Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases

eLife

Volumn 5, Issue JANUARY2016, 2016, Pages

  Steger, Martin ^a   Tonelli, Francesca ^b   Ito, Genta ^b   Davies, Paul ^b   Trost, Matthias ^b   Vetter, Melanie ^a   Wachter, Stefanie ^a   Lorentzen, Esben ^a   Duddy, Graham ^c,f   Wilson, Stephen ^c   Baptista, Marco A S ^d   Fiske, Brian K ^d   Fell, Matthew J ^e   Morrow, John A ^e   Reith, Alastair D ^c   Alessi, Dario R ^b   Mann, Matthias ^a  

^a MAX PLANCK INSTITUTE OF BIOCHEMISTRY   (Germany)

^b UNIVERSITY OF DUNDEE   (United Kingdom)

^c GLAXOSMITHKLINE   (United Kingdom)

^d THE MICHAEL J FOX FOUNDATION FOR PARKINSON'S RESEARCH   (United States)

^e MERCK RESEARCH LABORATORIES   (United States)

^f WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

GDP DISSOCIATION INHIBITORS; GSK2578215A; LEUCINE RICH REPEAT KINASE 2; NICKEL; PROTEIN INHIBITOR; RAB PROTEIN; RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR; UNCLASSIFIED DRUG; LRRK2 PROTEIN, HUMAN; PROTEOME;

ANIMAL CELL; ARTICLE; CONTROLLED STUDY; DRUG PROTEIN BINDING; EMBRYO; FIBROBLAST; GENE MUTATION; HUMAN; HUMAN CELL; IMMUNOPRECIPITATION; MOUSE; NONHUMAN; PARKINSON DISEASE; PHOSPHOPROTEOMICS; PLASMID; POLYACRYLAMIDE GEL ELECTROPHORESIS; PROTEIN PHOSPHORYLATION; PROTEIN PURIFICATION; PROTEOMICS; ANIMAL; GENE EXPRESSION REGULATION; KNOCKOUT MOUSE; METABOLISM; PATHOPHYSIOLOGY; PROTEIN PROCESSING;

ANIMALS; GENE EXPRESSION REGULATION; HUMANS; LEUCINE-RICH REPEAT SERINE-THREONINE PROTEIN KINASE-2; MICE, KNOCKOUT; PARKINSON DISEASE; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTEOME; RAB GTP-BINDING PROTEINS;

EID: 84958567797     PISSN: None     EISSN: 2050084X     Source Type: Journal    
DOI: 10.7554/eLife.12813.001     Document Type: Article

References (84)

