Leucine-rich repeat serine/threonine-protein kinase 2

Definition:

Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, autophagy, and vesicle trafficking. Is a key regulator of RAB GTPases by regulating the GTP/GDP exchange and interaction partners of RABs through phosphorylation. Phosphorylates RAB3A, RAB3B, RAB3C, RAB3D, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43. Regulates the RAB3IP-catalyzed GDP/GTP exchange for RAB8A through the phosphorylation of 'Thr-72' on RAB8A. Inhibits the interaction between RAB8A and GDI1 and/or GDI2 by phosphorylating 'Thr-72' on RAB8A. Regulates primary ciliogenesis through phosphorylation of RAB8A and RAB10, which promotes SHH signaling in the brain. Together with RAB29, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose-6-phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner. Regulates neuronal process morphology in the intact central nervous system (CNS). Plays a role in synaptic vesicle trafficking. Plays an important role in recruiting SEC16A to endoplasmic reticulum exit sites (ERES) and in regulating ER to Golgi vesicle-mediated transport and ERES organization. Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes. Phosphorylates PRDX3. By phosphorylating APP on 'Thr-743', which promotes the production and the nuclear translocation of the APP intracellular domain (AICD), regulates dopaminergic neuron apoptosis. Independent of its kinase activity, inhibits the proteosomal degradation of MAPT, thus promoting MAPT oligomerization and secretion. In addition, has GTPase activity via its Roc domain which regulates LRRK2 kinase activity.

References:

[1]. Elena Purlyte, et al. Rab29 activation of the Parkinson's disease-associated LRRK2 kinase. EMBO J. 2018 Jan 4;37(1):1-18. [Content Brief]

[2]. David MacLeod, et al. The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron. 2006 Nov 22;52(4):587-93. [Content Brief]

[3]. Pengfei Zhang, et al. Crystal structure of the WD40 domain dimer of LRRK2. Proc Natl Acad Sci U S A. 2019 Jan 29;116(5):1579-1584. [Content Brief]

[4]. Patrícia Silva Guerreiro, et al. LRRK2 Promotes Tau Accumulation, Aggregation and Release. Mol Neurobiol. 2016 Jul;53(5):3124-3135. [Content Brief]

[5]. Hyun Jin Cho, et al. Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export. EMBO J. 2014 Oct 16;33(20):2314-31. [Content Brief]

[6]. Martin Steger, et al. Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases. Elife. 2016 Jan 29;5:e12813. [Content Brief]

[7]. David A MacLeod, et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron. 2013 Feb 6;77(3):425-39. [Content Brief]

[8]. Herschel S Dhekne, et al. A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. Elife. 2018 Nov 6;7:e40202. [Content Brief]

[9]. Martin Steger, et al. Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. Elife. 2017 Nov 10;6:e31012. [Content Brief]

[10]. Patricia Gómez-Suaga, et al. Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet. 2012 Feb 1;21(3):511-25. [Content Brief]

[11]. Ying Fan, et al. Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils. Biochem J. 2018 Jan 2;475(1):23-44. [Content Brief]

[12]. Dario C Angeles, et al. Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. Hum Mutat. 2011 Dec;32(12):1390-7. [Content Brief]

[13]. Susanne Zach, et al. Signal transduction protein array analysis links LRRK2 to Ste20 kinases and PKC zeta that modulate neuronal plasticity. PLoS One. 2010 Oct 7;5(10):e13191. [Content Brief]

[14]. Giovanni Piccoli, et al. Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain. Mol Cell Biol. 2014 Jun;34(12):2147-61. [Content Brief]

[15]. Zhong-Can Chen, et al. Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease. Sci Signal. 2017 Jul 18;10(488):eaam6790. [Content Brief]

[16]. Junpeng Deng, et al. 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. 2008 Feb 5;105(5):1499-504. [Content Brief]

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