Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation

Nat Commun. 2013;4:1542. doi: 10.1038/ncomms2543.


A subset of transcription factors classified as neural crest 'specifiers' are also core epithelial-mesenchymal transition regulatory factors, both in the neural crest and in tumour progression. The bHLH factor Twist is among the least well studied of these factors. Here we demonstrate that Twist is required for cranial neural crest formation and fate determination in Xenopus. We further show that Twist function in the neural crest is dependent upon its carboxy-terminal WR domain. The WR domain mediates physical interactions between Twist and other core epithelial-mesenchymal transition factors, including Snail1 and Snail2, which are essential for proper function. Interaction with Snail1/2, and Twist function more generally, is regulated by GSK-3-β-mediated phosphorylation of conserved sites in the WR domain. Together, these findings elucidate a mechanism for coordinated control of a group of structurally diverse factors that function as a regulatory unit in both developmental and pathological epithelial-mesenchymal transitions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Body Patterning / genetics
  • Cell Movement
  • Epithelial-Mesenchymal Transition*
  • Gene Expression Regulation, Developmental
  • Glycogen Synthase Kinase 3 / metabolism*
  • Immunoprecipitation
  • In Situ Hybridization
  • Molecular Sequence Data
  • Mutation / genetics
  • Neural Crest / cytology
  • Neural Crest / enzymology
  • Neural Crest / growth & development
  • Phosphorylation
  • Protein Binding
  • Protein Stability
  • Protein Structure, Tertiary
  • Snail Family Transcription Factors
  • Substrate Specificity
  • Transcription Factors / metabolism*
  • Twist-Related Protein 1 / chemistry
  • Twist-Related Protein 1 / metabolism*
  • Xenopus Proteins / chemistry
  • Xenopus Proteins / metabolism*
  • Xenopus laevis / embryology*
  • Xenopus laevis / genetics


  • Snail Family Transcription Factors
  • Transcription Factors
  • Twist-Related Protein 1
  • Xenopus Proteins
  • twist basic helix-loop-helix transcription factor 1, Xenopus
  • GSK3B protein, Xenopus
  • Glycogen Synthase Kinase 3