1. Bailey RM, Covy JP, Melrose HL, Rousseau L, Watkinson R, Knight J, Miles S, Farrer MJ, Dickson DW, Giasson BI, Lewis J. 2013. LRRK2 phosphorylates novel tau epitopes and promotes tauopathy. Acta Neuropathologica 126: 809-827. doi: 10. 1007/s00401-013-1188-4.
2. Baptista MAS, Dave KD, Frasier MA, Sherer TB, Greeley M, Beck MJ, Varsho JS, Parker GA, Moore C, Churchill MJ, Meshul CK, Fiske BK. 2013. Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs. PLoS One 8: e80705. doi: 10. 1371/journal. pone. 0080705.
3. Bleimling N, Alexandrov K, Goody R, Itzen A. 2009. Chaperone-assisted production of active human Rab8A GTPase in escherichia coli. Protein Expression and Purification 65: 190-195. doi: 10. 1016/j. pep. 2008. 12. 002.
4. Burbulla LF, Krüger R. 2011. Converging environmental and genetic pathways in the pathogenesis of parkinson's disease. Journal of the Neurological Sciences 306: 1-8. doi: 10. 1016/j. jns. 2011. 04. 005.
5. Campbell DG, Morrice NA. 2002. Identification of protein phosphorylation sites by a combination of mass spectrometry and solid phase edman sequencing. Journal of Biomolecular Techniques 13: 119-130.
6. Chaugule VK, Burchell L, Barber KR, Sidhu A, Leslie SJ, Shaw GS, Walden H. 2011. Autoregulation of parkin activity through its ubiquitin-like domain. The EMBO Journal 30: 2853-2867. doi: 10. 1038/emboj. 2011. 204.
7. Chen C-Y, Weng Y-H, Chien K-Y, Lin K-J, Yeh T-H, Cheng Y-P, Lu C-S, Wang H-L. 2012. (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell Death and Differentiation 19: 1623-1633. doi: 10. 1038/cdd. 2012. 42.
8. Choi HG, Zhang J, Deng X, Hatcher JM, Patricelli MP, Zhao Z, Alessi DR, Gray NS. 2012. Brain penetrant LRRK2 inhibitor. ACS Medicinal Chemistry Letters 3: 658-662. doi: 10. 1021/ml300123a.
9. Cookson MR. 2015. LRRK2 pathways leading to neurodegeneration. Current Neurology and Neuroscience Reports 15: 42. doi: 10. 1007/s11910-015-0564-y.
10. Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S. 2006. Alpha-synuclein blocks ER-golgi traffic and Rab1 rescues neuron loss in parkinson's models. Science 313: 324-328. doi: 10. 1126/science. 1129462.
11. Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. 2014. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Molecular & Cellular Proteomics 13: 2513-2526. doi: 10. 1074/mcp. M113. 031591.
12. Cox J, Mann M. 2008. MaxQuant enables high peptide identification rates, individualized p. p. b.-range mass accuracies and proteome-wide protein quantification. Nature Biotechnology 26: 1367-1372. doi: 10. 1038/nbt. 1511.
13. Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M. 2011. Andromeda: a peptide search engine integrated into the MaxQuant environment. Journal of Proteome Research 10: 1794-1805. doi: 10. 1021/pr101065j.
14. Davies P, Hinkle KM, Sukar NN, Sepulveda B, Mesias R, Serrano G, Alessi DR, Beach TG, Benson DL, White CL, Cowell RM, Das SS, West AB, Melrose HL. 2013. Comprehensive characterization and optimization of anti-LRRK2 (leucine-rich repeat kinase 2) monoclonal antibodies. Biochemical Journal 453: 101-113. doi: 10. 1042/BJ20121742.
15. Delprato A, Merithew E, Lambright DG. 2004. Structure, exchange determinants, and family-wide rab specificity of the tandem helical bundle and Vps9 domains of rabex-5. Cell 118: 607-617. doi: 10. 1016/j. cell. 2004. 08. 009.
16. Dzamko N, Deak M, Hentati F, Reith AD, Prescott AR, Alessi DR, Nichols RJ. 2010. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser 910/Ser 935, disruption of 14-3-3 binding and altered cytoplasmic localization. Biochemical Journal 430: 405-413. doi: 10. 1042/BJ20100784.
