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

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.

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