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

James R. Faeder^*, William S. Hlavacek^*, Ilona Reischl^2,, Michael L. Blinov^*, Henry Metzger, Antonio Redondo, Carla Wofsy^*, and Byron Goldstein^3,*

^* Theoretical Biology and Biophysics Group and Theoretical Chemistry and Molecular Physics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545; Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and Department of Mathematics and Statistics, University of New Mexico, Albuquerque, NM 87131

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.

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