17. Dzamko N, Inesta-Vaquera F, Zhang J, Xie C, Cai H, Arthur S, Tan L, Choi H, Gray N, Cohen P, Pedrioli P, Clark K, Alessi DR. 2012. The IkappaB kinase family phosphorylates the parkinson's disease kinase LRRK2 at Ser935 and Ser910 during toll-like receptor signaling. PLoS One 7: e39132. doi: 10. 1371/journal. pone. 0039132.
18. Eberth A, Ahmadian MR. 2009. In vitro GEF and GAP assays. Current Protocols in Cell Biology/Editorial Board, Juan S Bonifacino [Et Al] 14. doi: 10. 1002/0471143030. cb1409s43.
19. Farley FW, Soriano P, Steffen LS, Dymecki SM. 2000. Widespread recombinase expression using FLPeR (flipper) mice. Genesis 28: 106-110. doi: 10. 1002/1526-968X(200011/12)28: 3/4<106:: AID-GENE30>3. 0. CO; 2-T.
20. Farrer MJ, Stone JT, Lin C-H, Dä chsel JC, Hulihan MM, Haugarvoll K, Ross OA, Wu R-M. 2007. Lrrk2 G2385R is an ancestral risk factor for parkinson's disease in asia. Parkinsonism & Related Disorders 13: 89-92. doi: 10. 1016/j. parkreldis. 2006. 12. 001.
21. Fell MJ, Mirescu C, Basu K, Cheewatrakoolpong B, DeMong DE, Ellis JM, Hyde LA, Lin Y, Markgraf CG, Mei H, Miller M, Poulet FM, Scott JD, Smith MD, Yin Z, Zhou X, Parker EM, Kennedy ME, Morrow JA. 2015. MLi-2, a potent, selective, and centrally active compound for exploring the therapeutic potential and safety of LRRK2 kinase inhibition. Journal of Pharmacology and Experimental Therapeutics 355: 397-409. doi: 10. 1124/jpet. 115. 227587.
22. Gardet A, Benita Y, Li C, Sands BE, Ballester I, Stevens C, Korzenik JR, Rioux JD, Daly MJ, Xavier RJ, Podolsky DK. 2010. LRRK2 is involved in the IFN-response and host response to pathogens. The Journal of Immunology 185: 5577-5585. doi: 10. 4049/jimmunol. 1000548.
23. Gillardon F. 2009. Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability-a point of convergence in parkinsonian neurodegeneration? Journal of Neurochemistry 110: 1514-1522. doi: 10. 1111/j. 1471-4159. 2009. 06235. x.
24. Gitler AD, Bevis BJ, Shorter J, Strathearn KE, Hamamichi S, Su LJ, Caldwell KA, Caldwell GA, Rochet J-C, McCaffery JM, Barlowe C, Lindquist S. 2008. The parkinson's disease protein-synuclein disrupts cellular rab homeostasis. Proceedings of the National Academy of Sciences of the United States of America 105: 145-150. doi: 10. 1073/pnas. 0710685105.
25. Gloeckner CJ, Schumacher A, Boldt K, Ueffing M. 2009. The parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro. Journal of Neurochemistry 109: 959-968. doi: 10. 1111/j. 1471-4159. 2009. 06024. x.
26. Guo Z, Hou X, Goody RS, Itzen A. 2013. Intermediates in the guanine nucleotide exchange reaction of Rab8 protein catalyzed by guanine nucleotide exchange factors Rabin8 and GRAB. Journal of Biological Chemistry 288: 32466-32474. doi: 10. 1074/jbc. M113. 498329.
27. Herzig MC, Kolly C, Persohn E, Theil D, Schweizer T, Hafner T, Stemmelen C, Troxler TJ, Schmid P, Danner S, Schnell CR, Mueller M, Kinzel B, Grevot A, Bolognani F, Stirn M, Kuhn RR, Kaupmann K, van der Putten PH, Rovelli G, Shimshek DR. 2011. LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Human Molecular Genetics 20: 4209-4223. doi: 10. 1093/hmg/ddr348.
28. Hinkle KM, Yue M, Behrouz B, Dä chsel JC, Lincoln SJ, Bowles EE, Beevers JE, Dugger B, Winner B, Prots I, Kent CB, Nishioka K, Lin W-L, Dickson DW, Janus CJ, Farrer MJ, Melrose HL. 2012. LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors. Molecular Neurodegeneration 7: 25. doi: 10. 1186/1750-1326-7-25.
29. Hubner NC, Bird AW, Cox J, Splettstoesser B, Bandilla P, Poser I, Hyman A, Mann M. 2010. Quantitative proteomics combined with BAC TransgeneOmics reveals in vivo protein interactions. The Journal of Cell Biology 189: 739-754. doi: 10. 1083/jcb. 200911091.
30. Humphrey SJ, Azimifar SB, Mann M. 2015. High-throughput phosphoproteomics reveals in vivo insulin signaling dynamics. Nature Biotechnology 33: 990-995. doi: 10. 1038/nbt. 3327.
