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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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COS Cells
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Casein Kinase II
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Cysteine Endopeptidases / metabolism
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Cytoskeletal Proteins / metabolism*
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Cytoskeletal Proteins / physiology
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DNA-Binding Proteins / metabolism
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Embryo, Mammalian
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Embryo, Nonmammalian
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Enzyme Inhibitors / pharmacology
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Lymphoid Enhancer-Binding Factor 1
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Mice
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Multienzyme Complexes / metabolism
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Phosphorylation
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Proteasome Endopeptidase Complex
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism*
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Protein Serine-Threonine Kinases / physiology
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / physiology*
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Repetitive Sequences, Nucleic Acid
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Signal Transduction
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Trans-Activators / metabolism*
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Trans-Activators / physiology
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Transcription Factors / metabolism
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Transcription, Genetic / drug effects
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Wnt Proteins
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Xenopus
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Xenopus Proteins
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Zebrafish Proteins*
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beta Catenin
Substances
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CTNNB1 protein, Xenopus
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Enzyme Inhibitors
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Lymphoid Enhancer-Binding Factor 1
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Multienzyme Complexes
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Proto-Oncogene Proteins
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Trans-Activators
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Transcription Factors
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Wnt Proteins
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Xenopus Proteins
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Zebrafish Proteins
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beta Catenin
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Casein Kinase II
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Protein Serine-Threonine Kinases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex