Investigation of Early Events in FcRI-Mediated Signaling Using a Detailed Mathematical Model1

Aggregation of FcRI 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 and subunits of FcRI, and Syk itself in the activation of Syk. Our approach was to build a detailed mathematical model of reactions involving FcRI, Lyn, Syk, and a bivalent ligand that aggregates FcRI. 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 - and -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 ITAM acts to amplify signaling in experimental systems where its role has been investigated, there are conditions under which the ITAM will act as an inhibitor. The Journal of Immunology, 2003, 170: 3769–3781. T here is increasing recognition that mathematical modelingcan be a valuable interpretive and predictive tool for un-derstanding cell signaling cascades (1, 2). In the case of the signaling cascade initiated by the aggregation of FcRI, the high affinity receptor for IgE, detailed molecular level models have been used to characterize the role of Lyn kinase in the initiatio