31. Hutagalung AH, Novick PJ. 2011. Role of rab GTPases in membrane traffic and cell physiology. Physiological Reviews 91: 119-149. doi: 10. 1152/physrev. 00059. 2009.
32. Imai Y, Gehrke S, Wang H-Q, Takahashi R, Hasegawa K, Oota E, Lu B. 2008. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in drosophila. The EMBO Journal 27: 2432-2443. doi: 10. 1038/emboj. 2008. 163.
33. Jaleel M, Nichols RJ, Deak M, Campbell DG, Gillardon F, Knebel A, Alessi DR. 2007. LRRK2 phosphorylates moesin at threonine-558: characterization of how parkinson's disease mutants affect kinase activity. Biochemical Journal 405: 307-317. doi: 10. 1042/BJ20070209.
34. Kanao T, Venderova K, Park DS, Unterman T, Lu B, Imai Y. 2010. Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in drosophila. Human Molecular Genetics 19: 3747-3758. doi: 10. 1093/hmg/ddq289.
35. Kawakami F, Yabata T, Ohta E, Maekawa T, Shimada N, Suzuki M, Maruyama H, Ichikawa T, Obata F. 2012. LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth. PLoS ONE 7: e30834. doi: 10. 1371/journal. pone. 0030834.
36. Khan NL, Jain S, Lynch JM, Pavese N, Abou-Sleiman P, Holton JL, Healy DG, Gilks WP, Sweeney MG, Ganguly M, Gibbons V, Gandhi S, Vaughan J, Eunson LH, Katzenschlager R, Gayton J, Lennox G, Revesz T, Nicholl D, Bhatia KP, Quinn N, Brooks D, Lees AJ, Davis MB, Piccini P, Singleton AB, Wood NW. 2005. Mutations in the gene LRRK2 encoding dardarin (pARK8) cause familial parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 128: 2786-2796. doi: 10. 1093/brain/awh667.
37. Krumova P, Reyniers L, Meyer M, Lobbestael E, Stauffer D, Gerrits B, Muller L, Hoving S, Kaupmann K, Voshol J, Fabbro D, Bauer A, Rovelli G, Taymans J-M, Bouwmeester T, Baekelandt V. 2015. Chemical genetic approach identifies microtubule affinity-regulating kinase 1 as a leucine-rich repeat kinase 2 substrate. The FASEB Journal 29: 2980-2992. doi: 10. 1096/fj. 14-262329.
38. Kumar A, Greggio E, Beilina A, Kaganovich A, Chan D, Taymans J-M, Wolozin B, Cookson MR. 2010. The parkinson's disease associated LRRK2 exhibits weaker in vitro phosphorylation of 4E-BP compared to autophosphorylation. PLoS One 5: e8730. doi: 10. 1371/journal. pone. 0008730.
39. Lai Y-C, Kondapalli C, Lehneck R, Procter JB, Dill BD, Woodroof HI, Gourlay R, Peggie M, Macartney TJ, Corti O, Corvol J-C, Campbell DG, Itzen A, Trost M, Muqit MM. 2015. Phosphoproteomic screening identifies rab GTPases as novel downstream targets of PINK1. The EMBO Journal 34: 2840-2861. doi: 10. 15252/embj. 201591593.
40. Lees AJ, Hardy J, Revesz T. 2009. Parkinson's disease. The Lancet 373: 2055-2066. doi: 10. 1016/S0140-6736(09) 60492-X.
41. Lemeer S, Heck AJR. 2009. The phosphoproteomics data explosion. Current Opinion in Chemical Biology 13: 414-420. doi: 10. 1016/j. cbpa. 2009. 06. 022.
42. Liu Z, Hamamichi S, Dae Lee B, Yang D, Ray A, Caldwell GA, Caldwell KA, Dawson TM, Smith WW, Dawson VL. 2011. Inhibitors of LRRK2 kinase attenuate neurodegeneration and parkinson-like phenotypes in caenorhabditis elegans and drosophila parkinson's disease models. Human Molecular Genetics 20: 3933-3942. doi: 10. 1093/hmg/ddr312.
43. MacLeod DA, Rhinn H, Kuwahara T, Zolin A, Di Paolo G, McCabe BD, MacCabe BD, Marder KS, Honig LS, Clark LN, Small SA, Abeliovich A. 2013. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and parkinson's disease risk. Neuron 77: 425-439. doi: 10. 1016/j. neuron. 2012. 11. 033.
44. Mallick P, Kuster B. 2010. Proteomics: a pragmatic perspective. Nature Biotechnology 28: 695-709. doi: 10. 1038/nbt. 1658.
45. Martin I, Kim JW, Dawson VL, Dawson TM. 2014. LRRK2 pathobiology in parkinson's disease. Journal of Neurochemistry 131: 554-565. doi: 10. 1111/jnc. 12949.
