Repression of Wnt/β-catenin signaling by SOX9 and Mastermind-like transcriptional coactivator 2

Wnt/β-catenin signaling requires inhibition of a multiprotein destruction complex that targets β-catenin for proteasomal degradation. SOX9 is a potent antagonist of the Wnt pathway and has been proposed to act through direct binding to β-catenin or the β-catenin destruction complex. Here, we demonstrate that SOX9 promotes turnover of β-catenin in mammalian cell culture, but this occurs independently of the destruction complex and the proteasome. This activity requires SOX9's ability to activate transcription. Transcriptome analysis revealed that SOX9 induces the expression of the Notch coactivator Mastermind-like transcriptional activator 2 (MAML2), which is required for SOX9-dependent Wnt/β-catenin antagonism. MAML2 promotes β-catenin turnover independently of Notch signaling, and MAML2 appears to associate directly with β-catenin in an in vitro binding assay. This work defines a previously unidentified pathway that promotes β-catenin degradation, acting in parallel to established mechanisms. SOX9 uses this pathway to restrict Wnt/β-catenin signaling.