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

Abstract

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 β-catenin. β-Catenin is a substrate for CK2 and inhibition of CK2 reduces levels of β-catenin and dishevelled. Here we report that inhibition of CK2 using pharmacologic agents or expression of kinase inactive subunits reduces β-catenin-dependent transcription and protein levels in a proteasome-dependent fashion. The major region of phosphorylation of β-catenin by CK2 is the central armadillo repeat domain, where carrier proteins like axin and the adenomatous polyposis coli gene product APC interact with β-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 β-catenin phosphorylation, cotranscriptional activity, and stability. Thus, CK2 is a positive regulator of Wnt signaling through phosphorylation of β-catenin at Thr393, leading to proteasome resistance and increased protein and co-transcriptional activity.