Sox9 inhibits Wnt signaling by promoting beta-catenin phosphorylation in the nucleus.
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.
Topol
Lilia
L
Genetics Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892.
Chen
Wen
W
Genetics Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892.
Song
Hai
H
Genetics Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892.
Day
Timothy F
TF
Genetics Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892.
Yang
Yingzi
Y
Genetics Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892. Electronic address: yingzi@mail.nih.gov.
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D017931:DNA Primers; D019084:Fluorescent Antibody Technique, Indirect; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D010766:Phosphorylation; D021381:Protein Transport; D055758:SOX9 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015293:Transducin / Q000737:chemistry / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D017931:DNA Primers; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3; D015293:Transducin