A New Cytosolic Pathway from a Parkinson Disease-associated Kinase, BRPK/PINK1 ACTIVATION OF AKT VIA MTORC2
A New Cytosolic Pathway from a Parkinson Disease-associated Kinase, BRPK/PINK1 ACTIVATION OF AKT VIA MTORC2
复制标题
DOI：
10.1074/jbc.m110.179390
复制
发表时间：
2011-03-04
影响因子：
4.8
通讯作者：
Huh, Nam-ho
中科院分区：
文献类型：
--
作者：
Murata, Hitoshi;Sakaguchi, Masakiyo;Huh, Nam-ho
越来越多的证据表明，线粒体功能障碍是帕金森病的共同特征。家族性帕金森病相关基因BRPK/PINK 1（PINK 1）的功能丧失导致线粒体功能恶化和最终的神经元细胞死亡。线粒体伴侣蛋白已被证明是PINK 1激酶活性的底物。在这项研究中，我们证明了PINK 1在细胞质中有另一个作用点。PINK 1的过表达增强了Akt在Ser-473的磷酸化，Akt的激活对于保护SH-SY 5 Y细胞免受各种细胞毒性剂（包括氧化应激）的影响至关重要。Akt磷酸化的增强不是由于磷脂酰肌醇3-激酶的激活，而是由于PINK 1激活了哺乳动物雷帕霉素复合物靶蛋白2（mTORC 2）。Rictor是mTORC 2的特异性组分，通过PINK 1的过表达而磷酸化。此外，PINK 1的过表达增强了细胞运动性。这些结果表明，PINK 1不仅在线粒体中发挥其细胞保护功能，而且通过激活mTORC 2在细胞质中发挥其细胞保护功能。
Accumulating evidence indicates that dysfunction of mitochondria is a common feature of Parkinson disease. Functional loss of a familial Parkinson disease-linked gene, BRPK/PINK1 (PINK1), results in deterioration of mitochondrial functions and eventual neuronal cell death. A mitochondrial chaperone protein has been shown to be a substrate of PINK1 kinase activity. In this study, we demonstrated that PINK1 has another action point in the cytoplasm. Phosphorylation of Akt at Ser-473 was enhanced by overexpression of PINK1, and the Akt activation was crucial for protection of SH-SY5Y cells from various cytotoxic agents, including oxidative stress. Enhanced Akt phosphorylation was not due to activation of phosphatidylinositol 3-kinase but due to activation of mammalian target of rapamycin complex 2 (mTORC2) by PINK1. Rictor, a specific component of mTORC2, was phosphorylated by overexpression of PINK1. Furthermore, overexpression of PINK1 enhanced cell motility. These results indicate that PINK1 exerts its cytoprotective function not only in mitochondria but also in the cytoplasm through activation of mTORC2.