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Molecular and Cellular Biology, October 2005, p. 9063-9072, Vol. 25, No. 20
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.20.9063-9072.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phosphorylation of ß-Catenin by Cyclic AMP-Dependent Protein Kinase Stabilizes ß-Catenin through Inhibition of Its Ubiquitination

Shin-ichiro Hino,1 Chie Tanji,1 Keiichi I. Nakayama,2 and Akira Kikuchi1*

Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan,1 Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan2

Received 28 May 2005/ Returned for modification 7 July 2005/ Accepted 22 July 2005

The mechanism of cross talk between the Wnt signaling and cyclic AMP (cAMP)-dependent protein kinase (protein kinase A [PKA]) pathways was studied. Prostaglandin E1 (PGE1), isoproterenol, and dibutyryl cAMP (Bt2cAMP), all of which activate PKA, increased the cytoplasmic and nuclear ß-catenin protein level, and these actions were suppressed by a PKA inhibitor and RNA interference for PKA. PGE1 and Bt2cAMP also increased T-cell factor (Tcf)-dependent transcription through ß-catenin. Bt2cAMP suppressed degradation of ß-catenin at the protein level. Although PKA did not affect the formation of a complex between glycogen synthase kinase 3ß (GSK-3ß), ß-catenin, and Axin, phosphorylation of ß-catenin by PKA inhibited ubiquitination of ß-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 ß-catenin attenuated inhibition of the ubiquitination of ß-catenin by PKA, PKA-induced stabilization of ß-catenin, and PKA-dependent activation of Tcf. These results indicate that PKA inhibits the ubiquitination of ß-catenin by phosphorylating ß-catenin, thereby causing ß-catenin to accumulate and the Wnt signaling pathway to be activated.

* Corresponding author. Mailing address: Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Phone: 81-82-257-5130. Fax: 81-82-257-5134. E-mail: akikuchi{at}hiroshima-u.ac.jp.

Molecular and Cellular Biology, October 2005, p. 9063-9072, Vol. 25, No. 20
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.20.9063-9072.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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