Abstract
The transcriptional coactivator beta-catenin mediates Wnt growth factor signaling. In the absence of a Wnt signal, casein kinase 1 (CK1) and glycogen synthase kinase-3beta (GSK-3beta) phosphorylate cytosolic beta-catenin, thereby flagging it for recognition and destruction by the ubiquitin/proteosome machinery. Phosphorylation occurs in a multiprotein complex that includes the kinases, beta-catenin, axin, and the Adenomatous Polyposis Coli (APC) protein. The role of APC in this process is poorly understood. CK1epsilon and GSK-3beta phosphorylate APC, which increases its affinity for beta-catenin. Crystal structures of phosphorylated and nonphosphorylated APC bound to beta-catenin reveal a phosphorylation-dependent binding motif generated by mutual priming of CK1 and GSK-3beta substrate sequences. Axin is shown to act as a scaffold for substrate phosphorylation by these kinases. Phosphorylated APC and axin bind to the same surface of, and compete directly for, beta-catenin. The structural and biochemical data suggest a novel model for how APC functions in beta-catenin degradation.
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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Adenomatous Polyposis Coli Protein / chemistry*
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Adenomatous Polyposis Coli Protein / genetics
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Adenomatous Polyposis Coli Protein / metabolism*
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Amino Acid Sequence
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Animals
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Axin Protein
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Casein Kinases
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Crystallography, X-Ray
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Cytoskeletal Proteins / chemistry*
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Mice
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Models, Molecular
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Molecular Sequence Data
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Phosphorylation
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Protein Binding
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / metabolism
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Repressor Proteins / chemistry
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Signal Transduction
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Trans-Activators / chemistry*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Wnt Proteins
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beta Catenin
Substances
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Adenomatous Polyposis Coli Protein
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Axin Protein
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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Trans-Activators
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Wnt Proteins
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beta Catenin
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Protein Kinases
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Casein Kinases
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Glycogen Synthase Kinase 3