Phosphorylation of LRRK2 serines 955 and 973 is disrupted by Parkinson's disease mutations and LRRK2 pharmacological inhibition

Journal of Neurochemistry

Volumn 120, Issue 1, 2012, Pages 37-45

  Doggett, Elizabeth A ^a   Zhao, Jing ^a   Mork, Christina N ^a   Hu, Dongmei ^a   Nichols, R Jeremy ^a  

^a PARKINSON S INSTITUTE   (United States)

Author keywords

biomarker; LRRK2; LRRK2 IN1; Parkinson's disease; phosphoantibodies

Indexed keywords

LEUCINE RICH REPEAT KINASE 2; SERINE;

ARTICLE; AUTOPHOSPHORYLATION; BINDING SITE; CELL STRAIN HEK293; CONTROLLED STUDY; CYTOPLASM; ENZYME ACTIVITY; GUANINE NUCLEOTIDE BINDING SITE; HUMAN; HUMAN CELL; MUTATION; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION;

CELL LINE; DNA; GUANINE NUCLEOTIDES; HUMANS; IMMUNOPRECIPITATION; MICROSCOPY, FLUORESCENCE; PARKINSON DISEASE; PHOSPHORYLATION; PROTEIN-SERINE-THREONINE KINASES; SERINE;

EID: 83855160771     PISSN: 00223042     EISSN: 14714159     Source Type: Journal    
DOI: 10.1111/j.1471-4159.2011.07537.x     Document Type: Article

References (31)

1. Berwick D. C., and, Harvey K., (2011a) LRRK2 signaling pathways: the key to unlocking neurodegeneration? Trends Cell Biol. 21, 257-265.
2. Biskup S., and, West A. B., (2008) Zeroing in on LRRK2-linked pathogenic mechanisms in Parkinson's disease. Biochim. Biophys. Acta 1792, 625-633.
3. Carballo-Carbajal I., Weber-Endress S., Rovelli G., Chan D., Wolozin B., Klein C. L., Patenge N., Gasser T., and, Kahle P. J., (2010) Leucine-rich repeat kinase 2 induces alpha-synuclein expression via the extracellular signal-regulated kinase pathway. Cell. Signal. 22, 821-827.
4. Chan D., Citro A., Cordy J. M., Shen G. C., and, Wolozin B., (2011) Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2). J. Biol. Chem. 286, 16140-16149.
5. Daniels V., Baekelandt V., and, Taymans J. M., (2011) On the road to leucine-rich repeat kinase 2 signalling: evidence from cellular and in vivo studies. Neurosignals 19, 1-15.
6. Deng X., Dzamko N., Prescott A., et al. (2011) Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat. Chem. Biol. 7, 203-205.
7. Ding X., and, Goldberg M. S., (2009) Regulation of LRRK2 stability by the E3 ubiquitin ligase CHIP. PLoS ONE 4, e5949.
8. Dzamko N., Deak M., Hentati F., Reith A. D., Prescott A. R., Alessi D. R., and, Nichols R. J., (2010) Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem. J. 430, 405-413.
9. Gloeckner C. J., Boldt K., von Zweydorf F., Helm S., Wiesent L., Sarioglu H., and, Ueffing M., (2010) Phosphopeptide analysis reveals two discrete clusters of phosphorylation in the N-terminus and the Roc domain of the Parkinson-disease associated protein kinase LRRK2. J. Proteome Res. 9, 1738-1745.
10. Greggio E., Taymans J. M., Zhen E. Y., et al. (2009) The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites. Biochem. Biophys. Res. Commun. 389, 449-454.
11. Healy D. G., Falchi M., O'Sullivan S. S., et al. (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 7, 583-590.
12. Jaleel M., Nichols R. J., Deak M., Campbell D. G., Gillardon F., Knebel A., and, Alessi D. R., (2007) LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem. J. 405, 307-317. (Pubitemid 47075166)
13. Kamikawaji S., Ito G., and, Iwatsubo T., (2009) Identification of the autophosphorylation sites of LRRK2. Biochemistry 48, 10963-10975.
14. Ko H. S., Bailey R., Smith W. W., et al. (2009) CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proc. Natl. Acad. Sci. USA 106, 2897-2902.
15. Kruger R., Kuhn W., Muller T., Woitalla D., Graeber M., Kosel S., Przuntek H., Epplen J. T., Schols L., and, Riess O., (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat. Genet. 18, 106-108.
16. Mata I. F., Wedemeyer W. J., Farrer M. J., Taylor J. P., and, Gallo K. A., (2006) LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci. 29, 286-293.
17. Moorhead G., Douglas P., Cotelle V., et al. (1999) Phosphorylation- dependent interactions between enzymes of plant metabolism and 14-3-3 proteins. Plant J. 18, 1-12.
18. Nichols R. J., Dzamko N., Hutti J. E., Cantley L. C., Deak M., Moran J., Bamborough P., Reith A. D., and, Alessi D. R., (2009) Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease. Biochem. J. 424, 47-60.
19. Nichols R. J., Dzamko N., Morrice N. A., et al. (2010) 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochem. J. 430, 393-404.
20. Paisan-Ruiz C., Jain S., Evans E. W., et al. (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600. (Pubitemid 39531224)
21. Polymeropoulos M. H., Lavedan C., Leroy E., et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276, 2045-2047. (Pubitemid 27443610)
22. Pungaliya P. P., Bai Y., Lipinski K., et al. (2010) Identification and characterization of a leucine-rich repeat kinase 2 (LRRK2) consensus phosphorylation motif. PLoS ONE 5, e13672.
23. Reed S. E., Staley E. M., Mayginnes J. P., Pintel D. J., and, Tullis G. E., (2006) Transfection of mammalian cells using linear polyethylenimine is a simple and effective means of producing recombinant adeno-associated virus vectors. J. Virol. Methods 138, 85-98. (Pubitemid 44633451)
24. Singleton A. B., Farrer M., Johnson J., et al. (2003) alpha-Synuclein locus triplication causes Parkinson's disease. Science 302, 841. (Pubitemid 37339619)
25. Taymans J. M., and, Cookson M. R., (2010) Mechanisms in dominant parkinsonism: the toxic triangle of LRRK2, alpha-synuclein, and tau. Bioessays 32, 227-235.
26. Taymans J. M., Vancraenenbroeck R., Ollikainen P., Beilina A., Lobbestael E., De Maeyer M., Baekelandt V., and, Cookson M. R., (2011) LRRK2 kinase activity is dependent on LRRK2 GTP binding capacity but independent of LRRK2 GTP binding. PLoS ONE 6, e23207.
27. Wang L., Xie C., Greggio E., et al. (2008) The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2. J. Neurosci. 28, 3384-3391. (Pubitemid 351469333)
28. Webber P. J., Smith A. D., Sen S., Renfrow M. B., Mobley J. A., and, West A. B., (2011) Autophosphorylation in the leucine-rich repeat kinase 2 (LRRK2) GTPase domain modifies kinase and GTP-binding activities. J. Mol. Biol. 412, 94-110.
29. West A. B., Moore D. J., Biskup S., Bugayenko A., Smith W. W., Ross C. A., Dawson V. L., and, Dawson T. M., (2005) Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. USA 102, 16842-16847. (Pubitemid 41688864)
30. Zarranz J. J., Alegre J., Gomez-Esteban J. C., et al. (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55, 164-173. (Pubitemid 38166992)
31. Zimprich A., Biskup S., Leitner P., et al. (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607. (Pubitemid 39531225)