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      Sox9 inhibits Wnt signaling by promoting beta-catenin phosphorylation in the nucleus.

      The Journal of Biological Chemistry

      Animals, Base Sequence, Blotting, Western, Cell Line, Cell Nucleus, metabolism, DNA Primers, Fluorescent Antibody Technique, Indirect, Glycogen Synthase Kinase 3, chemistry, Humans, Immunoprecipitation, Mice, Phosphorylation, Protein Transport, SOX9 Transcription Factor, physiology, Signal Transduction, Transducin, Wnt Proteins, beta Catenin

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          Abstract

          Chondrocyte fate determination and maintenance requires Sox9, an intrinsic transcription factor, but is inhibited by Wnt/beta-catenin signaling activated by extrinsic Wnt ligands. Here we explored the underlying molecular mechanism by which Sox9 antagonizes the Wnt/beta-catenin signaling in chondrocyte differentiation. We found that Sox9 employed two distinct mechanisms to inhibit Wnt/beta-catenin signaling: the Sox9 N terminus is necessary and sufficient to promote beta-catenin degradation, whereas the C terminus is required to inhibit beta-catenin transcriptional activity without affecting its stability. Sox9 binds to beta-catenin and components of the beta-catenin "destruction complex," glycogen synthase kinase 3 and beta-transducin repeat containing protein, to promote their nuclear localization. Independent of its DNA binding ability, nuclear localization of Sox9 is both necessary and sufficient to enhance beta-catenin phosphorylation and its subsequent degradation. Thus, one mechanism whereby Sox9 regulates chondrogenesis is to promote efficient beta-catenin phosphorylation in the nucleus. This mechanism may be broadly employed by other intrinsic cell fate determining transcription factors to promptly turn off extrinsic inhibitory Wnt signaling mediated by beta-catenin.

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          Author and article information

          Journal
          19047045
          2631972
          10.1074/jbc.M808048200

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