MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are prevalent causes of late-onset Parkinson's disease. Here, we show that LRRK2 binds to MAPK kinases (MKK) 3, 6, and 7, and that LRRK2 is able to phosphorylate MKK3, 6 and 7. Over-expression of LRRK2 and MKK6 increased the steady state levels of each protein beyond that observed with over-expression of either protein alone. Co-expression increased levels of MKK6 in the membrane more than in the cytoplasm. The increased expression of LRRK2 and MKK6 requires MKK6 activity. The disease-linked LRRK2 mutations, G2019S, R1441C and I2020T, enhance binding of LRRK2 to MKK6. This interaction was further supported by in vivo studies in C. elegans. RNAi knockdown in C. elegans of the endogenous orthologs for MKK6 or p38, sek-1 and pmk-1, abolishes LRRK2-mediated protection against mitochondrial stress. These results were confirmed by deletion of sek-1 in C. elegans. These data demonstrate that MKKs and LRRK2 function in similar biological pathways, and support a role for LRRK2 in modulating the cellular stress response.
Hsu
Cindy H
CH
Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118-2526, USA.
Chan
Diane
D
Greggio
Elisa
E
Saha
Shamol
S
Guillily
Maria D
MD
Ferree
Andrew
A
Raghavan
Kesav
K
Shen
Grace C
GC
Segal
Lilach
L
Ryu
Hoon
H
Cookson
Mark R
MR
Wolozin
Benjamin
B
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D017173:Caenorhabditis elegans; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D007306:Insecticides / Q000633:toxicity; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism*; D009026:Mortality; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D012402:Rotenone / Q000633:toxicity; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection / Q000379:methods
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; C501232:IRKI protein, Arabidopsis; D007306:Insecticides; D012402:Rotenone; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human