The Ste20 Family Kinases MAP4K4, MINK1, and TNIK Converge to Regulate Stress-Induced JNK Signaling in Neurons
The Ste20 Family Kinases MAP4K4, MINK1, and TNIK Converge to Regulate Stress-Induced JNK Signaling in Neurons
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DOI：
10.1523/jneurosci.0905-17.2017
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发表时间：
2017-11-15
影响因子：
5.3
通讯作者：
Lewcock, Joseph W.
中科院分区：
文献类型：
--
作者：
Larhammar, Martin;Huntwork-Rodriguez, Sarah;Lewcock, Joseph W.
c-Jun-N 末端激酶 (JNK) 信号通路可调节急性损伤或慢性神经退行性疾病后的神经系统发育、轴突再生和神经元变性。双亮氨酸拉链激酶 (DLK) 是神经元中应激诱导的 JNK 信号传导所必需的，但启动 DLK/JNK 通路活性的因素仍不清楚。在本研究中，我们确定了 Ste20 激酶 MAP4K4、畸形样激酶 1（MINK1 或 MAP4K6）以及 TNIK Traf2 和 Nck 相互作用激酶（TNIK 或 MAP4K7）作为神经元中 DLK/JNK 信号传导的上游调节因子。在雄性和雌性胚胎小鼠背根神经节神经元中使用基于营养因子撤回的神经变性模型，我们发现 MAP4K4、MINK1 和 TNIK 冗余地调节 DLK 激活和 c-Jun 响应应激的下游 JNK 依赖性磷酸化。靶向 MAP4K4、MINK1 和 TNIK，但不是单独靶向这些激酶中的任何一个，足以有效保护神经元免于退化。 MAP4K 的药理抑制可阻断轴突内 DLK 的稳定和磷酸化，以及随后 JNK 信号复合物逆行易位至细胞核。这些结果将 MAP4K 定位为 DLK/JNK 信号通路的重要调节因子。
The c-Jun-N-terminal kinase (JNK) signaling pathway regulates nervous system development, axon regeneration, and neuronal degeneration after acute injury or in chronic neurodegenerative disease. Dual leucine zipper kinase (DLK) is required for stress-induced JNK signaling in neurons, yet the factors that initiate DLK/JNK pathway activity remain poorly defined. In the present study, we identify the Ste20 kinases MAP4K4, misshapen-like kinase 1 (MINK1 or MAP4K6) and TNIK Traf2- and Nck-interacting kinase (TNIK or MAP4K7), as upstream regulators of DLK/JNK signaling in neurons. Using a trophic factor withdrawal-based model of neurodegeneration in both male and female embryonic mouse dorsal root ganglion neurons, we show that MAP4K4, MINK1, and TNIK act redundantly to regulate DLK activation and downstream JNK-dependent phosphorylation of c-Jun in response to stress. Targeting MAP4K4, MINK1, and TNIK, but not any of these kinases individually, is sufficient to protect neurons potently from degeneration. Pharmacological inhibition of MAP4Ks blocks stabilization and phosphorylation of DLK within axons and subsequent retrograde translocation of the JNK signaling complex to the nucleus. These results position MAP4Ks as important regulators of the DLK/JNK signaling pathway.