CK2 phosphorylation of the armadillo repeat region of beta-catenin potentiates Wnt signaling.
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.
Song
Diane H
DH
Department of Medicine, Boston University Medical Center, Boston University, Boston, Massachusetts 02118, USA.
Dominguez
Isabel
I
Mizuno
Junko
J
Kaut
Maurya
M
Mohr
Scott C
SC
Seldin
David C
DC
D000818:Animals; D019556:COS Cells; D047390:Casein Kinase II; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012091:Repetitive Sequences, Nucleic Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins; D014981:Xenopus; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495266:CTNNB1 protein, Xenopus; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D051821:Lymphoid Enhancer-Binding Factor 1; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex