OTUD7B Activates Wnt Signaling Pathway through the Interaction with LEF1

Area of Science:

• Molecular Biology
• Cell Signaling
• Oncology

Background:

• The Wnt signaling pathway is crucial for cellular functions like proliferation, differentiation, and apoptosis.
• Aberrant Wnt signaling is linked to various diseases, notably cancer, with β-catenin and LEF1 as key mediators.
• Deubiquitinases (DUBs) are enzymes that remove ubiquitin, playing roles in protein regulation.

Purpose of the Study:

• To identify deubiquitinases (DUBs) that regulate the Wnt signaling pathway via the LEF1 protein.
• To investigate the specific mechanism by which OTUD7B influences Wnt signaling.

Main Methods:

• Screening of a human DUB library to identify DUBs interacting with LEF1.
• Co-immunoprecipitation and domain analysis to confirm OTUD7B-LEF1 interaction.
• Immunofluorescence to assess the effect of OTUD7B on LEF1 nuclear localization.
• Quantitative PCR (qPCR) array analysis to evaluate Wnt target gene expression.

Main Results:

• OTUD7B was identified as a DUB that interacts with and activates Wnt signaling.
• The interaction between OTUD7B and LEF1 involves the UBA and HMG domains, respectively.
• OTUD7B enhances LEF1 nuclear localization, increasing its interaction with β-catenin in the nucleus.
• OTUD7B overexpression upregulates 75% of tested Wnt target genes.

Conclusions:

• OTUD7B positively regulates Wnt signaling by promoting LEF1 nuclear translocation and interaction with β-catenin.
• OTUD7B's role in activating Wnt signaling suggests it could be a therapeutic target in Wnt-dysregulated cancers.