Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Departement of Chemical Engineering, University of Delaware, Newark, DE 19716, USA.
Wiley Interdiscip Rev Syst Biol Med. 2009 Jul-Aug;1(1):28-44. doi: 10.1002/wsbm.16.
Mitogen activated protein kinase (MAPK) cascades process a myriad of stimuli received by cell-surface receptors and generate precise spatio-temporal guidance for multiple target proteins, dictating receptor-specific cellular outcomes. Computational modelling reveals that the intrinsic topology of MAPK cascades enables them to amplify signal sensitivity and amplitude, reduce noise and display intricate dynamic properties, which include toggle switches, excitation pulses and oscillations. Specificity of signaling responses can be brought about by signal-induced feedback and feedforward wiring imposed on the MAPK cascade backbone. Intracellular gradients of protein activities arise from the spatial separation of opposing reactions in kinase-phosphatase cycles. The membrane confinement of the initiating kinase in MAPK cascades and cytosolic localization of phosphatases can result in precipitous gradients of phosphorylated signal-transducers if they spread solely by diffusion. Endocytotic trafficking of active kinases driven by molecular motors and traveling waves of protein phosphorylation can propagate phosphorylation signals from the plasma membrane to the nucleus, especially in large cells, such as Xenopus eggs.
丝裂原活化蛋白激酶（MAPK）级联反应处理细胞表面受体接收的各种刺激，并为多个靶蛋白生成精确的时空导向，决定受体特异性的细胞结果。计算模型表明，MAPK 级联反应的固有拓扑结构使其能够放大信号灵敏度和幅度，降低噪声并显示出复杂的动态特性，包括切换开关、激励脉冲和振荡。信号诱导的反馈和前馈布线对 MAPK 级联主干的影响可以带来信号响应的特异性。蛋白活性的细胞内梯度源于激酶-磷酸酶循环中相反反应的空间分离。如果 MAPK 级联反应中起始激酶的膜限制和磷酸酶的细胞质定位仅通过扩散传播，那么磷酸化信号转导子的浓度梯度会非常陡峭。分子马达驱动的活性激酶的内吞运输和蛋白磷酸化的传播波可以将磷酸化信号从质膜传播到细胞核，特别是在大型细胞中，如非洲爪蟾卵。
