Shin Sung-Young, Rath Oliver, Choo Sang-Mok, Fee Frances, McFerran Brian, Kolch Walter, Cho Kwang-Hyun
Department of Bio and Brain Engineering and KI for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
J Cell Sci. 2009 Feb 1;122(Pt 3):425-35. doi: 10.1242/jcs.036319.
The Ras-Raf-MEK-ERK pathway (or ERK pathway) is an important signal transduction system involved in the control of cell proliferation, survival and differentiation. However, the dynamic regulation of the pathway by positive- and negative-feedback mechanisms, in particular the functional role of Raf kinase inhibitor protein (RKIP) are still incompletely understood. RKIP is a physiological endogenous inhibitor of MEK phosphorylation by Raf kinases, but also participates in a positive-feedback loop in which ERK can inactivate RKIP. The aim of this study was to elucidate the hidden dynamics of these feedback mechanisms and to identify the functional role of RKIP through combined efforts of biochemical experiments and in silico simulations based on an experimentally validated mathematical model. We show that the negative-feedback loop from ERK to SOS plays a crucial role in generating an oscillatory behavior of ERK activity. The positive-feedback loop in which ERK functionally inactivates RKIP also enhances the oscillatory activation pattern of ERK. However, RKIP itself has an important role in inducing a switch-like behavior of MEK activity. When overexpressed, RKIP also causes delayed and reduced responses of ERK. Thus, positive- and negative-feedback loops and RKIP work together to shape the response pattern and dynamical characteristics of the ERK pathway.
Ras-Raf-MEK-ERK信号通路（或ERK信号通路）是一个重要的信号转导系统，参与细胞增殖、存活和分化的调控。然而，该信号通路通过正反馈和负反馈机制进行的动态调控，尤其是Raf激酶抑制蛋白（RKIP）的功能作用，目前仍未完全明确。RKIP是一种生理性内源性抑制剂，可抑制Raf激酶对MEK的磷酸化作用，但它也参与一个正反馈回路，在此回路中ERK可使RKIP失活。本研究的目的是通过生化实验和基于经实验验证的数学模型的计算机模拟相结合的方法，阐明这些反馈机制的潜在动态变化，并确定RKIP的功能作用。我们发现，从ERK到SOS的负反馈回路在产生ERK活性的振荡行为中起着关键作用。ERK使RKIP功能失活的正反馈回路也增强了ERK的振荡激活模式。然而，RKIP本身在诱导MEK活性的开关样行为中具有重要作用。当RKIP过表达时，它还会导致ERK的反应延迟和减弱。因此，正反馈和负反馈回路以及RKIP共同作用，塑造了ERK信号通路的反应模式和动态特征。
