Sox9 Inhibits Wnt Signaling by Promoting β-Catenin Phosphorylation in the Nucleus

Chondrocyte fate determination and maintenance requires Sox9, an intrinsic transcription factor, but is inhibited by Wnt/β-catenin signaling activated by extrinsic Wnt ligands. Here we explored the underlying molecular mechanism by which Sox9 antagonizes the Wnt/β-catenin signaling in chondrocyte di...

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Bibliographic Details
Published in:	The Journal of biological chemistry 2009-01, Vol.284 (5), p.3323-3333
Main Authors:	Topol, Lilia, Chen, Wen, Song, Hai, Day, Timothy F., Yang, Yingzi
Format:	Article
Language:	eng
Subjects:	Animals Base Sequence beta Catenin - metabolism Blotting, Western Cell Line Cell Nucleus - metabolism DNA Primers Fluorescent Antibody Technique, Indirect Glycogen Synthase Kinase 3 - chemistry Glycogen Synthase Kinase 3 - metabolism Humans Immunoprecipitation Mice Phosphorylation Protein Transport Signal Transduction - physiology SOX9 Transcription Factor - physiology Transducin - chemistry Transducin - metabolism Wnt Proteins - metabolism
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Summary:	Chondrocyte fate determination and maintenance requires Sox9, an intrinsic transcription factor, but is inhibited by Wnt/β-catenin signaling activated by extrinsic Wnt ligands. Here we explored the underlying molecular mechanism by which Sox9 antagonizes the Wnt/β-catenin signaling in chondrocyte differentiation. We found that Sox9 employed two distinct mechanisms to inhibit Wnt/β-catenin signaling: the Sox9 N terminus is necessary and sufficient to promote β-catenin degradation, whereas the C terminus is required to inhibit β-catenin transcriptional activity without affecting its stability. Sox9 binds to β-catenin and components of the β-catenin “destruction complex,” glycogen synthase kinase 3 and β-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 β-catenin phosphorylation and its subsequent degradation. Thus, one mechanism whereby Sox9 regulates chondrogenesis is to promote efficient β-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 β-catenin.
ISSN:	0021-9258 1083-351X