Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination

Mol Cell Biol. 2005 Oct;25(20):9063-72. doi: 10.1128/MCB.25.20.9063-9072.2005.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alprostadil / pharmacology
  • Animals
  • Axin Protein
  • Base Sequence
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Binding Sites
  • Bucladesine / pharmacology
  • COS Cells
  • Cell Line
  • Cell Nucleus / metabolism
  • Chlorocebus aethiops
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cytoplasm / metabolism
  • Drug Stability
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • In Vitro Techniques
  • Isoproterenol / pharmacology
  • L Cells
  • Mice
  • Mutagenesis, Site-Directed
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation
  • RNA Interference
  • Repressor Proteins / metabolism
  • Serine / chemistry
  • Signal Transduction
  • TCF Transcription Factors / metabolism
  • Transcription Factor 4
  • Ubiquitin / metabolism

Substances

  • Axin Protein
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Nerve Tissue Proteins
  • Repressor Proteins
  • TCF Transcription Factors
  • Tcf4 protein, mouse
  • Transcription Factor 4
  • Ubiquitin
  • Serine
  • Bucladesine
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Cyclic AMP-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • Alprostadil
  • Isoproterenol