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.
Yook
Jong In
JI
Department of Oral Pathology, BK21 Project for Medical Science, College of Dentistry, Yonsei University, Seoul 120-742, Korea.
Li
Xiao-Yan
XY
Ota
Ichiro
I
Fearon
Eric R
ER
Weiss
Stephen J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000502:physiology; D002645:Chickens; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D004848:Epithelium / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008648:Mesoderm / Q000473:pathology; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D012097:Repressor Proteins / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D051153:Wnt Proteins; D044844:beta-Transducin Repeat-Containing Proteins / Q000502:physiology
D015820:Cadherins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051153:Wnt Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3