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Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase.

Beta-catenin is a signaling molecule that promotes cell proliferation by the induction of gene transcription through the activation of T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription factors. The canonical mechanism of the regulation of beta-catenin involves its phosphorylation by casein kinase 1 at the Ser-45 site and by glycogen synthase kinase 3 (GSK3) at the Thr-41, Ser-37, and Ser-33 sites. This phosphorylation targets beta-catenin to ubiquitination and degradation by the proteasome system. Mitogenic factors promote beta-catenin signaling through the inhibition of GSK3, resulting in reduced beta-catenin phosphorylation, its stabilization, and subsequent accumulation in the nucleus, where it stimulates TCF/LEF-dependent gene transcription. In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase A (PKA) in vitro and in intact cells at two novel sites, Ser-552 and Ser-675; (ii) phosphorylation by PKA promotes the transcriptional activity (TCF/LEF transactivation) of beta-catenin; (iii) mutation of Ser-675 attenuates the promoting effect of PKA; (iv) phosphorylation by PKA does not affect the GSK3-dependent phosphorylation of beta-catenin, its stability, or intracellular localization; and (v) phosphorylation at the Ser-675 site promotes the binding of beta-catenin to its transcriptional coactivator, CREB-binding protein. In conclusion, this study identifies a novel, noncanonical mechanism of modulation of beta-catenin signaling through direct phosphorylation of beta-catenin by PKA, promoting its interaction with CREB-binding protein.

Pubmed ID: 16476742


  • Taurin S
  • Sandbo N
  • Qin Y
  • Browning D
  • Dulin NO


The Journal of biological chemistry

Publication Data

April 14, 2006

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL 071755

Mesh Terms

  • Animals
  • Binding Sites
  • Blotting, Western
  • COS Cells
  • CREB-Binding Protein
  • Casein Kinase I
  • Cell Line
  • Cercopithecus aethiops
  • Cyclic AMP-Dependent Protein Kinases
  • DNA
  • DNA, Complementary
  • Fluorescent Antibody Technique, Indirect
  • Genes, Reporter
  • Glycogen Synthase Kinase 3
  • Humans
  • Immunoprecipitation
  • Luciferases
  • Models, Genetic
  • Mutation
  • Phosphorylation
  • Protein Binding
  • Serine
  • Signal Transduction
  • Threonine
  • Transcription, Genetic
  • Transcriptional Activation
  • beta Catenin