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


RESULTS
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
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.
Department of Medical Genetics, Institute of Human Genetics, University of Tuebingen, Tuebingen, Germany.
Karina
K
Haebig
Christian Johannes
CJ
Gloeckner
Marta Garcia
MG
Miralles
Frank
F
Gillardon
Claudia
C
Schulte
Olaf
O
Riess
Marius
M
Ueffing
Saskia
S
Biskup
Michael
M
Bonin
D002460:Cell Line; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors
C576606:ARHGEF7 protein, human; D020662:Guanine Nucleotide Exchange Factors; D011994:Recombinant Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases