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Repression of Wnt/β-catenin signaling by SOX9 and Mastermind-like transcriptional coactivator 2
Abhishek Sinha1, Vinson B Fan1, Aravinda-Bharathi Ramakrishnan1
1Department of Molecular, Cellular and Developmental Biology, University of Michigan, Biological Sciences Building, 1105 North University Avenue, Ann Arbor, MI 48109, USA.
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.
Insights
SOX9 antagonizes Wnt/β-catenin signaling by inducing Mastermind-like transcriptional activator 2 (MAML2). MAML2 promotes β-catenin turnover independently of the destruction complex and proteasome, revealing a new degradation pathway.
Area of Science:
- Cellular Biology
- Molecular Biology
- Signal Transduction
Background:
- Wnt/β-catenin signaling is crucial for development and disease.
- This pathway is regulated by a destruction complex targeting β-catenin for degradation.
- SOX9 is a known Wnt pathway antagonist, but its mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism by which SOX9 inhibits Wnt/β-catenin signaling.
- To identify novel pathways regulating β-catenin stability.
Main Methods:
- Mammalian cell culture experiments.
- Transcriptome analysis (RNA sequencing).
- In vitro binding assays.
Main Results:
- SOX9 promotes β-catenin turnover independently of the canonical destruction complex and proteasome.
- SOX9 transcriptional activity is required for this effect.
- SOX9 induces MAML2 expression, which mediates β-catenin turnover.
- MAML2 interacts with β-catenin and antagonizes Wnt signaling independently of Notch.
Conclusions:
- SOX9 utilizes a novel, non-canonical pathway to degrade β-catenin.
- This pathway involves SOX9-induced MAML2 expression.
- This discovery offers new insights into Wnt/β-catenin signaling regulation.
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