Faeder James R, Hlavacek William S, Reischl Ilona, Blinov Michael L, Metzger Henry, Redondo Antonio, Wofsy Carla, Goldstein Byron
Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
J Immunol. 2003 Apr 1;170(7):3769-81. doi: 10.4049/jimmunol.170.7.3769.
Aggregation of Fc epsilon RI on mast cells and basophils leads to autophosphorylation and increased activity of the cytosolic protein tyrosine kinase Syk. We investigated the roles of the Src kinase Lyn, the immunoreceptor tyrosine-based activation motifs (ITAMs) on the beta and gamma subunits of Fc epsilon RI, and Syk itself in the activation of Syk. Our approach was to build a detailed mathematical model of reactions involving Fc epsilon RI, Lyn, Syk, and a bivalent ligand that aggregates Fc(epsilon)RI. We applied the model to experiments in which covalently cross-linked IgE dimers stimulate rat basophilic leukemia cells. The model makes it possible to test the consistency of mechanistic assumptions with data that alone provide limited mechanistic insight. For example, the model helps sort out mechanisms that jointly control dephosphorylation of receptor subunits. In addition, interpreted in the context of the model, experimentally observed differences between the beta- and gamma-chains with respect to levels of phosphorylation and rates of dephosphorylation indicate that most cellular Syk, but only a small fraction of Lyn, is available to interact with receptors. We also show that although the beta ITAM acts to amplify signaling in experimental systems where its role has been investigated, there are conditions under which the beta ITAM will act as an inhibitor.
肥大细胞和嗜碱性粒细胞上的FcεRI聚集会导致胞质蛋白酪氨酸激酶Syk的自身磷酸化及活性增加。我们研究了Src激酶Lyn、FcεRIβ和γ亚基上基于免疫受体酪氨酸的激活基序（ITAM）以及Syk自身在Syk激活中的作用。我们的方法是构建一个涉及FcεRI、Lyn、Syk和使Fc(ε)RI聚集的二价配体的详细反应数学模型。我们将该模型应用于共价交联的IgE二聚体刺激大鼠嗜碱性白血病细胞的实验。该模型使得检验机制假设与仅提供有限机制见解的数据之间的一致性成为可能。例如，该模型有助于梳理共同控制受体亚基去磷酸化的机制。此外，在模型背景下进行解释时，实验观察到的β链和γ链在磷酸化水平和去磷酸化速率方面的差异表明，大多数细胞内的Syk，但只有一小部分Lyn，可与受体相互作用。我们还表明，尽管β ITAM在其作用已被研究的实验系统中起到放大信号的作用，但在某些条件下，β ITAM将起到抑制剂的作用。
