Neurodegeneration Laboratories, Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA.
J Cell Biol. 2011 Sep 5;194(5):751-64. doi: 10.1083/jcb.201103153.
The c-Jun N-terminal kinase (JNK) signaling pathway is essential for neuronal degeneration in multiple contexts but also regulates neuronal homeostasis. It remains unclear how neurons are able to dissociate proapoptotic JNK signaling from physiological JNK activity. In this paper, we show that the mixed lineage kinase dual leucine zipper kinase (DLK) selectively regulates the JNK-based stress response pathway to mediate axon degeneration and neuronal apoptosis without influencing other aspects of JNK signaling. This specificity is dependent on interaction of DLK with the scaffolding protein JIP3 to form a specialized JNK signaling complex. Local activation of DLK-based signaling in the axon results in phosphorylation of c-Jun and apoptosis after redistribution of JNK to the cell body. In contrast, regulation of axon degeneration by DLK is c-Jun independent and mediated by distinct JNK substrates. DLK-null mice displayed reduced apoptosis in multiple neuronal populations during development, demonstrating that prodegenerative DLK signaling is required in vivo.
c-Jun N-末端激酶（JNK）信号通路对于多种情况下的神经元变性至关重要，但也调节神经元的内稳态。目前尚不清楚神经元如何将促凋亡的 JNK 信号与生理 JNK 活性区分开来。在本文中，我们表明混合谱系激酶双亮氨酸拉链激酶（DLK）选择性调节基于 JNK 的应激反应途径，以介导轴突变性和神经元凋亡，而不影响 JNK 信号的其他方面。这种特异性取决于 DLK 与支架蛋白 JIP3 的相互作用，以形成专门的 JNK 信号复合物。在轴突中局部激活基于 DLK 的信号导致 c-Jun 的磷酸化，并在 JNK 重新分布到细胞体后发生细胞凋亡。相比之下，DLK 调节的轴突变性不依赖于 c-Jun，而是由不同的 JNK 底物介导。在发育过程中，DLK 缺失小鼠的多种神经元群中的细胞凋亡减少，表明体内需要促变性的 DLK 信号。
Zotero 插件
