Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination.
The mechanism of cross talk between the Wnt signaling and cyclic AMP (cAMP)-dependent protein kinase (protein kinase A [PKA]) pathways was studied. Prostaglandin E(1) (PGE(1)), isoproterenol, and dibutyryl cAMP (Bt(2)cAMP), all of which activate PKA, increased the cytoplasmic and nuclear beta-catenin protein level, and these actions were suppressed by a PKA inhibitor and RNA interference for PKA. PGE(1) and Bt(2)cAMP also increased T-cell factor (Tcf)-dependent transcription through beta-catenin. Bt(2)cAMP suppressed degradation of beta-catenin at the protein level. Although PKA did not affect the formation of a complex between glycogen synthase kinase 3beta (GSK-3beta), beta-catenin, and Axin, phosphorylation of beta-catenin by PKA inhibited ubiquitination of beta-catenin in intact cells and in vitro. Ser675 was found to be a site for phosphorylation by PKA, and substitution of this serine residue with alanine in beta-catenin attenuated inhibition of the ubiquitination of beta-catenin by PKA, PKA-induced stabilization of beta-catenin, and PKA-dependent activation of Tcf. These results indicate that PKA inhibits the ubiquitination of beta-catenin by phosphorylating beta-catenin, thereby causing beta-catenin to accumulate and the Wnt signaling pathway to be activated.
Pubmed ID: 16199882 RIS Download
Alprostadil | Animals | Axin Protein | Base Sequence | Basic Helix-Loop-Helix Leucine Zipper Transcription Factors | Binding Sites | Bucladesine | COS Cells | Cell Line | Cell Nucleus | Cercopithecus aethiops | Cyclic AMP-Dependent Protein Kinases | Cytoplasm | Drug Stability | Glycogen Synthase Kinase 3 | Glycogen Synthase Kinase 3 beta | Humans | In Vitro Techniques | Isoproterenol | L Cells (Cell Line) | Mice | Mutagenesis, Site-Directed | Nerve Tissue Proteins | Phosphorylation | RNA Interference | Repressor Proteins | Serine | Signal Transduction | TCF Transcription Factors | Ubiquitin