46. Martin I, Kim JW, Lee BD, Kang HC, Xu J-C, Jia H, Stankowski J, Kim M-S, Zhong J, Kumar M, Andrabi SA, Xiong Y, Dickson DW, Wszolek ZK, Pandey A, Dawson TM, Dawson VL. 2014. Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in parkinson's disease. Cell 157: 472-485. doi: 10. 1016/j. cell. 2014. 01. 064.
47. Mata IF, Jang Y, Kim C-H, Hanna DS, Dorschner MO, Samii A, Agarwal P, Roberts JW, Klepitskaya O, Shprecher DR, Chung KA, Factor SA, Espay AJ, Revilla FJ, Higgins DS, Litvan I, Leverenz JB, Yearout D, Inca-Martinez M, Martinez E, Thompson TR, Cholerton BA, Hu S-C, Edwards KL, Kim K-S, Zabetian CP. 2015. The RAB39B p. G192R mutation causes x-linked dominant parkinson's disease. Molecular Neurodegeneration 10: 50. doi: 10. 1186/s13024-015-0045-4.
48. Matta S, Van Kolen K, da Cunha R, van den Bogaart G, Mandemakers W, Miskiewicz K, De Bock P-J, Morais VA, Vilain S, Haddad D, Delbroek L, Swerts J, Chá vez-Gutié rrez L, Esposito G, Daneels G, Karran E, Holt M, Gevaert K, Moechars DW, De Strooper B, Verstreken P. 2012. LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 75: 1008-1021. doi: 10. 1016/j. neuron. 2012. 08. 022.
49. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R, Ikram MA, Ioannidis JP, Hadjigeorgiou GM, Bis JC, Martinez M, Perlmutter JS, Goate A, Marder K, Fiske B, Sutherland M, Xiromerisiou G, Myers RH, Clark LN, Stefansson K, Hardy JA, Heutink P, Chen H, Wood NW, Houlden H, Payami H, Brice A, Scott WK, Gasser T, Bertram L, Eriksson N, Foroud T, Singleton AB. International Parkinson's Disease Genomics Consortium (IPDGC); Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI); 23andMe; GenePD; NeuroGenetics Research Consortium (NGRC); Hussman Institute of Human Genomics (HIHG); Ashkenazi Jewish Dataset Investigator; Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE); North American Brain Expression Consortium (NABEC); United Kingdom Brain Expression Consortium (UKBEC); Greek Parkinson's Disease Consortium; Alzheimer Genetic Analysis Group. 2014. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for parkinson's disease. Nature Genetics 46: 989-993. doi: 10. 1038/ng. 3043.
50. Nichols RJ, Dzamko N, Hutti JE, Cantley LC, Deak M, Moran J, Bamborough P, Reith AD, Alessi DR. 2009. Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in parkinson's disease. Biochemical Journal 424: 47-60. doi: 10. 1042/BJ20091035.
51. Nichols RJ, Dzamko N, Morrice NA, Campbell DG, Deak M, Ordureau A, Macartney T, Tong Y, Shen J, Prescott AR, Alessi DR. 2010. 14-3-3 binding to LRRK2 is disrupted by multiple parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochemical Journal 430: 393-404. doi: 10. 1042/BJ20100483.
52. Ohta E, Kawakami F, Kubo M, Obata F. 2011. LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: impairment of the kinase activity by parkinson's disease-associated mutations. FEBS Letters 585: 2165-2170. doi: 10. 1016/j. febslet. 2011. 05. 044.
53. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M. 2006. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127: 635-648. doi: 10. 1016/j. cell. 2006. 09. 026.
54. Ong SE, Blagoev B, Kratchmarova I, Kristensen DB, Steen H, Pandey A, Mann M. 2002. Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Molecular & Cellular Proteomics 1: 376-386. doi: 10. 1074/mcp. M200025-MCP200.
55. Papkovskaia TD, Chau K-Y, Inesta-Vaquera F, Papkovsky DB, Healy DG, Nishio K, Staddon J, Duchen MR, Hardy J, Schapira AHV, Cooper JM. 2012. G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization. Human Molecular Genetics 21: 4201-4213. doi: 10. 1093/hmg/dds244.
56. Pfeffer SR. 2005. Structural clues to rab GTPase functional diversity. Journal of Biological Chemistry 280: 15485-15488. doi: 10. 1074/jbc. R500003200.
57. Pylypenko O, Rak A, Reents R, Niculae A, Sidorovitch V, Cioaca M-D, Bessolitsyna E, Thomä NH, Waldmann H, Schlichting I, Goody RS, Alexandrov K. 2003. Structure of rab escort protein-1 in complex with rab geranylgeranyltransferase. Molecular Cell 11: 483-494. doi: 10. 1016/S1097-2765(03)00044-3.
58. Qing H, Wong W, McGeer EG, McGeer PL. 2009. Lrrk2 phosphorylates alpha synuclein at serine 129: parkinson disease implications. Biochemical and Biophysical Research Communications 387: 149-152. doi: 10. 1016/j. bbrc. 2009. 06. 142.
59. Rak A, Pylypenko O, Durek T, Watzke A, Kushnir S, Brunsveld L, Waldmann H, Goody RS, Alexandrov K. 2003. Structure of rab GDP-dissociation inhibitor in complex with prenylated YPT1 GTPase. Science 302: 646-650. doi: 10. 1126/science. 1087761.
60. Reith AD, Bamborough P, Jandu K, Andreotti D, Mensah L, Dossang P, Choi HG, Deng X, Zhang J, Alessi DR, Gray NS. 2012. GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-n-arylbenzamide LRRK2 kinase inhibitor. Bioorganic & Medicinal Chemistry Letters 22: 5625-5629. doi: 10. 1016/j. bmcl. 2012. 06. 104.
61. Rivero-Ríos P, Gó mez-Suaga P, Ferná ndez B, Madero-Pé rez J, Schwab AJ, Ebert AD, Hilfiker S. 2015. Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked parkinson's disease. Biochemical Society Transactions 43: 390-395. doi: 10. 1042/BST20140301.
62. Roux PP, Thibault P. 2013. The coming of age of phosphoproteomics-from large data sets to inference of protein functions. Molecular & Cellular Proteomics 12: 3453-3464. doi: 10. 1074/mcp. R113. 032862.
63. Rudenko IN, Cookson MR. 2014. Heterogeneity of leucine-rich repeat kinase 2 mutations: genetics, mechanisms and therapeutic implications. Neurotherapeutics 11: 738-750. doi: 10. 1007/s13311-014-0284-z.
64. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T. 2009. Genome-wide association study identifies common variants at four loci as genetic risk factors for parkinson's disease. Nature Genetics 41: 1303-1307. doi: 10. 1038/ng. 485.
65. Satpathy S, Wagner SA, Beli P, Gupta R, Kristiansen TA, Malinova D, Francavilla C, Tolar P, Bishop GA, Hostager BS, Choudhary C. 2015. Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation. Molecular Systems Biology 11: 810. doi: 10. 15252/msb. 20145880.
66. Schapansky J, Nardozzi JD, Felizia F, LaVoie MJ. 2014. Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. Human Molecular Genetics 23: 4201-4214. doi: 10. 1093/hmg/ddu138.
67. Schapansky J, Nardozzi JD, LaVoie MJ. 2015. The complex relationships between microglia, alpha-synuclein, and LRRK2 in parkinson's disease. Neuroscience 302: 74-88. doi: 10. 1016/j. neuroscience. 2014. 09. 049.
68. Seabra MC, Wasmeier C. 2004. Controlling the location and activation of rab GTPases. Current Opinion in Cell Biology 16: 451-457. doi: 10. 1016/j. ceb. 2004. 06. 014.
69. Sharma K, D'Souza RCJ, Tyanova S, Schaab C, Wiśniewski JR, Cox J, Mann M. 2014. Ultradeep human phosphoproteome reveals a distinct regulatory nature of tyr and Ser/Thr-based signaling. Cell Reports 8: 1583-1594. doi: 10. 1016/j. celrep. 2014. 07. 036.
70. Sheng Z, Zhang S, Bustos D, Kleinheinz T, Le Pichon CE, Dominguez SL, Solanoy HO, Drummond J, Zhang X, Ding X, Cai F, Song Q, Li X, Yue Z, van der Brug MP, Burdick DJ, Gunzner-Toste J, Chen H, Liu X, Estrada AA, Sweeney ZK, Scearce-Levie K, Moffat JG, Kirkpatrick DS, Zhu H. 2012. Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Science Translational Medicine 4: 164ra161. doi: 10. 1126/scitranslmed. 3004485.
71. Simó n-Sá nchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Krüger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T. 2009. Genome-wide association study reveals genetic risk underlying parkinson's disease. Nature Genetics 41: 1308-1312. doi: 10. 1038/ng. 487.
