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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

Authors

  • Hino S
  • Tanji C
  • Nakayama KI
  • Kikuchi A

Journal

Molecular and cellular biology

Publication Data

October 3, 2005

Associated Grants

None

Mesh Terms

  • 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
  • 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