Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Int J Mol Sci. 2023 Aug 31;24(17):13527. doi: 10.3390/ijms241713527.
The response of cells to extracellular signals is mediated by a variety of intracellular signaling pathways that determine stimulus-dependent cell fates. One such pathway is the cJun-N-terminal Kinase (JNK) cascade, which is mainly involved in stress-related processes. The cascade transmits its signals via a sequential activation of protein kinases, organized into three to five tiers. Proper regulation is essential for securing a proper cell fate after stimulation, and the mechanisms that regulate this cascade may involve the following: (1) Activatory or inhibitory phosphorylations, which induce or abolish signal transmission. (2) Regulatory dephosphorylation by various phosphatases. (3) Scaffold proteins that bring distinct components of the cascade in close proximity to each other. (4) Dynamic change of subcellular localization of the cascade's components. (5) Degradation of some of the components. In this review, we cover these regulatory mechanisms and emphasize the mechanism by which the JNK cascade transmits apoptotic signals. We also describe the newly discovered PP2A switch, which is an important mechanism for JNK activation that induces apoptosis downstream of the Gq protein coupled receptors. Since the JNK cascade is involved in many cellular processes that determine cell fate, addressing its regulatory mechanisms might reveal new ways to treat JNK-dependent pathologies.
细胞对外界信号的反应是由多种细胞内信号通路介导的，这些通路决定了刺激依赖性的细胞命运。其中一种途径是 cJun-N 末端激酶 (JNK) 级联反应，它主要参与应激相关过程。级联通过蛋白激酶的顺序激活来传递信号，这些激酶组织成三到五个层次。在刺激后确保适当的细胞命运，适当的调节是必不可少的，调节这个级联的机制可能包括以下几点：(1)激活或抑制磷酸化，诱导或消除信号传递。(2)各种磷酸酶的调节去磷酸化。(3)支架蛋白将级联的不同成分紧密地聚集在一起。(4)级联成分的亚细胞定位的动态变化。(5)一些成分的降解。在这篇综述中，我们涵盖了这些调节机制，并强调了 JNK 级联传递凋亡信号的机制。我们还描述了新发现的 PP2A 开关，这是 JNK 激活的一个重要机制，它在 Gq 蛋白偶联受体下游诱导凋亡。由于 JNK 级联参与了许多决定细胞命运的细胞过程，研究其调节机制可能会揭示出治疗 JNK 依赖性疾病的新方法。
