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-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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Motifs
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Binding Sites
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Breast Neoplasms / pathology
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Cadherins / metabolism
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Cell Line, Tumor
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Cell Nucleus / chemistry
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Consensus Sequence
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Cysteine Endopeptidases / metabolism
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enzyme Inhibitors / pharmacology
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Epithelial Cells / cytology
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Epithelial Cells / metabolism*
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Gene Expression Regulation, Neoplastic*
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Glycogen Synthase Kinase 3 / metabolism*
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Glycogen Synthase Kinase 3 beta
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Humans
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Leupeptins / pharmacology
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Lithium / pharmacology
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Mesoderm / cytology
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Mesoderm / metabolism*
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Multienzyme Complexes / metabolism
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Mutation
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Phosphorylation
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Proteasome Endopeptidase Complex
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Protein Binding
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Snail Family Transcription Factors
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Substrate Specificity
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Transcription Factors / chemistry
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Transcription Factors / drug effects
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Zinc Fingers
Substances
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Cadherins
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DNA-Binding Proteins
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Enzyme Inhibitors
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Leupeptins
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Multienzyme Complexes
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Snail Family Transcription Factors
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Transcription Factors
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Lithium
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde