Data-driven modeling reconciles kinetics of ERK phosphorylation, localization, and activity states.
Data-driven modeling reconciles kinetics of ERK phosphorylation, localization, and activity states.
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数据驱动的建模可以调解ERK磷酸化，定位和活动状态的动力学。
DOI：
10.1002/msb.134708
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发表时间：
2014
影响因子：
9.9
通讯作者：
Haugh, Jason M.
中科院分区：
文献类型：
--
作者：
Ahmed, Shoeb;Grant, Kyle G.;Edwards, Laura E.;Rahman, Anisur;Cirit, Murat;Goshe, Michael B.;Haugh, Jason M.
关键词：
细胞外信号调节激酶（ERK）信号通路控制多细胞动物中的细胞增殖和分化。其动力学的两个标志是ERK磷酸化的适应，这与负反馈有关，以及核质穿梭，这允许活性ERK磷酸化细胞核和胞质中的蛋白质底物。为了整合这些复杂的特征，我们获得了定量生化和活细胞显微镜数据，以协调ERK的磷酸化、定位和活性状态。虽然最大的生长因子刺激激发瞬时ERK磷酸化和核转位反应，ERK活动可磷酸化底物的细胞质和细胞核显示相对较少或没有适应。细胞核中的游离ERK活性在时间上滞后于核转位的峰值，表明这是一个缓慢的过程。另外的实验，动力学模型的指导下，表明这一过程是一致的ERK的修改和释放核底物锚。因此，全细胞ERK磷酸化的适应是磷酸酶瞬时保护的副产品。与该解释一致，实验证实了关于通路反应的剂量依赖性及其通过抑制MEK而中断的预测。
The extracellular signal‐regulated kinase (ERK) signaling pathway controls cell proliferation and differentiation in metazoans. Two hallmarks of its dynamics are adaptation of ERK phosphorylation, which has been linked to negative feedback, and nucleocytoplasmic shuttling, which allows active ERK to phosphorylate protein substrates in the nucleus and cytosol. To integrate these complex features, we acquired quantitative biochemical and live‐cell microscopy data to reconcile phosphorylation, localization, and activity states of ERK. While maximal growth factor stimulation elicits transient ERK phosphorylation and nuclear translocation responses, ERK activities available to phosphorylate substrates in the cytosol and nuclei show relatively little or no adaptation. Free ERK activity in the nucleus temporally lags the peak in nuclear translocation, indicating a slow process. Additional experiments, guided by kinetic modeling, show that this process is consistent with ERK's modification of and release from nuclear substrate anchors. Thus, adaptation of whole‐cell ERK phosphorylation is a by‐product of transient protection from phosphatases. Consistent with this interpretation, predictions concerning the dose‐dependence of the pathway response and its interruption by inhibition of MEK were experimentally confirmed.
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影响因子：
3.3
作者：
Hao N;Yildirim N;Nagiec MJ;Parnell SC;Errede B;Dohlman HG;Elston TC
通讯作者：
Elston TC
影响因子：
16
作者：
Cohen-Saidon, Cellina;Cohen, Ariel A.;Alon, Uri
通讯作者：
Alon, Uri
影响因子：
4.4
作者：
Chien, Ko-yi;Liu, Hsiao-Ching;Goshe, Michael B.
通讯作者：
Goshe, Michael B.
影响因子：
3.3
作者：
GARDNER, AM;VAILLANCOURT, RR;JOHNSON, GL
通讯作者：
JOHNSON, GL
影响因子：
4.1
作者：
Bardwell, AJ;Abdollahi, M;Bardwell, L
通讯作者：
Bardwell, L