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Wnt-dependent regulation of the E-cadherin repressor snail.

Down-regulation of E-cadherin marks the initiation of the epithelial-mesenchymal transition, a process exploited by invasive cancer cells. The zinc finger transcription factor, Snail, functions as a potent repressor of E-cadherin expression that can, acting alone or in concert with the Wnt/beta-catenin/T cell factor axis, induce an epithelial-mesenchymal transition. Although mechanisms that coordinate signaling events initiated by Snail and Wnt remain undefined, we demonstrate that Snail displays beta-catenin-like canonical motifs that support its GSK3beta-dependent phosphorylation, beta-TrCP-directed ubiquitination, and proteasomal degradation. Accordingly, Wnt signaling inhibits Snail phosphorylation and consequently increases Snail protein levels and activity while driving an in vivo epithelial-mesenchymal transition that is suppressed following Snail knockdown. These findings define a potential mechanism whereby Wnt signaling stabilizes Snail and beta-catenin proteins in tandem fashion so as to cooperatively engage transcriptional programs that control an epithelial-mesenchymal transition.

Pubmed ID: 15647282

Authors

  • Yook JI
  • Li XY
  • Ota I
  • Fearon ER
  • Weiss SJ

Journal

The Journal of biological chemistry

Publication Data

March 25, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA071699
  • Agency: NCI NIH HHS, Id: R01 CA085463
  • Agency: NCI NIH HHS, Id: R01 CA088308

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Cadherins
  • Chickens
  • DNA-Binding Proteins
  • Epithelium
  • Glycogen Synthase Kinase 3
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Mesoderm
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Neoplasms
  • Phosphorylation
  • Repressor Proteins
  • Transcription Factors
  • Wnt Proteins
  • beta-Transducin Repeat-Containing Proteins