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Updated: Jan 19, 2026
Reconstitution Of β-catenin Degradation In Xenopus Egg Extract
Published on: June 17, 2014
USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin
Lei Ji1, Bo Lu1, Raffaella Zamponi1,2
1Novartis Institutes for Biomedical Research, Novartis Pharma AG, Cambridge, MA, USA.
Abstract:
Axin is a key scaffolding protein responsible for the formation of the β-catenin destruction complex. Stability of Axin protein is regulated by the ubiquitin-proteasome system, and modulation of cellular concentration of Axin protein has a profound effect on Wnt/β-catenin signaling. Although E3s promoting Axin ubiquitination have been identified, the deubiquitinase responsible for Axin deubiquitination and stabilization remains unknown. Here, we identify USP7 as a potent negative regulator of Wnt/β-catenin signaling through CRISPR screens. Genetic ablation or pharmacological inhibition of USP7 robustly increases Wnt/β-catenin signaling in multiple cellular systems. USP7 directly interacts with Axin through its TRAF domain, and promotes deubiquitination and stabilization of Axin. Inhibition of USP7 regulates osteoblast differentiation and adipocyte differentiation through increasing Wnt/β-catenin signaling. Our study reveals a critical mechanism that prevents excessive degradation of Axin and identifies USP7 as a target for sensitizing cells to Wnt/β-catenin signaling.
Insights
Researchers found that USP7 deubiquitinates and stabilizes Axin, a key protein in Wnt/β-catenin signaling. Inhibiting USP7 boosts this signaling pathway, impacting cell differentiation and offering a new therapeutic target.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Axin is a crucial scaffolding protein in the β-catenin destruction complex.
- Axin protein stability, regulated by the ubiquitin-proteasome system, significantly impacts Wnt/β-catenin signaling.
- The deubiquitinase responsible for Axin stabilization was previously unknown.
Purpose of the Study:
- To identify the deubiquitinase regulating Axin stability.
- To investigate the role of USP7 in Wnt/β-catenin signaling.
- To explore the therapeutic potential of targeting USP7.
Main Methods:
- CRISPR screens were employed to identify key regulators.
- Genetic ablation and pharmacological inhibition of USP7 were utilized.
- Protein interaction assays and cellular differentiation studies were performed.
Main Results:
- USP7 was identified as a negative regulator of Wnt/β-catenin signaling.
- USP7 directly interacts with Axin, promoting its deubiquitination and stabilization.
- USP7 inhibition increased Wnt/β-catenin signaling, affecting osteoblast and adipocyte differentiation.
Conclusions:
- USP7 plays a critical role in preventing Axin degradation.
- USP7 is a key deubiquitinase stabilizing Axin.
- USP7 inhibition represents a potential strategy to enhance Wnt/β-catenin signaling.
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