Article abstract
Nature Cell Biology 6, 931 - 940 (2004)
Published online: 26 September 2004 | doi:10.1038/ncb1173
Dual regulation of Snail by GSK-3
-mediated phosphorylation in control of epithelial–mesenchymal transition
Binhua P. Zhou1,2, Jiong Deng1,2, Weiya Xia1, Jihong Xu1, Yan M. Li1, Mehmet Gunduz1 & Mien-Chie Hung1
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-3
binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein. Phosphorylation of the first motif regulates its -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-3 results in the upregulation of Snail and downregulation of E-cadherin in vivo. Thus, Snail and GSK-3 together function as a molecular switch for many signalling pathways that lead to EMT.
- Department of Molecular and Cellular Oncology, Breast Cancer Basic Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
- These authors contributed equally to this work.
Correspondence to: Mien-Chie Hung1 e-mail: mhung@mdanderson.org
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