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.
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
Nat. Cell Biol.
Date: Oct. 01, 2004
Download Curated Data For This Publication
108318
Switch View:
  • Interactions 3
  • PTM Genes 1