Evidence for a role of mixed lineage kinases in neuronal apoptosis
Evidence for a role of mixed lineage kinases in neuronal apoptosis
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DOI：
10.1523/jneurosci.21-14-04949.2001
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发表时间：
2001-07-15
影响因子：
5.3
通讯作者：
Bazenet, CE
中科院分区：
文献类型：
--
作者：
Mota, M;Reeder, M;Bazenet, CE
当缺乏神经生长因子（NGF）时，颈上神经节（SCG）交感神经元会因细胞凋亡而死亡。先前已表明，NGF 撤除时诱导这些神经元凋亡需要小 GTP 结合蛋白 Cdc42 的活性和 c-Jun N 末端激酶 (JNK) 途径的激活。混合谱系激酶 3 (MLK3) 属于丝裂原激活蛋白 (MAP) 激酶激酶家族。 MLK3 包含 Cdc42/Rac 交互结合 (CRIB) 结构域，并激活 JNK 和 p38 MAP 激酶通路。在本研究中，研究了 MLK3 在诱导交感神经元凋亡中的作用。活性 MLK3 的过度表达会诱导 JNK 通路的激活和 SCG 神经元的凋亡。此外，MLK3 激酶死亡突变体的过度表达可阻断 NGF 剥夺诱导的细胞凋亡和 c-Jun 磷酸化。更重要的是，在分化的 PC12 细胞和 SCG 神经元中，NGF 撤除后 5 小时，MLK3 活性似乎增加。我们还表明 MLK3 位于神经元死亡途径中 Cdc42 的下游。神经元中 MLK3 的调节似乎依赖于 MLK3 活性，并且可能依赖于额外的细胞成分，但不依赖于其与 Cdc42 的结合。这些结果表明 MLK3 或一种密切相关的激酶是 NGF 撤除诱导的 Cdc42-c-Jun 通路激活和神经元死亡的生理元件。因此，MLK3 可能成为许多涉及神经元凋亡的神经退行性疾病的一个有趣的治疗靶点。
Superior cervical ganglion (SCG) sympathetic neurons die by apoptosis when deprived of nerve growth factor (NGF). It has been shown previously that the induction of apoptosis in these neurons at NGF withdrawal requires both the activity of the small GTP-binding protein Cdc42 and the activation of the c-Jun N-terminal kinase (JNK) pathway. The mixed lineage kinase 3 (MLK3) belongs to a family of mitogen-activated protein (MAP) kinase kinase kinases. MLK3 contains a Cdc42/Rac interactive-binding (CRIB) domain and activates both the JNK and the p38 MAP kinase pathways. In this study the role of MLK3 in the induction of apoptosis in sympathetic neurons has been investigated. Overexpression of an active MLK3 induces activation of the JNK pathway and apoptosis in SCG neurons. In addition, overexpression of kinase dead mutants of MLK3 blocks apoptosis as well as c-Jun phosphorylation induced by NGF deprivation. More importantly, MLK3 activity seems to increase by 5 hr after NGF withdrawal in both differentiated PC12 cells and SCG neurons. We also show that MLK3 lies downstream of Cdc42 in the neuronal death pathway. Regulation of MLK3 in neurons seems to be dependent on MLK3 activity and possibly on an additional cellular component, but not on its binding to Cdc42. These results suggest that MLK3, or a closely related kinase, is a physiological element of NGF withdrawal-induced activation of the Cdc42-c-Jun pathway and neuronal death. MLK3 therefore could be an interesting therapeutic target in a number of neurodegenerative diseases involving neuronal apoptosis.