From the Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto 606-8501; Innovative Techno-Hub for Integrated Medical Bio-Imaging, Kyoto University, Kyoto 606-8501.
Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto 606-8501.
J Biol Chem. 2010 Oct 22;285(43):33540-33548. doi: 10.1074/jbc.M110.135517. Epub 2010 Aug 19.
EGF-induced activation of ERK has been extensively studied by both experimental and theoretical approaches. Here, we used a simulation model based mostly on experimentally determined parameters to study the ERK-mediated negative feedback regulation of the Ras guanine nucleotide exchange factor, son of sevenless (SOS). Because SOS1 is phosphorylated at multiple serine residues upon stimulation, we evaluated the role of the multiplicity by building two simulation models, which we termed the decisive and cooperative phosphorylation models. The two models were constrained by the duration of Ras activation and basal phosphorylation level of SOS1. Possible solutions were found only in the decisive model wherein at least three, and probably more than four, phosphorylation sites decisively suppress the SOS activity. Thus, the combination of experimental approaches and the model analysis has suggested an unexpected role of multiple phosphorylations of SOS1 in the negative regulation.
表皮生长因子（EGF）诱导的 ERK 激活已经通过实验和理论方法得到了广泛的研究。在这里，我们使用了一个主要基于实验确定参数的模拟模型来研究 ERK 介导的 Ras 鸟苷酸交换因子，SOS 的儿子（SOS）的负反馈调节。由于 SOS1 在受到刺激时会在多个丝氨酸残基上磷酸化，我们通过构建两个模拟模型来评估这种多磷酸化的作用，我们将这两个模型分别称为决定性磷酸化模型和协同磷酸化模型。这两个模型受到 Ras 激活持续时间和 SOS1 的基础磷酸化水平的约束。只有在决定性模型中才能找到可能的解决方案，其中至少有三个，可能有四个以上的磷酸化位点可以决定性地抑制 SOS 的活性。因此，实验方法和模型分析的结合表明，SOS1 的多磷酸化在负调控中可能发挥了意想不到的作用。
