Combined computational and experimental analysis reveals mitogen-activated protein kinase-mediated feedback phosphorylation as a mechanism for signaling specificity.
Combined computational and experimental analysis reveals mitogen-activated protein kinase-mediated feedback phosphorylation as a mechanism for signaling specificity.
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DOI：
10.1091/mbc.e12-04-0333
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发表时间：
2012-10
影响因子：
3.3
通讯作者：
Elston TC
中科院分区：
文献类型：
--
作者：
Hao N;Yildirim N;Nagiec MJ;Parnell SC;Errede B;Dohlman HG;Elston TC
一系列的数学模型被用来定量表征信息素刺激的激酶激活，并确定如何实现丝裂原活化蛋白（MAP）激酶特异性。这些发现揭示了一个共同的途径组件的反馈磷酸化如何通过一个共同的激活剂的反馈磷酸化来限制竞争性MAP激酶的活性，从而促进信号保真度。不同的环境刺激通常使用相同的信号蛋白来实现非常不同的生理结果。酵母中的交配和侵入性生长途径均采用丝裂原活化蛋白（MAP）激酶级联，包括Ste20、Ste11和Ste7。而适当的交配需要Ste7激活MAP激酶Fus3，侵入性生长需要激活替代MAP激酶Kss1。为了确定MAP激酶特异性是如何实现的，我们使用了一系列数学模型来定量表征信息素刺激的激酶活化。根据计算分析，MAP激酶反馈磷酸化的Ste7的结果在减少激活Kss1，但不是Fus3。这些发现揭示了一个共同的途径组件的反馈磷酸化如何可以限制竞争性MAP激酶的活性，通过反馈磷酸化的共同激活剂，从而促进信号保真度。
A series of mathematical models was used to quantitatively characterize pheromone-stimulated kinase activation and determine how mitogen-activated protein (MAP) kinase specificity is achieved. The findings reveal how feedback phosphorylation of a common pathway component can limit the activity of a competing MAP kinase through feedback phosphorylation of a common activator, and thereby promote signal fidelity. Different environmental stimuli often use the same set of signaling proteins to achieve very different physiological outcomes. The mating and invasive growth pathways in yeast each employ a mitogen-activated protein (MAP) kinase cascade that includes Ste20, Ste11, and Ste7. Whereas proper mating requires Ste7 activation of the MAP kinase Fus3, invasive growth requires activation of the alternate MAP kinase Kss1. To determine how MAP kinase specificity is achieved, we used a series of mathematical models to quantitatively characterize pheromone-stimulated kinase activation. In accordance with the computational analysis, MAP kinase feedback phosphorylation of Ste7 results in diminished activation of Kss1, but not Fus3. These findings reveal how feedback phosphorylation of a common pathway component can limit the activity of a competing MAP kinase through feedback phosphorylation of a common activator, and thereby promote signal fidelity.