LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: Impairment of the kinase activity by Parkinson's disease-associated mutations
LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: Impairment of the kinase activity by Parkinson's disease-associated mutations
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DOI：
10.1016/j.febslet.2011.05.044
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发表时间：
2011-07-21
期刊：
影响因子：
3.5
通讯作者：
Obata, Fumiya
中科院分区：
文献类型：
--
作者：
Ohta, Etsuro;Kawakami, Fumitaka;Obata, Fumiya
LRRK2是常染色体显性遗传家族性帕金森病的致病分子，尽管其真正的功能，包括其生理底物，仍然未知。在这里，使用重组蛋白的体外激酶测定，我们首次证明了LRRK2直接磷酸化Akt1，这是一种参与细胞存活和预防凋亡的信号转导的中心分子。Ser473是激活Akt1所必需的两个氨基酸之一，是LRRK2的靶位点。使用完整细胞的敲除实验也证明了LRRK2介导的Akt1磷酸化（Ser473），表明Akt1是LRRK2的生理底物的令人信服的候选者。与疾病相关的突变R1441C、G2019S和I2020T表现出与Akt1的相互作用和Akt1的磷酸化减少，提示了LRRK2突变引起神经退行性变的一种可能机制。蛋白质相互作用的结构化总结：通过蛋白激酶测定，LRRK2磷酸化Akt1（查看相互作用1，2，3）。通过蛋白激酶测定，LRRK2磷酸化MBP（查看相互作用1，2）。LRRK2通过下拉结合Akt1（查看相互作用1，2，3）。(C)2011年欧洲生物化学学会联合会。Elsevier B.V.出版，保留所有权利。
LRRK2 is the causal molecule for autosomal-dominant familial Parkinson's disease, although its true function, including its physiological substrates, remains unknown. Here, using in vitro kinase assay with recombinant proteins, we demonstrated for the first time that LRRK2 directly phosphorylates Akt1, a central molecule involved in signal transduction for cell survival and prevention of apoptosis. Ser473, one of two amino acids essential for Akt1 activation, was the target site for LRRK2. A knockdown experiment using intact cells also demonstrated LRRK2-mediated phosphorylation of Akt1 (Ser473), suggesting that Akt1 is a convincing candidate for the physiological substrate of LRRK2. The disease-associated mutations, R1441C, G2019S, and I2020T, exhibited reduced interaction with, and phosphorylation of, Akt1, suggesting one possible mechanism for the neurodegeneration caused by LRRK2 mutations.Structured summary of protein interactions:LRRK2 phosphorylates Akt1 by protein kinase assay (View Interaction 1, 2, 3).LRRK2 phosphorylates MBP by protein kinase assay (View Interaction 1, 2).LRRK2 binds to Akt1 by pull down (View Interaction 1, 2, 3). (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.