A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling
A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling
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DOI：
10.1042/bj20021824
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发表时间：
2003-07-15
影响因子：
4.1
通讯作者：
Konagaya, A
中科院分区：
文献类型：
--
作者：
Hatakeyama, M;Kimura, S;Konagaya, A
ErbB酪氨酸激酶受体通过结合多种配体和募集不同的衔接蛋白盒来介导促有丝分裂信号级联。在本研究中，我们研究了调蛋白（HRG）诱导的Erb 134受体的信号转导，发现磷脂酰肌醇3 '-激酶（PI 3 K）-Akt通路通过磷酸化Ser（259）上的Raf-1负性调节细胞外信号调节激酶（ERK）级联。由于Akt和ERK活性的时程动力学似乎是短暂的和复杂的，我们构建了一个数学模拟模型HRG诱导的Erb 134受体信号转导来解释在这个信号转导级联的调节机制的动力学。该模型很好地反映了在HRG诱导的Erb 134细胞和其他生长激素诱导的细胞信号传导模式中观察到的实验结果，这些细胞信号传导涉及Raf-Akt串扰。该模型表明，HRG信号传导受蛋白磷酸酶2A以及Raf-Akt串扰的调节，并且蛋白磷酸酶2A调节PI 3 K-Akt和MAPK（丝裂原活化蛋白激酶）途径中的激酶活性。
ErbB tyrosine kinase receptors mediate mitogenic signal cascade by binding a variety of ligands and recruiting the different cassettes of adaptor proteins. In the present study, we examined heregulin (HRG)-induced signal transduction of Erb134 receptor and found that the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway negatively regulated the extracellular signal-regulated kinase (ERK) cascade by phosphorylating Raf-1 on Ser(259). As the time-course kinetics of Akt and ERK activities seemed to be transient and complex, we constructed a mathematical simulation model for HRG-induced Erb134 receptor signalling to explain the dynamics of the regulation mechanism in this signal transduction cascade. The model reflected well the experimental results observed in HRG-induced Erb134 cells and in other modes of growth hormone-induced cell signalling that involve Raf-Akt cross-talk. The model suggested that HRG signalling is regulated by protein phosphatase 2A as well as Raf-Akt cross-talk, and protein phosphatase 2A modulates the kinase activity in both the PI3K-Akt and MAPK (mitogen-activated protein kinase) pathways.