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Updated: May 26, 2026
Modeling Paracrine Noncanonical Wnt Signaling In Vitro
Published on: December 10, 2021
Malin regulates Wnt signaling pathway through degradation of dishevelled2
Jaiprakash Sharma1, Shalaka Mulherkar, Diptendu Mukherjee
1Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122 050, India.
Abstract:
Using yeast-two hybrid screening followed by co-immunoprecipitation assay, we have found that the Lafora disease ubiquitin ligase malin interacts with dishevelled2, a key mediator of Wnt signaling pathway. Overexpression of malin enhances the degradation of dishevelled2 and inhibits Wnt signaling, which is evident from the down-regulation of β-catenin target genes and the decrease in β-catenin-mediated transcriptional activity. Partial knockdown of malin significantly increases the level of dishevelled2 and up-regulates Wnt signaling. Several malin mutants are found to be ineffective in degrading dishevelled2 and regulating the Wnt pathway. We have also found that malin enhances K48- and K63-linked ubiquitination of dishevelled2 that could lead to its degradation through both proteasome and autophagy. Altogether, our results indicate that malin regulates Wnt signaling pathway through the degradation of dishevelled2 and suggest possible deregulation of Wnt signaling in Lafora disease.
Insights
The Lafora disease protein malin interacts with dishevelled2, a Wnt signaling mediator. Malin degrades dishevelled2, inhibiting Wnt signaling and suggesting its deregulation in Lafora disease.
Area of Science:
- Molecular Biology
- Cell Signaling
- Neuroscience
Background:
- Lafora disease is a rare, fatal neurodegenerative disorder.
- The Wnt signaling pathway is crucial for embryonic development and cellular processes.
- Malin is an E3 ubiquitin ligase implicated in Lafora disease pathogenesis.
Purpose of the Study:
- To investigate the interaction between malin and dishevelled2.
- To elucidate the role of malin in regulating Wnt signaling.
- To explore the potential link between Wnt pathway deregulation and Lafora disease.
Main Methods:
- Yeast-two hybrid screening
- Co-immunoprecipitation assays
- Overexpression and knockdown studies
- Western blotting for protein levels and ubiquitination
- Analysis of β-catenin target gene expression
Main Results:
- Malin directly interacts with dishevelled2.
- Malin overexpression leads to dishevelled2 degradation and Wnt pathway inhibition.
- Malin knockdown increases dishevelled2 levels and up-regulates Wnt signaling.
- Malin promotes dishevelled2 ubiquitination, targeting it for proteasomal and autophagic degradation.
- Malin mutants lose their ability to degrade dishevelled2 and regulate Wnt signaling.
Conclusions:
- Malin negatively regulates the Wnt signaling pathway by promoting dishevelled2 degradation.
- Dysregulation of the Wnt signaling pathway, via malin-dishevelled2 interaction, may contribute to Lafora disease.
- This study identifies a novel mechanism of Wnt pathway regulation by an E3 ubiquitin ligase.
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