Phosphorylation of β-Catenin by Cyclic AMP-dependent Protein Kinase

• Published in: The Journal of biological chemistry 2006-04, Vol.281 (15), p.9971-9976
• Main Authors: Taurin, Sebastien, Sandbo, Nathan, Qin, Yimin, Browning, Darren, Dulin, Nickolai O.
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - chemistry; beta Catenin - metabolism; Binding Sites; Blotting, Western; Casein Kinase I - metabolism; Cell Line; Chlorocebus aethiops; COS Cells; CREB-Binding Protein - chemistry; Cyclic AMP-Dependent Protein Kinases - chemistry; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA - chemistry; DNA, Complementary - metabolism; Fluorescent Antibody Technique, Indirect; Genes, Reporter; Glycogen Synthase Kinase 3 - metabolism; Humans; Immunoprecipitation; Luciferases - metabolism; Models, Genetic; Mutation; Phosphorylation; Protein Binding; Serine - chemistry; Signal Transduction; Threonine - chemistry; Transcription, Genetic; Transcriptional Activation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M508778200

β-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 β-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 β-catenin to ubiquitination and degradation by the proteasome system. Mitogenic factors promote β-catenin signaling through the inhibition of GSK3, resulting in reduced β-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) β-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) ofβ-catenin; (iii) mutation of Ser-675 attenuates the promoting effect of PKA; (iv) phosphorylation by PKA does not affect the GSK3-dependent phosphorylation ofβ-catenin, its stability, or intracellular localization; and (v) phosphorylation at the Ser-675 site promotes the binding of β-catenin to its transcriptional coactivator, CREB-binding protein. In conclusion, this study identifies a novel, noncanonical mechanism of modulation of β-catenin signaling through direct phosphorylation of β-catenin by PKA, promoting its interaction with CREB-binding protein.