A systems-biology analysis of feedback inhibition in the Sho1 osmotic-stress-response pathway
A systems-biology analysis of feedback inhibition in the Sho1 osmotic-stress-response pathway
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DOI：
10.1016/j.cub.2007.02.044
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发表时间：
2007-04-17
期刊：
影响因子：
9.2
通讯作者：
Dohlman, Henrik G.
中科院分区：
文献类型：
--
作者：
Hao, Nan;Behar, Marcelo;Dohlman, Henrik G.
背景：信号转导系统的一个共同特性是它们迅速失去对给定刺激的反应能力。例如，在酵母中，促分裂原活化蛋白（MAP）激酶Hog 1被激活和失活在几分钟内，即使当astrophic应力stimulation.Results：在这里，我们使用了实验和计算分析相结合的动态行为Hog 1在体内激活。计算模型表明，负反馈回路在通路的早期起作用，并导致Hog 1信号的快速衰减。实验分析表明，膜结合的Hog 1传感器Sho 1被Hog 1磷酸化，并且磷酸化发生在Ser-166上。此外，Sho 1存在于同源寡聚体复合物中，并且Hog 1的磷酸化促进从寡聚体到单体状态的转变。磷酸化位点突变（Shol S166 E）减少了Sho 1-寡聚体的形成，抑制了Hog 1激酶的激活，并损害了高盐或山梨糖醇conditions.Conclusions的增长：这些研究结果揭示了一种新的磷酸化依赖的反馈回路，导致减少细胞对干旱应激刺激的反应。
Background: A common property of signal transduction systems is that they rapidly lose their ability to respond to a given stimulus. For instance in yeast, the mitogen-activated protein (MAP) kinase Hog1 is activated and inactivated within minutes, even when the osmotic-stress stimulus is sustained.Results: Here, we used a combination of experimental and computational analyses to investigate the dynamic behavior of Hog1 activation in vivo. Computational modeling suggested that a negative-feed back loop operates early in the pathway and leads to rapid attenuation of Hog1 signaling. Experimental analysis revealed that the membrane-bound osmosensor Sho1 is phosphorylated by Hog1 and that phosphorylation occurs on Ser-166. Moreover, Sho1 exists in a homo-oligomeric complex, and phosphorylation by Hog1 promotes a transition from the oligomeric to monomeric state. A phosphorylation-site mutation (Shol S166E) diminishes the formation of Sho1-oligomers, dampens activation of the Hog1 kinase, and impairs growth in high-salt or sorbitol conditions.Conclusions: These findings reveal a novel phosphorylation-dependent feedback loop leading to diminished cellular responses to an osmotic-stress stimulus.