Sensitivity analysis predicts that the ERK-pMEK interaction regulates ERK nuclear translocation.
Sensitivity analysis predicts that the ERK-pMEK interaction regulates ERK nuclear translocation.
复制标题
敏感性分析预测 ERK-pMEK 相互作用调节 ERK 核易位。
DOI：
10.1049/iet-syb.2009.0010
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发表时间：
2009
影响因子：
2.3
通讯作者：
Oliver,JM
中科院分区：
文献类型：
--
作者：
Radhakrishnan,K;Edwards,JS;Lidke,DS;Jovin,TM;Wilson,BS;Oliver,JM
在磷酸化之后，核易位的分裂原活化蛋白激酶（MAPKs）， ERK1和ERK2，对于生长因子诱导的基因表达和DNA复制都是至关重要的。因此，人们对ERK核易位进行了广泛的研究，但许多细节仍未解决，包括易位是否需要ERK二聚化。在这里，我们模拟ERK核易位与室室计算模型，包括系统敏感性分析。利用后向微分公式和解耦直接法求解控制常微分方程。为了更好地理解ERK核易位的调控，我们将该模型与先前发表的ERK途径模型结合使用，该模型不包括ERK二聚体物种，并与野生型ERK和突变型ERK1-Δ4的核易位实验测量相结合，后者无法二聚。敏感性分析显示，与野生型ERK1相比，ERK1-Δ4的核摄取延迟可以通过ERK1-Δ4与磷酸化的MEK （MAPK/ERK激酶）相互作用的改变来解释，因此可能与二聚化无关。我们的研究还确定了可以验证这一解释的生物学实验。
Following phosphorylation, nuclear translocation of the mitogen-activated protein kinases (MAPKs), ERK1 and ERK2, is critical for both gene expression and DNA replication induced by growth factors. ERK nuclear translocation has therefore been studied extensively, but many details remain unresolved, including whether or not ERK dimerisation is required for translocation. Here, we simulate ERK nuclear translocation with a compartmental computational model that includes systematic sensitivity analysis. The governing ordinary differential equations are solved with the backward differentiation formula and decoupled direct methods. To better understand the regulation of ERK nuclear translocation, we use this model in conjunction with a previously published model of the ERK pathway that does not include an ERK dimer species and with experimental measurements of nuclear translocation of wild-type ERK and a mutant form, ERK1-Δ4, which is unable to dimerise. Sensitivity analysis reveals that the delayed nuclear uptake of ERK1-Δ4 compared to that of wild-type ERK1 can be explained by the altered interaction of ERK1-Δ4 with phosphorylated MEK (MAPK/ERK kinase), and so may be independent of dimerisation. Our study also identifies biological experiments that can verify this explanation.