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.
Mesh Terms:
Alprostadil, Animals, Base Sequence, Binding Sites, Bucladesine, COS Cells, Cell Line, Cell Nucleus, Cercopithecus aethiops, Cyclic AMP-Dependent Protein Kinases, Cytoplasm, Drug Stability, Glycogen Synthase Kinase 3, Humans, Isoproterenol, L Cells (Cell Line), Mice, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Phosphorylation, RNA Interference, Repressor Proteins, Serine, Signal Transduction, TCF Transcription Factors, Ubiquitin
Alprostadil, Animals, Base Sequence, Binding Sites, Bucladesine, COS Cells, Cell Line, Cell Nucleus, Cercopithecus aethiops, Cyclic AMP-Dependent Protein Kinases, Cytoplasm, Drug Stability, Glycogen Synthase Kinase 3, Humans, Isoproterenol, L Cells (Cell Line), Mice, Mutagenesis, Site-Directed, Nerve Tissue Proteins, Phosphorylation, RNA Interference, Repressor Proteins, Serine, Signal Transduction, TCF Transcription Factors, Ubiquitin
Mol. Cell. Biol.
Date: Oct. 01, 2005
PubMed ID: 16199882
View in: Pubmed Google Scholar
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- Interactions 3
- PTM Genes 1