Malin regulates Wnt signaling pathway through degradation of dishevelled2

Jaiprakash Sharma, Shalaka Mulherkar, Diptendu Mukherjee, Nihar Ranjan Jana

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.Wehave 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.

Original languageEnglish
Pages (from-to)6830-6839
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number9
DOIs
StatePublished - Feb 24 2012

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