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ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2.
PLoS ONE 5:e13762 (2010)
Background: Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial and sporadic Parkinson's disease. The multidomain protein LRRK2 exhibits overall low GTPase and kinase activity in vitro. Methodology/Principal Findings: Here, we show that the rho guanine nucleotide exchange factor ARHGEF7 and the small GTPase CDC42 are interacting with LRRK2 in vitro and in vivo. GTPase activity of full-length LRRK2 increases in the presence of recombinant ARHGEF7. Interestingly, LRRK2 phosphorylates ARHGEF7 in vitro at previously unknown phosphorylation sites. We provide evidence that ARHGEF7 might act as a guanine nucleotide exchange factor for LRRK2 and that R1441C mutant LRRK2 with reduced GTP hydrolysis activity also shows reduced binding to ARHGEF7. Conclusions/Significance: Downstream effects of phosphorylation of ARHGEF7 through LRRK2 could be (i) a feedback control mechanism for LRRK2 activity as well as (ii) an impact of LRRK2 on actin cytoskeleton regulation. A newly identified familial mutation N1437S, localized within the GTPase domain of LRRK2, further underlines the importance of the GTPase domain of LRRK2 in Parkinson's disease pathogenesis.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
FAMILIAL PARKINSONS-DISEASE; LEUCINE-RICH-REPEAT-KINASE-2 LRRK2; NEURONAL TOXICITY; SH-SY5Y CELLS; GTP-BINDING; MUTATIONS; GENE; PROTEIN; TANDEM; DOMAIN
Language
english
Publication Year
2010
HGF-reported in Year
2010
ISSN (print) / ISBN
1932-6203
Journal
PLoS ONE
Quellenangaben
Volume: 5,
Issue: 10,
Article Number: e13762
Publisher
Public Library of Science (PLoS)
Publishing Place
Lawrence, Kan.
Reviewing status
Peer reviewed
Institute(s)
CF Metabolomics & Proteomics (CF-MPC)
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Enabling and Novel Technologies
PSP Element(s)
G-505700-001
PubMed ID
21048939
WOS ID
000283645300040
Scopus ID
78149446290
Erfassungsdatum
2010-12-03