Abstract
Beta-catenin is a multifunctional protein involved in both cell adhesion and transcriptional activation. Transcription mediated by the beta-catenin/Tcf complex is involved in embryological development and is upregulated in various cancers. We have determined the crystal structure at 2.5 A resolution of a complex between beta-catenin and ICAT, a protein that prevents the interaction between beta-catenin and Tcf/Lef family transcription factors. ICAT contains a 3-helix bundle that binds armadillo repeats 10-12 and a C-terminal tail that, similar to Tcf and E-cadherin, binds in the groove formed by armadillo repeats 5-9 of beta-catenin. We show that ICAT selectively inhibits beta-catenin/Tcf binding in vivo, without disrupting beta-catenin/cadherin interactions. Thus, it should be possible to design cancer therapeutics that inhibit beta-catenin-mediated transcriptional activation without interfering with cell adhesion.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Amino Acid Sequence
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Animals
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Cell Adhesion / physiology
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Cell Cycle Proteins*
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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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DNA-Binding Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins
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Macromolecular Substances
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Models, Molecular
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Muscle Proteins / chemistry*
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Neoplasms / metabolism
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Neoplasms / therapy
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Protein Binding
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Protein Structure, Tertiary*
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Proto-Oncogene Proteins / metabolism
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Repressor Proteins*
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Sequence Alignment
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Signal Transduction / physiology
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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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Transcription Factors / metabolism
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Transcriptional Activation
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Wnt Proteins
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Xenopus Proteins
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Xenopus laevis / embryology
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Zebrafish Proteins*
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beta Catenin
Substances
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Adaptor Proteins, Signal Transducing
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CTNNB1 protein, Xenopus
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CTNNB1 protein, human
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CTNNBIP1 protein, human
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Cell Cycle Proteins
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Macromolecular Substances
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Muscle 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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beta Catenin