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

Abstract

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.

Single-cell Atlas Unveils Cellular Heterogeneity and Novel Markers in Human Neonatal and Adult Intervertebral Discs

“…7b). The SOX4, as a positive regulator of the Wnt/β-catenin canonical pathway (Sinner et al, 2007), decreased over pseudo-time but SOX9, as a negative regulator (Sinha et al, 2021), increased (Fig. 7c), which is consistent with Fig.…”

SOX9 binds TCFs to mediate Wnt/β-catenin target gene activation

“…To test whether Defa5 was co-regulated by SOX9 and the Wnt pathway, we examined its expression in a HEK293 cell line with a DOX-inducible SOX9 overexpression construct (DOX-SOX9 cells) ( 20 ). We found that Defa5 mRNA levels were synergistically upregulated under high-Wnt, high-SOX9 levels induced by DOX treatment in conjunction with the β-catenin destruction complex inhibitor CHIR-99021 (Fig.…”

“…In several different mammalian cell lines, the overexpression of SOX9 causes a reduction in Wnt transcriptional readouts and in β-catenin protein levels ( 18 – 21 ). Recent work from our group found that SOX9 promoted β-catenin degradation in a destruction complex and proteasome-independent manner by transcriptionally activating the Notch pathway coactivator MAML2, which associates with β-catenin ( 20 ).…”

Yiqi Huoxue Recipe alleviates intervertebral disc degeneration by suppressing interleukin-17, nucleus pulposus cell apoptosis and promoting SOX9/β-catenin pathway

“…Aquaporin 3 could inhibit the degradation of ECM and promote the proliferation of human nucleus pulposus cells, thereby alleviating IVDD, and these effects are partly related to the inhibition of wnt/β-catenin (Xie et al, 2016). In addition, β-catenin was inhibited when chondrocytes were infected with adenovirus-mediated SOX-9 gene in vitro (Sinha et al, 2021;Topol et al, 2009), which might be the key way for SOX-9 to promote ECM synthesis. In our study, puncture of annulus fibrosus decreased phosphorylation of Sox-9, BMP 2, and collagen 2, while increased expression of b-catenin, MMP-3, MMP-13, and ADAMTS5 in IVD, and these effects were attenuated by YQHXF intervention.…”