Exp Neurobiol.  2019 Apr;28(2):134-145. 10.5607/en.2019.28.2.134.

Rab GTPases as Physiological Substrates of LRRK2 Kinase

• Seol W
• Nam D
• Son I

• KMID: 2450209
• DOI: http://doi.org/10.5607/en.2019.28.2.134

Abstract

LRRK2 (Leucine-Rich Repeat Kinase 2) is a gene whose specific mutations cause Parkinson's disease (PD), the most common neurodegenerative movement disorder. LRRK2 harbors GTPase and kinase activities, two enzyme activities that play critical roles in the regulation of cellular signal transduction. Among the several LRRK2 pathogenic mutations, the most prevalent G2019S mutation increases its kinase activity when compared with the wild-type (WT), suggesting that LRRK2 kinase substrates are potential culprits of PD pathogenesis. Although there were several studies to identify LRRK2 kinase substrates, most of them mainly employed in vitro kinase assays. Therefore, it remains uncertain whether the identified substrates were real physiological substrates. However, efforts to determine physiological LRRK2 kinase substrates have recently identified several members of the Rab GTPase family as physiological LRRK2 kinase substrates. A conserved threonine or serine in the switch II domain of certain Rab GTPase family members (Rab3A/B/C/D, Rab5A/B, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) has been pinpointed to be phosphorylated by LRRK2 in cells using sophisticated phosphoproteomics technology in combination with LRRK2-specific kinase inhibitors. The Rab GTPases regulate vesicle trafficking, suggesting that LRRK2 may be a regulator of such vesicle trafficking, confirming previously suggested LRRK2 functions. However, how the consequence of the LRRK2-mediated Rab phosphorylation is related to PD pathogenesis is not clear. This review briefly summarizes the recent results about LRRK2-mediated Rab phosphorylation studies.

Keyword

LRRK2; Rab GTPase; Parkinson's disease; Kinase; Vesicle trafficking

MeSH Terms

Genes, vif
GTP Phosphohydrolases
Humans
In Vitro Techniques
Movement Disorders
Parkinson Disease
Phosphorylation
Phosphotransferases*
rab GTP-Binding Proteins*
Serine
Signal Transduction
Threonine
GTP Phosphohydrolases
Phosphotransferases
Serine
Threonine
rab GTP-Binding Proteins