Determinants of cell-to-cell variability in protein kinase signaling.
Determinants of cell-to-cell variability in protein kinase signaling.
复制标题
DOI：
10.1371/journal.pcbi.1003357
复制
发表时间：
2013
影响因子：
4.3
通讯作者：
Legewie S
中科院分区：
文献类型：
--
作者：
Jeschke M;Baumgärtner S;Legewie S
尽管存在内部和外部波动，细胞仍能可靠地感知环境变化，但鲁棒性背后的机制仍不清楚。我们使用分析理论和数值模拟分析了信号蛋白浓度的波动如何引起蛋白激酶信号传导的细胞间变异。我们通过计算通路响应的刺激水平（“通路敏感性”）和强刺激时的最大激活水平来表征信号级联的剂量反应行为。具有逐渐剂量反应行为的最小激酶级联显示出很强的可变性，因为途径敏感性和最大激活水平不能同时保持不变。负反馈调节解决了这种权衡问题，并协调地减少了通路敏感性和最大激活的波动。级联中不同水平的反馈控制剂量反应曲线的不同方面，从而协同减少变异性。我们还研究了更复杂、超灵敏的信号级联，能够做出类似开关的决策，并发现它们对蛋白质浓度波动具有固有的鲁棒性。我们描述了如何主动调节超敏感信号系统的细胞间变异，例如通过改变磷酸酶的表达或通过反馈/前馈循环。我们的计算表明，缓慢的转录负反馈循环可以抑制变异性，同时保持类似开关的决策。综上所述，我们描述了促进鲁棒性的信号级联的设计原则。我们的结果可以解释为什么某些信号级联（如酵母信息素途径）显示出类似开关的决策，且细胞间差异很小。细胞感知周围环境并对细胞外空间中的可溶性因子做出反应。细胞外因子经常诱导异质反应，从而将生物学结果限制于细胞群的一小部分。然而，问题是如何控制这种细胞间的变异性，因为一些细胞系统在特定水平的细胞外刺激下表现出非常均匀的反应。我们得出了一个分析框架来系统地表征转导外部信号的细胞内信号通路的细胞间变异性。我们分析了信号蛋白总浓度波动如何产生异质性，因为这是真核系统变异的主要来源。我们发现信号通路可以是高度可变的或本质上不变的，这取决于级联的动力学参数和结构特征。我们的结果表明，可以通过级联中的负反馈或平行通路之间的信号串扰来减少细胞间的变异性。我们精确定义了负反馈环在变异性抑制中的作用，并表明可以根据级联中的反馈动力学和作用位点来控制剂量反应曲线的不同方面。这项工作构成了系统了解信号转导中细胞间变异性的第一步。
Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell-to-cell variability in protein kinase signaling using analytical theory and numerical simulations. We characterized the dose-response behavior of signaling cascades by calculating the stimulus level at which a pathway responds (‘pathway sensitivity’) and the maximal activation level upon strong stimulation. Minimal kinase cascades with gradual dose-response behavior show strong variability, because the pathway sensitivity and the maximal activation level cannot be simultaneously invariant. Negative feedback regulation resolves this trade-off and coordinately reduces fluctuations in the pathway sensitivity and maximal activation. Feedbacks acting at different levels in the cascade control different aspects of the dose-response curve, thereby synergistically reducing the variability. We also investigated more complex, ultrasensitive signaling cascades capable of switch-like decision making, and found that these can be inherently robust to protein concentration fluctuations. We describe how the cell-to-cell variability of ultrasensitive signaling systems can be actively regulated, e.g., by altering the expression of phosphatase(s) or by feedback/feedforward loops. Our calculations reveal that slow transcriptional negative feedback loops allow for variability suppression while maintaining switch-like decision making. Taken together, we describe design principles of signaling cascades that promote robustness. Our results may explain why certain signaling cascades like the yeast pheromone pathway show switch-like decision making with little cell-to-cell variability. Cells sense their surroundings and respond to soluble factors in the extracellular space. Extracellular factors frequently induce heterogeneous responses, thereby restricting the biological outcome to a fraction of the cell population. However, the question arises how such cell-to-cell variability can be controlled, because some cellular systems show a very homogenous response at a defined level of an extracellular stimulus. We derived an analytical framework to systematically characterize the cell-to-cell variability of intracellular signaling pathways which transduce external signals. We analyzed how heterogeneity arises from fluctuations in the total concentrations of signaling proteins because this is the main source of variability in eukaryotic systems. We find that signaling pathways can be highly variable or inherently invariant, depending on the kinetic parameters and the structural features of the cascade. Our results indicate that the cell-to-cell variability can be reduced by negative feedback in the cascade or by signaling crosstalk between parallel pathways. We precisely define the role of negative feedback loops in variability suppression, and show that different aspects of the dose-response curve can be controlled, depending on the feedback kinetics and site of action in the cascade. This work constitutes a first step towards a systematic understanding of cell-to-cell variability in signal transduction.
登录
查看更多内容
DOI：
10.1016/j.cub.2008.09.027
发表时间：
2008-11-11
期刊：
Current biology : CB
影响因子：
--
作者：
Hilioti Z;Sabbagh W Jr;Paliwal S;Bergmann A;Goncalves MD;Bardwell L;Levchenko A
通讯作者：
Levchenko A
影响因子：
16
作者：
Heinrich, R;Neel, BG;Rapoport, TA
通讯作者：
Rapoport, TA
影响因子：
64.8
作者：
Barkai, N;Leibler, S
通讯作者：
Leibler, S
影响因子：
64.8
作者：
Becskei, A;Serrano, L
通讯作者：
Serrano, L
影响因子：
16
作者：
Hao, Nan;Nayak, Sujata;Dohlman, Henrik G.
通讯作者：
Dohlman, Henrik G.