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 RIS Download
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