CK2 phosphorylation of the armadillo repeat region of beta-catenin potentiates Wnt signaling

• Published in: The Journal of biological chemistry 2003-06, Vol.278 (26), p.24018-24025
• Main Authors: Song, Diane H, Dominguez, Isabel, Mizuno, Junko, Kaut, Maurya, Mohr, Scott C, Seldin, David C
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin; Casein Kinase II; COS Cells; Cysteine Endopeptidases - metabolism; Cytoskeletal Proteins - metabolism; Cytoskeletal Proteins - physiology; DNA-Binding Proteins - metabolism; Embryo, Mammalian; Embryo, Nonmammalian; Enzyme Inhibitors - pharmacology; Lymphoid Enhancer-Binding Factor 1; Mice; Multienzyme Complexes - metabolism; Phosphorylation; Proteasome Endopeptidase Complex; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins - physiology; Repetitive Sequences, Nucleic Acid; Signal Transduction; Trans-Activators - metabolism; Trans-Activators - physiology; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Wnt Proteins; Xenopus; Xenopus Proteins; Zebrafish Proteins
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M212260200

Protein kinase CK2 is a ubiquitous serine/threonine kinase involved in many biological processes. It is overexpressed in many malignancies including rodent and human breast cancer, and is up-regulated in Wnt-transfected mammary epithelial cells, where it can be found in a complex with dishevelled and beta-catenin. beta-Catenin is a substrate for CK2 and inhibition of CK2 reduces levels of beta-catenin and dishevelled. Here we report that inhibition of CK2 using pharmacologic agents or expression of kinase inactive subunits reduces beta-catenin-dependent transcription and protein levels in a proteasome-dependent fashion. The major region of phosphorylation of beta-catenin by CK2 is the central armadillo repeat domain, where carrier proteins like axin and the adenomatous polyposis coli gene product APC interact with beta-catenin. The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability. Thus, CK2 is a positive regulator of Wnt signaling through phosphorylation of beta-catenin at Thr393, leading to proteasome resistance and increased protein and co-transcriptional activity.