72. Stenmark H. 2009. Rab GTPases as coordinators of vesicle traffic. Nature Reviews Molecular Cell Biology 10: 513-525. doi: 10. 1038/nrm2728.
73. Taymans J-M, Nkiliza A, Chartier-Harlin M-C. 2015. Deregulation of protein translation control, a potential game-changing hypothesis for parkinson's disease pathogenesis. Trends in Molecular Medicine 21: 466-472. doi: 10. 1016/j. molmed. 2015. 05. 004.
74. Vizcaíno JA, Deutsch EW, Wang R, Csordas A, Reisinger F, Ríos D, Dianes JA, Sun Z, Farrah T, Bandeira N, Binz P-A, Xenarios I, Eisenacher M, Mayer G, Gatto L, Campos A, Chalkley RJ, Kraus H-J, Albar JP, Martinez-Bartolomé S, Apweiler R, Omenn GS, Martens L, Jones AR, Hermjakob H. 2014. ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Nature Biotechnology 32: 223-226. doi: 10. 1038/nbt. 2839.
75. Wandinger-Ness A, Zerial M. 2014. Rab proteins and the compartmentalization of the endosomal system. Cold Spring Harbor Perspectives in Biology 6: a022616-: a022616 doi: 10. 1101/cshperspect. a022616.
76. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM. 2005. From the cover: parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proceedings of the National Academy of Sciences of the United States of America 102: 16842-16847. doi: 10. 1073/pnas. 0507360102.
77. Westlake CJ, Baye LM, Nachury MV, Wright KJ, Ervin KE, Phu L, Chalouni C, Beck JS, Kirkpatrick DS, Slusarski DC, Sheffield VC, Scheller RH, Jackson PK. 2011. Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (tRAPPII) complex-dependent trafficking of Rabin8 to the centrosome. Proceedings of the National Academy of Sciences of the United States of America 108: 2759-2764. doi: 10. 1073/pnas. 1018823108.
78. Wiggin GR, Soloaga A, Foster JM, Murray-Tait V, Cohen P, Arthur JSC. 2002. MSK1 and MSK2 are required for the mitogen-and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. Molecular and Cellular Biology 22: 2871-2881. doi: 10. 1128/MCB. 22. 8. 2871-2881. 2002.
79. Wilson GR, Sim JCH, McLean C, Giannandrea M, Galea CA, Riseley JR, Stephenson SEM, Fitzpatrick E, Haas SA, Pope K, Hogan KJ, Gregg RG, Bromhead CJ, Wargowski DS, Lawrence CH, James PA, Churchyard A, Gao Y, Phelan DG, Gillies G, Salce N, Stanford L, Marsh APL, Mignogna ML, Hayflick SJ, Leventer RJ, Delatycki MB, Mellick GD, Kalscheuer VM, D'Adamo P, Bahlo M, Amor DJ, Lockhart PJ. 2014. Mutations in RAB39B cause x-linked intellectual disability and early-onset parkinson disease with a-synuclein pathology. The American Journal of Human Genetics 95: 729-735. doi: 10. 1016/j. ajhg. 2014. 10. 015.
80. Xiong Y, Yuan C, Chen R, Dawson TM, Dawson VL. 2012. ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2. Journal of Neuroscience 32: 3877-3886. doi: 10. 1523/JNEUROSCI. 4566-11. 2012.
81. Yao C, Johnson WM, Gao Y, Wang W, Zhang J, Deak M, Alessi DR, Zhu X, Mieyal JJ, Roder H, Wilson-Delfosse AL, Chen SG. 2013. Kinase inhibitors arrest neurodegeneration in cell and c. elegans models of LRRK2 toxicity. Human Molecular Genetics 22: 328-344. doi: 10. 1093/hmg/dds431.
82. Yun HJ, Kim H, Ga I, Oh H, Ho DH, Kim J, Seo H, Son I, Seol W. 2015. An early endosome regulator, Rab5b, is an LRRK2 kinase substrate. Journal of Biochemistry 157: 485-495. doi: 10. 1093/jb/mvv005.
83. Yun HJ, Park J, Ho DH, Kim H, Kim C-H, Oh H, Ga I, Seo H, Chang S, Son I, Seol W. 2013. LRRK2 phosphorylates snapin and inhibits interaction of snapin with SNAP-25. Experimental & Molecular Medicine 45: e36. doi: 10. 1038/emm. 2013. 68.
84. Zhang Q, Pan Y, Yan R, Zeng B, Wang H, Zhang X, Li W, Wei H, Liu Z. 2015. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nature Immunology 16: 918-926. doi: 10. 1038/ni. 3233.