Larhammar Martin, Huntwork-Rodriguez Sarah, Rudhard York, Sengupta-Ghosh Arundhati, Lewcock Joseph W
Department of Neuroscience, Genentech, Inc., San Francisco, California 94080.
Denali Therapeutics Inc., South San Francisco, California 94080.
J Neurosci. 2017 Nov 15;37(46):11074-11084. doi: 10.1523/JNEUROSCI.0905-17.2017. Epub 2017 Oct 9.
The c-Jun--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. Neuronal degeneration occurs in disparate circumstances: during development to refine neuronal connections, after injury to clear damaged neurons, or pathologically during disease. The dual leucine zipper kinase (DLK)/c-Jun--terminal kinase (JNK) pathway represents a conserved regulator of neuronal injury signaling that drives both neurodegeneration and axon regeneration, yet little is known about the factors that initiate DLK activity. Here, we uncover a novel role for a subfamily of MAP4 kinases consisting of MAP4K4, Traf2- and Nck-interacting kinase (TNIK or MAP4K7), and misshapen-like kinase 1 (MINK1 or MAP4K6) in regulating DLK/JNK signaling in neurons. Inhibition of these MAP4Ks blocks stress-induced retrograde JNK signaling and protects from neurodegeneration, suggesting that these kinases may represent attractive therapeutic targets.
c-Jun末端激酶（JNK）信号通路调节神经系统发育、轴突再生以及急性损伤后或慢性神经退行性疾病中的神经元变性。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途径活性的因素仍不清楚。在本研究中，我们确定了丝氨酸/苏氨酸激酶MAP4K4、类畸形激酶1（MINK1或MAP4K6）和Traf2与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。使用基于营养因子剥夺的雄性和雌性胚胎小鼠背根神经节神经元神经退行性变模型，我们发现MAP4K4、MINK1和TNIK发挥冗余作用，以调节DLK激活以及应激反应中c-Jun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种，足以有效保护神经元免于变性。对MAP4Ks的药理学抑制会阻断轴突内DLK的稳定和磷酸化以及随后JNK信号复合物向细胞核的逆行转运。这些结果将MAP4Ks定位为DLK/JNK信号通路的重要调节因子。神经元变性发生在不同的情况下：在发育过程中以优化神经元连接，损伤后清除受损神经元，或在疾病过程中发生病理性变化。双亮氨酸拉链激酶（DLK）/c-Jun末端激酶（JNK）途径代表了一种保守的神经元损伤信号调节因子，它驱动神经退行性变和轴突再生，但对于启动DLK活性的因素知之甚少。在这里，我们揭示了由MAP4K4、Traf2与Nck相互作用激酶（TNIK或MAP4K7）和类畸形激酶1（MINK1或MAP4K6）组成的MAP4激酶亚家族在调节神经元中DLK/JNK信号传导方面的新作用。抑制这些MAP4Ks可阻断应激诱导的逆行JNK信号传导并防止神经退行性变，表明这些激酶可能是有吸引力的治疗靶点。
