Malin regulates Wnt signaling pathway through degradation of dishevelled2.
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.
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122 050, India.
Jaiprakash
J
Sharma
Shalaka
S
Mulherkar
Diptendu
D
Mukherjee
Nihar Ranjan
NR
Jana
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D000072261:Dishevelled Proteins; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020192:Lafora Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D051176:beta Catenin; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex