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 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.
Highlights
Protein kinase CK2 is ubiquitously expressed in both the cytoplasm and nucleus of eukaryotic cells
Protein kinase CK2 is a ubiquitous serine/threonine kinase involved in many biological processes
Inhibition of CK2 Activity Reduces LEF-1-dependent Transcription—Previously, we showed that inhibition of CK2 activity by the selective flavonoid CK2 inhibitor apigenin accelerates the degradation of -catenin [36]
Summary
Protein kinase CK2 is ubiquitously expressed in both the cytoplasm and nucleus of eukaryotic cells. Phosphorylation of IB in its C-terminal PEST domain accelerates degradation, favoring NFB activation (30 –34). In addition to its role in development, the Wnt pathway is increasingly recognized to play a role in human cancers, through mutation of genes encoding -catenin itself or its regulators, APC, the adenomatous polyposis coli gene product, or axin. These two proteins act as a bridge between -catenin and GSK3, facilitating GSK3 phosphorylation of -catenin at the N terminus on Ser, Ser, and Thr. Mutations of -catenin, This paper is available on line at http://www.jbc.org
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