Junttila Melissa R, Li Song-Ping, Westermarck Jukka
Turku Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
FASEB J. 2008 Apr;22(4):954-65. doi: 10.1096/fj.06-7859rev. Epub 2007 Nov 26.
Mitogen-activated protein kinase (MAPK) pathways constitute a large modular network that regulates a variety of physiological processes, such as cell growth, differentiation, and apoptotic cell death. The function of the ERK pathway has been depicted as survival-promoting, in essence by opposing the proapoptotic activity of the stress-activated c-Jun NH(2)-terminal kinase (JNK)/p38 MAPK pathways. However, recently published work suggests that extracellular regulated kinase (ERK) pathway activity is suppressed by JNK/p38 kinases during apoptosis induction. In this review, we will summarize the current knowledge about JNK/p38-mediated mechanisms that negatively regulate the ERK pathway. In particular, we will focus on phosphatases (PP2A, MKPs) as inhibitors of ERK pathway activity in regulating apoptosis. A model proposed in this review places the negative regulation of the ERK pathway in a central position for the cellular decision-making process that determines whether cells will live or die in response to apoptosis-promoting signals. In addition, we will discuss the potential functional relevance of negative regulation of ERK pathway activity, for physiological and pathological conditions (e.g., cellular transformation).
丝裂原活化蛋白激酶（MAPK）通路构成了一个庞大的模块化网络，可调节多种生理过程，如细胞生长、分化和凋亡性细胞死亡。ERK通路的功能被描述为具有促生存作用，本质上是通过对抗应激激活的c-Jun氨基末端激酶（JNK）/p38 MAPK通路的促凋亡活性来实现的。然而，最近发表的研究表明，在凋亡诱导过程中，细胞外调节激酶（ERK）通路的活性会被JNK/p38激酶抑制。在这篇综述中，我们将总结目前关于JNK/p38介导的对ERK通路进行负调控机制的相关知识。特别是，我们将重点关注作为ERK通路活性抑制剂的磷酸酶（PP2A、MKPs）在调节细胞凋亡中的作用。本综述中提出的一个模型将ERK通路的负调控置于细胞决策过程的中心位置，该过程决定细胞在凋亡促进信号作用下是存活还是死亡。此外，我们还将讨论ERK通路活性负调控在生理和病理条件（如细胞转化）下的潜在功能相关性。
