Catozzi S, Sepulchre J-A
Institut de Physique de Nice UMR 7010, Université Côte d'Azur, CNRS, 1361 route des lucioles, 06560, Valbonne Sophia Antipolis, France.
Bull Math Biol. 2017 Aug;79(8):1691-1735. doi: 10.1007/s11538-017-0296-z. Epub 2017 Jun 28.
In living organisms, cascades of covalent modification cycles are one of the major intracellular signaling mechanisms, allowing to transduce physical or chemical stimuli of the external world into variations of activated biochemical species within the cell. In this paper, we develop a novel method to study the stimulus-response of signaling cascades and overall the concept of pathway activation profile which is, for a given stimulus, the sequence of activated proteins at each tier of the cascade. Our approach is based on a correspondence that we establish between the stationary states of a cascade and pieces of orbits of a 2D discrete dynamical system. The study of its possible phase portraits in function of the biochemical parameters, and in particular of the contraction/expansion properties around the fixed points of this discrete map, as well as their bifurcations, yields a classification of the cascade tiers into three main types, whose biological impact within a signaling network is examined. In particular, our approach enables to discuss quantitatively the notion of cascade amplification/attenuation from this new perspective. The method allows also to study the interplay between forward and "retroactive" signaling, i.e., the upstream influence of an inhibiting drug bound to the last tier of the cascade.
在活生物体中，共价修饰循环级联是主要的细胞内信号传导机制之一，它能将外部世界的物理或化学刺激转化为细胞内活化生化物种的变化。在本文中，我们开发了一种新方法来研究信号级联的刺激响应以及通路激活谱的整体概念，对于给定的刺激，通路激活谱是级联各层上活化蛋白的序列。我们的方法基于我们在级联的稳态与二维离散动力系统的轨道片段之间建立的对应关系。研究其可能的相图作为生化参数的函数，特别是该离散映射不动点周围的收缩/扩张特性及其分岔，可将级联层分为三种主要类型，并研究了它们在信号网络中的生物学影响。特别是，我们的方法能够从这个新角度定量地讨论级联放大/衰减的概念。该方法还允许研究正向和“逆向”信号传导之间的相互作用，即与级联最后一层结合的抑制药物的上游影响。
