细胞信号传导中的涌现记忆：级联中持续的适应性动力学可源于弛豫时间尺度的多样性
Emergent memory in cell signaling: Persistent adaptive dynamics in cascades can arise from the diversity of relaxation time-scales
AI总结：
本文通过计算模型揭示MAPK信号级联因组分弛豫速率差异而在刺激撤除后产生持续尖峰和回响，表现出细胞短期记忆，无需反馈或串扰。
摘要：
丝裂原活化蛋白激酶（MAPK）信号级联是一种在所有真核细胞中都存在的进化保守基序，参与协调关键的细胞命运决定、调控蛋白质合成以及介导学习和记忆。虽然该通路在时不变信号刺激下的稳态行为已相对清楚，但我们通过一个计算模型表明，它对刺激变化表现出丰富的瞬态适应性响应库。当信号开启时，响应的特征是在频率和幅度上都出现长时程的调制。在撤除刺激后，活性衰减的时间尺度远长于磷酸化-去磷酸化过程的时间尺度，并表现出以活化MAPK浓度反复尖峰为特征的回响。这种刺激后活性的长期持续表明，即使在没有任何明确反馈或与其他通路串扰的情况下，该级联在信号移除后仍能在相当长的时间内保留对信号的记忆。我们发现，这种行为背后的分子机制与级联不同组分具有不同的弛豫速率有关。这导致级联不同层之间的通量失衡，当活化的激酶从复合物中的隔离状态释放出来时，它们作为酶被反复再利用，从而在刺激移除后引发一次或多次尖峰事件。本文报道的这种持续适应性响应表明细胞具有“短期”记忆，提示这一普遍存在的信号通路在真核细胞信息处理中发挥着更为核心的作用。
英文摘要：
The mitogen-activated protein kinase (MAPK) signaling cascade, an evolutionarily conserved motif present in all eukaryotic cells, is involved in coordinating critical cell-fate decisions, regulating protein synthesis, and mediating learning and memory. While the steady-state behavior of the pathway stimulated by a time-invariant signal is relatively well-understood, we show using a computational model that it exhibits a rich repertoire of transient adaptive responses to changes in stimuli. When the signal is switched on, the response is characterized by long-lived modulations in frequency as well as amplitude. On withdrawing the stimulus, the activity decays over timescales much longer than that of phosphorylation-dephosphorylation processes, exhibiting reverberations characterized by repeated spiking in the activated MAPK concentration. The long-term persistence of such post-stimulus activity suggests that the cascade retains memory of the signal for a significant duration following its removal, even in the absence of any explicit feedback or cross-talk with other pathways. We find that the molecular mechanism underlying this behavior is related to the existence of distinct relaxation rates for the different cascade components. This results in the imbalance of fluxes between different layers of the cascade, with the repeated reuse of activated kinases as enzymes when they are released from sequestration in complexes leading to one or more spike events following the removal of the stimulus. The persistent adaptive response reported here, indicative of a cellular "short-term" memory, suggests that this ubiquitous signaling pathway plays an even more central role in information processing by eukaryotic cells.
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