PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk.
PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk.
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DOI：
10.1038/msb.2009.4
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发表时间：
2009
影响因子：
9.9
通讯作者：
Haugh, Jason M.
中科院分区：
文献类型：
--
作者：
Wang, Chun-Chao;Cirit, Murat;Haugh, Jason M.
关键词：
虽然人们意识到，规范的信号转导通路代表了嵌入较大相互作用网络中的主要调节模式，但对此类网络中的通路串扰进行量化的工作相对较少。通过系统地绘制一系列刺激和分子扰动条件的定量测量，结合计算模型和分析，我们阐明了血小板衍生生长因子(PDGF)受体信号网络中的串扰机制，在该网络中，磷脂酰肌醇3-激酶(PI3K)和RAS/细胞外信号调节激酶(ERK)通路显著激活。我们发现，虽然PI3K信号不受串扰的影响，但PI3K增强了RAS上下游的ERK激活。这些效应的大小强烈地依赖于刺激条件，受到各自通路和负反馈回路中的饱和效应的影响。在这些动力学的推动下，建立了一个网络的动力学模型，并用来精确地量化依赖于PI3K和非依赖于Ras/Erk激活模式的相对贡献。
Although it is appreciated that canonical signal-transduction pathways represent dominant modes of regulation embedded in larger interaction networks, relatively little has been done to quantify pathway cross-talk in such networks. Through quantitative measurements that systematically canvas an array of stimulation and molecular perturbation conditions, together with computational modeling and analysis, we have elucidated cross-talk mechanisms in the platelet-derived growth factor (PDGF) receptor signaling network, in which phosphoinositide 3-kinase (PI3K) and Ras/extracellular signal-regulated kinase (Erk) pathways are prominently activated. We show that, while PI3K signaling is insulated from cross-talk, PI3K enhances Erk activation at points both upstream and downstream of Ras. The magnitudes of these effects depend strongly on the stimulation conditions, subject to saturation effects in the respective pathways and negative feedback loops. Motivated by those dynamics, a kinetic model of the network was formulated and used to precisely quantify the relative contributions of PI3K-dependent and -independent modes of Ras/Erk activation.
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影响因子：
4.1
作者：
Kaur, H;Park, CS;Haugh, JM
通讯作者：
Haugh, JM
影响因子：
9.2
作者：
Chaudhary, A;King, WG;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
5.3
作者：
Chiloeches, A;Mason, CS;Marais, R
通讯作者：
Marais, R
影响因子：
4.8
作者：
Hayashi, H;Matsuzaki, O;Nishida, E
通讯作者：
Nishida, E
影响因子：
4.8
作者：
Jiménez, C;Hernández, C;Carrera, AC
通讯作者：
Carrera, AC