ARHGEF7 (BETA-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2

Abstract

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 action 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. © 2010 Haebig et al.