Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118-2526, USA.
J Neurochem. 2010 Mar;112(6):1593-604. doi: 10.1111/j.1471-4159.2010.06568.x. Epub 2010 Jan 7.
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.
LRRK2 基因突变是导致迟发性帕金森病的常见原因。在这里，我们表明 LRRK2 与 MAPK 激酶（MKK）3、6 和 7 结合，并且 LRRK2 能够磷酸化 MKK3、6 和 7。LRRK2 和 MKK6 的过表达使每种蛋白质的稳态水平超过单独过表达任何一种蛋白质时的观察水平。共表达使 MKK6 在膜中的表达水平高于细胞质中的表达水平。LRRK2 和 MKK6 的过度表达需要 MKK6 活性。与疾病相关的 LRRK2 突变 G2019S、R1441C 和 I2020T 增强了 LRRK2 与 MKK6 的结合。这一相互作用在秀丽隐杆线虫的体内研究中得到了进一步支持。秀丽隐杆线虫中 MKK6 或 p38、sek-1 和 pmk-1 的内源性同源物的 RNAi 敲低消除了 LRRK2 介导的对线粒体应激的保护作用。这些结果通过在秀丽隐杆线虫中缺失 sek-1 得到了证实。这些数据表明 MKK 和 LRRK2 在相似的生物学途径中发挥作用，并支持 LRRK2 在调节细胞应激反应中的作用。
