Investigation of early events in Fc epsilon RI-mediated signaling using a detailed mathematical model.
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.
Faeder
James R
JR
Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Hlavacek
William S
WS
Reischl
Ilona
I
Blinov
Michael L
ML
Metzger
Henry
H
Redondo
Antonio
A
Wofsy
Carla
C
Goldstein
Byron
B
D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D019281:Dimerization; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology; D004792:Enzyme Precursors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D018448:Models, Immunological; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017455:Receptors, IgE / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D012984:Software; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism
D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D021122:Protein Subunits; D017455:Receptors, IgE; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases