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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2004-10

AUTHORS

Binhua P Zhou, Jiong Deng, Weiya Xia, Jihong Xu, Yan M Li, Mehmet Gunduz, Mien-Chie Hung

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. More... »

PAGES

931-940

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ncb1173

    DOI

    http://dx.doi.org/10.1038/ncb1173

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1020586906

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/15448698


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