7. Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, et al. (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 23: 329–341. 8. MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, et al. (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52: 587–593. 9. Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans JM, et al. (2008) The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem 283: 16906–16914. 10. Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, et al. (2008) Structure of the ROC domain from the Parkinson’s disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proc Natl Acad Sci U S A 105: 1499–1504. 11. Sen S, Webber PJ, West AB (2009) Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. J Biol Chem 284: 36346–36356. 12. Lee BD, Shin JH, VanKampen J, Petrucelli L, West AB, et al. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease. Nat Med 16: 998–1000. 13. Parisiadou L, Xie C, Cho HJ, Lin X, Gu XL, et al. (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J Neurosci 29: 13971–13980. 14. Plowey ED, Cherra SJ, 3rd, Liu YJ, Chu CT (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105: 1048–1056. 15. Fu H, Subramanian RR, Masters SC (2000) 14-3-3 proteins: structure, function, and regulation. Annu Rev Pharmacol Toxicol 40: 617–647. 16. Yaffe MB, Rittinger K, Volinia S, Caron PR, Aitken A, et al. (1997) The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91: 961–971. 17. Wang H, Zhang L, Liddington R, Fu H (1998) Mutations in the hydrophobic surface of an amphipathic groove of 14-3-3zeta disrupt its interaction with Raf-1 kinase. J Biol Chem 273: 16297–16304. 18. Jin Y, Dai MS, Lu SZ, Xu Y, Luo Z, et al. (2006) 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation. EMBO J 25: 1207–1218. 19. Darling DL, Yingling J, Wynshaw-Boris A (2005) Role of 14-3-3 proteins in eukaryotic signaling and development. Curr Top Dev Biol 68: 281–315. 20. Braselmann S, McCormick F (1995) Bcr and Raf form a complex in vivo via 14- 3-3 proteins. EMBO J 14: 4839–4848. 21. Li X, Patel JC, Wang J, Avshalumov MV, Nicholson C, et al. (2019S) Enhanced striatal dopamine transmission and motor performance with LRRK2 overex- pression in mice is eliminated by familial Parkinson’s disease mutation G2019S. J Neurosci 30: 1788–1797. 22. Ito G, Okai T, Fujino G, Takeda K, Ichijo H, et al. (2007) GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson’s disease. Biochemistry 46: 1380–1388. 23. Daaka Y, Luttrell LM, Lefkowitz RJ (1997) Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. Nature 390: 88–91. 24. Nichols RJ, Dzamko N, Morrice NA, Campbell DG, Deak M, et al. 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson’s disease-associated mutations and regulates cytoplasmic localization. Biochem J 430: 393–404. 25. Dzamko N, Deak M, Hentati F, Reith AD, Prescott AR, et al. 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. 26. Wakui H, Wright AP, Gustafsson J, Zilliacus J (1997) Interaction of the ligand- activated glucocorticoid receptor with the 14-3-3 eta protein. J Biol Chem 272: 8153–8156. Phosphorylation and 14-3-3 Binding of LRRK2 and PD 27. Craparo A, Freund R, Gustafson TA (1997) 14-3-3 (epsilon) interacts with the insulin-like growth factor I receptor and insulin receptor substrate I in a phosphoserine-dependent manner. J Biol Chem 272: 11663–11669. 28. Meller N, Liu YC, Collins TL, Bonnefoy-Berard N, Baier G, et al. (1996) Direct interaction between protein kinase C theta (PKC theta) and 14-3-3 tau in T cells: 14-3-3 overexpression results in inhibition of PKC theta translocation and function. Mol Cell Biol 16: 5782–5791. 29. Yoshida K, Yamaguchi T, Natsume T, Kufe D, Miki Y (2005) JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nat Cell Biol 7: 278–285. 30. Dubois T, Rommel C, Howell S, Steinhussen U, Soneji Y, et al. (1997) 14-3-3 is phosphorylated by casein kinase I on residue 233. Phosphorylation at this site in vivo regulates Raf/14-3-3 interaction. J Biol Chem 272: 28882–28888. 31. Lizcano JM, Morrice N, Cohen P (2000) Regulation of BAD by cAMP- dependent protein kinase is mediated via phosphorylation of a novel site, Ser155. Biochem J 349: 547–557. 32. Feng L, Yunoue S, Tokuo H, Ozawa T, Zhang D, et al. (2004) PKA phosphorylation and 14-3-3 interaction regulate the function of neurofibroma- tosis type I tumor suppressor, neurofibromin. FEBS Lett 557: 275–282. 33. Palmer D, Jimmo SL, Raymond DR, Wilson LS, Carter RL, et al. (2007) Protein kinase A phosphorylation of human phosphodiesterase 3B promotes 14- 3-3 protein binding and inhibits phosphatase-catalyzed inactivation. J Biol Chem 282: 9411–9419. 34. Thomas D, Guthridge M, Woodcock J, Lopez A (2005) 14-3-3 protein signaling in development and growth factor responses. Curr Top Dev Biol 67: 285–303. 35. Kaeser PS, Kwon HB, Blundell J, Chevaleyre V, Morishita W, et al. (2008) RIM1alpha phosphorylation at serine-413 by protein kinase A is not required for presynaptic long-term plasticity or learning. Proc Natl Acad Sci U S A 105: 14680–14685. 36. Lonart G, Schoch S, Kaeser PS, Larkin CJ, Sudhof TC, et al. (2003) Phosphorylation of RIM1alpha by PKA triggers presynaptic long-term potentiation at cerebellar parallel fiber synapses. Cell 115: 49–60. 37. Wolf ME, Mangiavacchi S, Sun X (2003) Mechanisms by which dopamine receptors may influence synaptic plasticity. Ann N Y Acad Sci 1003: 241–249. 38. Svenningsson P, Nishi A, Fisone G, Girault JA, Nairn AC, et al. (2004) DARPP- 32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol 44: 269–296. 39. Melrose HL, Dachsel JC, Behrouz B, Lincoln SJ, Yue M, et al. Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol Dis 40: 503–517. 40. Tong Y, Pisani A, Martella G, Karouani M, Yamaguchi H, et al. (2009) R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proc Natl Acad Sci U S A 106: 14622–14627. 41. Li Y, Liu W, Oo TF, Wang L, Tang Y, et al. (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson’s disease. Nat Neurosci 12: 826–828. 42. Wang QJ, Ding Y, Kohtz DS, Mizushima N, Cristea IM, et al. (2006) Induction of autophagy in axonal dystrophy and degeneration. J Neurosci 26: 8057–8068. 43. Cheng Z, Tang Y, Chen Y, Kim S, Liu H, et al. (2009) Molecular characterization of propionyllysines in non-histone proteins. Mol Cell Proteo- mics 8: 45–52. 44. Olsen JV, de Godoy LM, Li G, Macek B, Mortensen P, et al. (2005) Parts per million mass accuracy on an Orbitrap mass spectrometer via lock mass injection into a C-trap. Mol Cell Proteomics 4: 2010–2021. 45. Chen Y, Kwon SW, Kim SC, Zhao Y (2005) Integrated approach for manual evaluation of peptides identified by searching protein sequence databases with tandem mass spectra. J Proteome Res 4: 998–1005. PLoS ONE | www.plosone.org 13 March 2011 | Volume 6 | Issue 3 | e17153