A second protein kinase CK1-mediated step negatively regulates Wnt signalling by disrupting the lymphocyte enhancer factor-1/beta-catenin complex

Cell Mol Life Sci. 2005 Mar;62(5):606-18. doi: 10.1007/s00018-005-4507-7.


Deregulated activation of the canonical Wnt signalling pathway leads to stabilization of beta-catenin and is critically involved in carcinogenesis by an inappropriate induction of lymphocyte enhancer factor (LEF-1)/beta-catenin-dependent transcription of Wnt target genes. Phosphorylation of the pathway components beta-catenin, Dishevelled, Axin and APC (adenomatous polyposis coli) by glycogen synthase kinase-3beta, CK1 and CK2 is of central importance in the regulation of the beta-catenin destruction complex. Here, we identify CK1 and CK2 as major kinases that directly bind to and phosphorylate LEF-1 inducing distinct, kinase-specific changes in the LEF-1/DNA complex. Moreover, CK1-dependent phosphorylation in contrast to CK2 disrupts the association of beta-catenin and LEF-1 but does not impair DNA binding of LEF-1. Sequential phosphorylation assays revealed that for efficient disruption of the LEF-1/beta-catenin complex, beta-catenin also has to be phosphorylated. Consistent with these observations, CK1-dependent phosphorylation inhibits, whereas CK2 activates LEF-1/beta-catenin transcriptional activity in reporter gene assays. These data are in line with a negative regulatory function of CK1 in the Wnt signalling pathway, where CK1 in addition to the beta-catenin destruction complex at a second level acts as a negative regulator of the LEF-1/beta-catenin transcription complex, thereby protecting cells from development of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Casein Kinase I / metabolism
  • Casein Kinase I / physiology*
  • Casein Kinase II / metabolism
  • Casein Kinase II / physiology*
  • Cell Line, Tumor
  • Cytoskeletal Proteins / metabolism*
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation*
  • Genes, Reporter / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Luciferases / analysis
  • Luciferases / genetics
  • Lymphoid Enhancer-Binding Factor 1
  • Phosphorylation
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Serine / metabolism
  • Signal Transduction
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Transcription, Genetic / physiology
  • Wnt Proteins
  • beta Catenin


  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • Trans-Activators
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • Serine
  • DNA
  • Luciferases
  • Casein Kinase I
  • Casein Kinase II