Input-output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data.
Input-output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data.
复制标题
DOI：
10.1038/msb.2008.74
复制
发表时间：
2009
影响因子：
9.9
通讯作者：
Sorger, Peter K.
中科院分区：
文献类型：
--
作者：
Chen, William W.;Schoeberl, Birgit;Jasper, Paul J.;Niepel, Mario;Nielsen, Ulrik B.;Lauffenburger, Douglas A.;Sorger, Peter K.
ErbB信号通路调节多种生理反应，如细胞存活、增殖和运动，已经受到广泛的分子分析。然而，不同的配体如何诱导不同的反应，以及这种反应如何受到致癌突变的影响，人们仍然知之甚少。为了量化erbb激活通路的信号流，我们构建、训练并分析了ErbB1-4受体（EGFR、HER2/Neu2、ErbB3和ErbB4）的即时早期信号的质量作用模型，以及MAPK和PI3K/Akt级联。我们发现参数敏感性强烈依赖于被检测的特征（如ERK或Akt激活）或条件（如EGF或heregulin刺激），并且这种环境依赖性与信号传播机制有关。建模预测对数线性扩增，因此在远低于受体结合Kd的配体浓度下观察到显著的ERK和Akt活化。然而，从ErbB模型中分离的MAPK和Akt模块继续表现出开关样反应。因此，ErbB信号的关键全系统特征源于信号元件之间的非线性相互作用，其特性在上下和孤立情况下表现得截然不同。
The ErbB signaling pathways, which regulate diverse physiological responses such as cell survival, proliferation and motility, have been subjected to extensive molecular analysis. Nonetheless, it remains poorly understood how different ligands induce different responses and how this is affected by oncogenic mutations. To quantify signal flow through ErbB-activated pathways we have constructed, trained and analyzed a mass action model of immediate-early signaling involving ErbB1–4 receptors (EGFR, HER2/Neu2, ErbB3 and ErbB4), and the MAPK and PI3K/Akt cascades. We find that parameter sensitivity is strongly dependent on the feature (e.g. ERK or Akt activation) or condition (e.g. EGF or heregulin stimulation) under examination and that this context dependence is informative with respect to mechanisms of signal propagation. Modeling predicts log-linear amplification so that significant ERK and Akt activation is observed at ligand concentrations far below the Kd for receptor binding. However, MAPK and Akt modules isolated from the ErbB model continue to exhibit switch-like responses. Thus, key system-wide features of ErbB signaling arise from nonlinear interaction among signaling elements, the properties of which appear quite different in context and in isolation.
登录
查看更多内容
影响因子：
16
作者：
Heinrich, R;Neel, BG;Rapoport, TA
通讯作者：
Rapoport, TA
DOI：
10.1073/pnas.91.17.8132
发表时间：
1994-08-16
影响因子：
11.1
作者：
GUY, PM;PLATKO, JV;CARRAWAY, KL
通讯作者：
CARRAWAY, KL
影响因子：
5.8
作者：
Hengl, S.;Kreutz, C.;Maiwald, T.
通讯作者：
Maiwald, T.
影响因子：
5.3
作者：
FELDER, S;ZHOU, M;SCHLESSINGER, J
通讯作者：
SCHLESSINGER, J
影响因子：
11.4
作者：
GrausPorta, D;Beerli, RR;Hynes, NE
通讯作者：
Hynes, NE