Abstract
Dysregulation of Wnt-beta-catenin signaling disrupts axis formation in vertebrate embryos and underlies multiple human malignancies. The adenomatous polyposis coli (APC) protein, axin, and glycogen synthase kinase 3beta form a Wnt-regulated signaling complex that mediates the phosphorylation-dependent degradation of beta-catenin. A protein phosphatase 2A (PP2A) regulatory subunit, B56, interacted with APC in the yeast two-hybrid system. Expression of B56 reduced the abundance of beta-catenin and inhibited transcription of beta-catenin target genes in mammalian cells and Xenopus embryo explants. The B56-dependent decrease in beta-catenin was blocked by oncogenic mutations in beta-catenin or APC, and by proteasome inhibitors. B56 may direct PP2A to dephosphorylate specific components of the APC-dependent signaling complex and thereby inhibit Wnt signaling.
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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Adenomatous Polyposis Coli Protein
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Line
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Cysteine Endopeptidases / metabolism
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Cysteine Proteinase Inhibitors / pharmacology
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Down-Regulation
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Genes, Reporter
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinases
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Humans
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Leupeptins / pharmacology
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Multienzyme Complexes / metabolism
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Mutation
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Phosphoprotein Phosphatases / chemistry
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism*
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Phosphorylation
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Proteasome Endopeptidase Complex
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Protein Phosphatase 2
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Proto-Oncogene Proteins / metabolism*
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Signal Transduction*
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Trans-Activators*
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Transcriptional Activation
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Transfection
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Tumor Cells, Cultured
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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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Adenomatous Polyposis Coli Protein
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CTNNB1 protein, Xenopus
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CTNNB1 protein, human
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Cysteine Proteinase Inhibitors
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Cytoskeletal Proteins
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Leupeptins
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Multienzyme Complexes
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Proto-Oncogene Proteins
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Trans-Activators
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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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acetylleucyl-leucyl-norleucinal
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Glycogen Synthase Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3
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Phosphoprotein Phosphatases
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Protein Phosphatase 2
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde