The c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

中文翻译：

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JNK信号：基于复杂蛋白质-蛋白质伙伴关系的调控和功能。

作为有丝分裂原活化蛋白激酶（MAPK）家族成员的c-Jun N端激酶（JNKs）介导真核细胞对多种非生物和生物应激损伤的反应。JNK通过影响基因表达，细胞骨架蛋白动力学和细胞死亡/存活途径，还调节重要的生理过程，包括神经元功能，免疫作用和胚胎发育。尽管JNK途径已经研究了20多年，但是其复杂性仍然令人困惑，JNK的多个蛋白伴侣是作用多样性的基础。在这里，我们回顾了JNK结构和同工型以及JNK与一系列细胞内蛋白的伙伴关系的当前知识。这些蛋白质中有许多是JNK的直接底物。我们根据JNK对它们的调控，在它们的分类框架内详细分析了这些靶蛋白中的近100种。这些JNK底物的例子包括各种各样的核转录因子（Jun，ATF2，Myc，Elk1），参与细胞骨架调节的细胞质蛋白（DCX，Tau，WDR62）或囊泡转运（JIP1，JIP3），细胞膜受体（BMPR2） ）和线粒体蛋白（Mcl1，Bim）。此外，由于上游信号传导成分会影响JNK活性，因此我们严格评估了信号传导支架的参与以及JNK途径中反馈机制的作用。尽管在过去的十年中澄清了JNK依赖性信号传导中的许多调控事件，但许多其他结构和机制的见解才刚刚开始被揭示。