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.
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
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
J. Biol. Chem.
Date: Apr. 14, 2006
PubMed ID: 16476742
View in: Pubmed Google Scholar
Download Curated Data For This Publication
101785
Switch View:
- Interactions 1