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Dual regulation of Snail by GSK-3beta-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-3beta binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein. Phosphorylation of the first motif regulates its beta-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-3beta results in the upregulation of Snail and downregulation of E-cadherin in vivo. Thus, Snail and GSK-3beta together function as a molecular switch for many signalling pathways that lead to EMT.

Pubmed ID: 15448698

Authors

  • Zhou BP
  • Deng J
  • Xia W
  • Xu J
  • Li YM
  • Gunduz M
  • Hung MC

Journal

Nature cell biology

Publication Data

October 1, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA10193
  • Agency: NCI NIH HHS, Id: CA16672
  • Agency: NCI NIH HHS, Id: CA58880
  • Agency: NCI NIH HHS, Id: CA83639
  • Agency: NCI NIH HHS, Id: CA99031

Mesh Terms

  • Amino Acid Motifs
  • Binding Sites
  • Breast Neoplasms
  • Cadherins
  • Cell Line, Tumor
  • Cell Nucleus
  • Consensus Sequence
  • Cysteine Endopeptidases
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Epithelial Cells
  • Gene Expression Regulation, Neoplastic
  • Glycogen Synthase Kinase 3
  • Humans
  • Leupeptins
  • Lithium
  • Mesoderm
  • Multienzyme Complexes
  • Mutation
  • Phosphorylation
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Substrate Specificity
  • Transcription Factors
  • Zinc Fingers