Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, USA.
Biophys J. 2013 Jul 2;105(1):231-41. doi: 10.1016/j.bpj.2013.05.013.
The transcription factor NFκB, a key component of the immune system, shows intricate stimulus-specific temporal dynamics. Those dynamics are thought to play a role in controlling the physiological response to cytokines and pathogens. Biochemical evidence suggests that the NFκB inducing kinase, IKK, a signaling hub onto which many signaling pathways converge, is regulated via a regulatory cycle comprising a poised, an active, and an inactive state. We hypothesize that it operates as a modulator of signal dynamics, actively reshaping the signals generated at the receptor proximal level. Here we show that a regulatory cycle can function in at least three dynamical regimes, tunable by regulating a single kinetic parameter. In particular, the simplest three-state regulatory cycle can generate signals with two well-defined phases, each with distinct coding capabilities in terms of the information they can carry about the stimulus. We also demonstrate that such a kinase cycle can function as a signal categorizer classifying diverse incoming signals into outputs with a limited set of temporal activity profiles. Finally, we discuss the extension of the results to other regulatory motifs that could be understood in terms of the regimes of the three-state cycle.
转录因子 NFκB 是免疫系统的关键组成部分，表现出复杂的刺激特异性时间动态。这些动态被认为在控制细胞因子和病原体的生理反应中发挥作用。生化证据表明，NFκB 诱导激酶 IKK 是一个信号枢纽，许多信号途径都汇聚于此，它通过一个包含静止、活跃和非活跃状态的调节循环进行调节。我们假设它作为信号动态的调节剂，主动重塑受体近端水平产生的信号。在这里，我们表明，调节循环至少可以在三种动态状态下发挥作用，通过调节单个动力学参数进行调节。特别是，最简单的三态调节循环可以产生具有两个明确定义相位的信号，每个相位在它们可以携带关于刺激的信息方面都具有不同的编码能力。我们还证明，这种激酶循环可以作为信号分类器，将不同的输入信号分类为具有有限时间活动分布的输出。最后，我们讨论了将结果扩展到其他调节基序的问题，这些基序可以根据三态循环的状态来理解。
