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A Dual Specificity Phosphatase and Control of Beta-Catenin Signaling

Matthew Gentry

Appointment Period: 2003-2005 / Grant Years: [19,20]

Matthew GentryLafora disease (LD) is a fatal form of progressive myoclonus epilepsy caused by recessive mutations in either a gene encoding a dual-specificity phosphatase, known as laforin, or a recently identified gene encoding the protein known as malin. Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation. Missense mutations in malin that are present in LD patients abolish its ability to polyubiquitinate and signal the degradation of laforin. Our results demonstrate that laforin is a physiologic substrate of malin, and we propose possible models to explain how recessive mutations in either malin or laforin result in LD. Furthermore, these data distinguish malin as an E3 Ub ligase whose activity is necessary to prevent a neurodegenerative disease that involves formation of nonproteinacious inclusion bodies. Laforin activates glycogen synthatase kinase 3 (GSK3) by dephosphorylation of GSK3 on serine 9. GSK 3 in turn alters -catenin function leading to cancer in the immune system. Elucidating how laforin is regulated will provide definitive answers to the regulation of -catenin and cancers of the immune system.

Gentry MS, Worby CA, Dixon JE. Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proc Natl Acad Sci USA. (2005) 102:8501-6. PMID: 15930137; PMCID: PMC1150849.

Gentry MS, Li Y, Wei H, Syed FF, Patel SH, Hallberg RL, Pallas DC. A novel assay for protein phosphatase 2A (PP2A) complexes in vivo reveals differential effects of covalent modifications on different Saccharomyces cerevisiae PP2A heterotrimers. Eukaryot Cell. (2005) 4:1029-40. PMID: 15947195; PMCID: PMC1151991.

Worby CA, Gentry MS, Dixon JE. Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J Biol Chem. (2006) 281:30412-8. PMID: 16901901; PMCID: PMC2774450.

Cheng A, Zhang M, Gentry MS, Worby CA, Dixon JE, Saltiel AR. A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori's disease. Genes Dev. (2007) 21:2399-409. PMID: 17908927; PMCID: PMC1993871.

Gentry MS, Dowen RH 3rd, Worby CA, Mattoo S, Ecker JR, Dixon JE. The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease. J Cell Biol. (2007) 178:477-88. PMID: 17646401; PMCID: PMC2064834.

Kim Y, Gentry MS, Harris TE, Wiley SE, Lawrence JC Jr, Dixon JE. A conserved phosphatase cascade that regulates nuclear membrane biogenesis. Proc Natl Acad Sci USA. (2007) 104:6596-601. PMID: 17420445; PMCID: PMC1871831.

Worby CA, Gentry MS, Dixon JE. Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J Biol Chem. (2008) 283:4069-76. PMID: 18070875; PMCID: PMC2251628.

Gentry MS, Dixon JE, Worby CA. Lafora disease: insights into neurodegeneration from plant metabolism. Trends Biochem Sci. (2009) 34:628-39. PMID: 19818631; PMCID: PMC2805077.