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.
Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Sebastien
S
Taurin
Nathan
N
Sandbo
Yimin
Y
Qin
Darren
D
Browning
Nickolai O
NO
Dulin
D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D019556:COS Cells; D050882:CREB-Binding Protein / Q000737:chemistry; D047389:Casein Kinase I / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013912:Threonine / Q000737:chemistry; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051176:beta Catenin / Q000737:chemistry* / Q000378:metabolism
D018076:DNA, Complementary; D051176:beta Catenin; D013912:Threonine; D012694:Serine; D004247:DNA; D008156:Luciferases; D050882:CREB-Binding Protein; D047389:Casein Kinase I; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3