Computational modelling of ErbB family phosphorylation dynamics in response to transforming growth factor alpha and heregulin indicates spatial compartmentation of phosphatase activity
Computational modelling of ErbB family phosphorylation dynamics in response to transforming growth factor alpha and heregulin indicates spatial compartmentation of phosphatase activity
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DOI：
10.1049/ip-syb:20050057
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发表时间：
2006-01-01
期刊：
影响因子：
--
通讯作者：
de Graaf, D
中科院分区：
文献类型：
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作者：
Hendriks, BS;Cook, J;de Graaf, D
ErbB受体家族的成员与几种癌症相关，并且似乎为肺和乳腺肿瘤的药物治疗提供了有用的靶点。这些疗法的进一步改进可以通过对ErbB二聚化、运输和激活的复杂性的定量、动态综合系统理解来指导，因为正是这些复杂性使得难以直观地理解诸如药物干预的扰动将如何影响ErbB信号传导活动。为了实现这一目标，我们已经开发了一个计算模型，实现普遍接受的原则，ErbB受体的相互作用，贩运，磷酸化和去磷酸化。使用这个模型，我们能够调查几个假设关于房室定位的去磷酸化。模型结果应用于实验数据ErbB1，ErbB2和ErbB3磷酸化在H292人肺癌细胞支持一个假设，这些受体的关键去磷酸化活性主要发生在细胞内，内体室，而不是在细胞表面质膜。因此，内吞运输相关的去磷酸化区室化可能定义了ErbB信号对配体的反应的一个关键方面。
Members of the ErbB receptor family are associated with several cancers and appear to be providing useful targets for pharmacological therapeutics for tumours of the lung and breast. Further improvements of these therapies may be guided by a quantitative, dynamic integrative systems understanding of the complexities of ErbB dimerisation, trafficking and activation, for it is these complexities that render difficult intuiting how perturbations such as drug intervention will affect ErbB signalling activities. Towards this goal, we have developed a computational model implementing commonly accepted principles governing ErbB receptor interaction, trafficking, phosphorylation and dephosphorylation. Using this model, we are able to investigate several hypotheses regarding the compartmental localisation of dephosphorylation. Model results applied to experimental data on ErbB1, ErbB2 and ErbB3 phosphorylation in H292 human lung carcinoma cells support a hypothesis that key dephosphorylation activity for these receptors occurs largely in an intracellular, endosomal compartment rather than at the cell surface plasma membrane. Thus, the endocytic trafficking-related compartmentalisation of dephosphorylation may define a critical aspect of the ErbB signalling response to ligand.