The combination of positive and negative feedback loops confers exquisite flexibility to biochemical switches
The combination of positive and negative feedback loops confers exquisite flexibility to biochemical switches
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DOI：
10.1088/1478-3975/6/4/046013
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发表时间：
2009-12-01
期刊：
影响因子：
2
通讯作者：
Kaneko, Kunihiko
中科院分区：
文献类型：
--
作者：
Pfeuty, Benjamin;Kaneko, Kunihiko
广泛的细胞过程需要分子调节途径将分级信号转换为离散响应。一种普遍的切换机制依赖于由正反馈调节引起的两个稳定状态（双稳态）的共存。有趣的是，正反馈通常会辅以负反馈，这就提出了一个问题：这两种反馈是否以及如何合作来控制离散的细胞反应。为了解决这个问题，我们制定了一个典型的蛋白质-蛋白质相互作用网络模型，并分析了一个原型的两个组件电路的动力学。负反馈回路和正反馈回路的适当组合可以使振荡电路接近振荡状态。值得注意的是，急剧激活的负反馈可以产生一个稳定的制度，其中两个稳定的不动点共存，并可能与两个鞍点成对碰撞。发现这种特定类型的双稳态允许单独且灵活地控制接通和关断事件，例如（i）联合收割机结合快速和可逆的转变，（ii）实现瞬时切换响应和（iii）显示可调的噪声诱导转变率。最后，我们讨论的相关性，这种开关行为，电路拓扑结构考虑，特定的生物过程，如适应性代谢反应，随机命运的决定和细胞周期的转变。综上所述，我们的研究结果表明，积极和消极的反馈回路合作，以推动灵活的和多方面的切换行为在生物系统中出现的一种有效的机制。
A wide range of cellular processes require molecular regulatory pathways to convert a graded signal into a discrete response. One prevalent switching mechanism relies on the coexistence of two stable states (bistability) caused by positive feedback regulations. Intriguingly, positive feedback is often supplemented with negative feedback, raising the question of whether and how these two types of feedback can cooperate to control discrete cellular responses. To address this issue, we formulate a canonical model of a protein-protein interaction network and analyze the dynamics of a prototypical two-component circuit. The appropriate combination of negative and positive feedback loops can bring a bistable circuit close to the oscillatory regime. Notably, sharply activated negative feedback can give rise to a bistable regime wherein two stable fixed points coexist and may collide pairwise with two saddle points. This specific type of bistability is found to allow for separate and flexible control of switch-on and switch-off events, for example (i) to combine fast and reversible transitions, (ii) to enable transient switching responses and (iii) to display tunable noise-induced transition rates. Finally, we discuss the relevance of such bistable switching behavior, and the circuit topologies considered, to specific biological processes such as adaptive metabolic responses, stochastic fate decisions and cell-cycle transitions. Taken together, our results suggest an efficient mechanism by which positive and negative feedback loops cooperate to drive the flexible and multifaceted switching behaviors arising in biological systems.