Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades
Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades
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DOI：
10.1046/j.1432-1327.2000.01197.x
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发表时间：
2000-03-01
期刊：
影响因子：
--
通讯作者：
Kholodenko, BN
中科院分区：
文献类型：
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作者：
Kholodenko, BN
信号转导向蛋白质磷酸化级联反应的功能组织，例如有丝分裂原激活的蛋白激酶（MAPK）级联反应，极大地增强了细胞对外部刺激的敏感性。灵敏度随级联水平的数量而倍增，因此刺激的微小变化会导致反应发生很大变化，这种现象称为超敏。在多种细胞类型中，MAPK级联反应嵌入了长的反馈回路中，取决于末端激酶是刺激还是抑制初始水平的激活。在这里，我们证明了负反馈回路与MAPK级联反应的内在超敏性结合可以在MAPK磷酸化中引起持续的振荡。基于MAPK级联反应的最新动力学数据，我们预测振荡周期的范围从分钟到几个小时。磷酸化水平可以在基本水平和几乎100％的总蛋白质之间变化。磷酸化级联反应的振荡和细胞质中蛋白质的缓慢扩散会导致磷酸蛋白质的细胞内波。
Functional organization of signal transduction into protein phosphorylation cascades, such as the mitogen-activated protein kinase (MAPK) cascades, greatly enhances the sensitivity of cellular targets to external stimuli. The sensitivity increases multiplicatively with the number of cascade levels, so that a tiny change in a stimulus results in a large change in the response, the phenomenon referred to as ultrasensitivity. In a variety of cell types, the MAPK cascades are imbedded in long feedback loops, positive or negative, depending on whether the terminal kinase stimulates or inhibits the activation of the initial level. Here we demonstrate that a negative feedback loop combined with intrinsic ultrasensitivity of the MAPK cascade can bring about sustained oscillations in MAPK phosphorylation. Based on recent kinetic data on the MAPK cascades, we predict that the period of oscillations can range from minutes to hours. The phosphorylation level can vary between the base level and almost 100% of the total protein. The oscillations of the phosphorylation cascades and slow protein diffusion in the cytoplasm can lead to intracellular waves of phospho-proteins.