Abstract
Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). Here we describe another Axin-associated kinase, whose phosphorylation of beta-catenin precedes and is required for subsequent GSK-3 phosphorylation of beta-catenin. This "priming" kinase is casein kinase Ialpha (CKIalpha). Depletion of CKIalpha inhibits beta-catenin phosphorylation and degradation and causes abnormal embryogenesis associated with excessive Wnt/beta-catenin signaling. Our study uncovers distinct roles and steps of beta-catenin phosphorylation, identifies CKIalpha as a component in Wnt/beta-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Armadillo Domain Proteins
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Axin Protein
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Body Patterning / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Casein Kinases
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Cell Line
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Cytoskeletal Proteins / metabolism*
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Drosophila
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Drosophila Proteins*
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Enzyme Activation / physiology
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Gene Expression / physiology
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinases
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Humans
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Insect Proteins / metabolism
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Molecular Sequence Data
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Phosphorylation
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Rabbits
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Rats
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Repressor Proteins*
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Signal Transduction / physiology*
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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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Xenopus laevis
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Zebrafish Proteins*
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beta Catenin
Substances
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ARM protein, Drosophila
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Armadillo Domain Proteins
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Axin Protein
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CTNNB1 protein, Xenopus
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CTNNB1 protein, human
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Ctnnb1 protein, rat
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Cytoskeletal Proteins
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Drosophila Proteins
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Insect Proteins
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Proteins
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Proto-Oncogene Proteins
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Repressor 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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axin1 protein, Xenopus
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beta Catenin
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Protein Kinases
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Glycogen Synthase Kinases
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Casein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3