Division of Theoretical Bioinformatics, German Cancer Research Center, 69120 Heidelberg, Germany.
Sci Signal. 2011 May 31;4(175):ra36. doi: 10.1126/scisignal.2001325.
Natural killer (NK) cells are effector cells of the immune system whose activation is carefully regulated by the interplay of signals from activating and inhibitory receptors. Signals from activating receptors induce phosphorylation of the guanine nucleotide exchange factor Vav1, whereas those from inhibitory receptors lead to the dephosphorylation of Vav1 by the Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1). Here, we used mathematical modeling and experiments with NK cells to gain insight into this integration of positive and negative signals at a molecular level. Our data showed a switch-like regulation of Vav1 phosphorylation, the extent of which correlated with the cytotoxic activity of NK cells. Comparison of our experimental results with the predictions that we derived from an ensemble of 72 mathematical models showed that a physical association between Src family kinases and activating receptors on NK cells was essential to generate the cytotoxic response. Our data support a central role for Vav1 in determining the cytotoxic activity of NK cells and provide insight into the molecular mechanism of the integration of positive and negative signals during lymphocyte activation.
自然杀伤 (NK) 细胞是免疫系统的效应细胞，其激活受到激活和抑制受体信号相互作用的精细调节。激活受体的信号诱导鸟嘌呤核苷酸交换因子 Vav1 的磷酸化，而抑制受体的信号则导致 Src 同源 2 结构域含蛋白酪氨酸磷酸酶 1 (SHP-1) 对 Vav1 的去磷酸化。在这里，我们使用数学建模和 NK 细胞实验来深入了解这种正负信号在分子水平上的整合。我们的数据显示 Vav1 磷酸化的开关样调节，其程度与 NK 细胞的细胞毒性活性相关。将我们的实验结果与我们从 72 个数学模型的集合中得出的预测进行比较表明，NK 细胞上的 Src 家族激酶和激活受体之间的物理关联对于产生细胞毒性反应是必不可少的。我们的数据支持 Vav1 在决定 NK 细胞细胞毒性活性中的核心作用，并为淋巴细胞激活过程中正负信号整合的分子机制提供了深入了解。
