motility and invasiveness of cancer cells are reminiscent of the epithelial-mesenchymal transition (EMT) that occurs during embryonic development. Snail, a zinc-finger transcription factor, triggers this process by repressing E-cadherin expression; however, the mechanisms that regulate Snail remain elusive. Here we find that Snail is highly unstable, with a short half-life about 25 min. We show that GSK-3β binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein. Phosphorylation of the first motif regulates its β-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization. A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT. Furthermore, inhibition of GSK-3β results in the upregulation of Snail and downregulation of E-cadherin in vivo. Thus, Snail and GSK-3β together function as a molecular switch for many signalling pathways that lead to EMT.

Original languageEnglish
Pages (from-to)931-940
Number of pages10
JournalNature Cell Biology
Volume6
Issue number10
DOIs
StatePublished - Oct 2004

ASJC Scopus subject areas

  • Cell Biology

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