title: Shaping the response: the role of FcεRI and Syk expression levels in mast cell signaling.
abstract: Many receptor systems initiate cell signaling through ligand-induced receptor aggregation. For bivalent ligands binding to mono- or bivalent receptors, a plot of the equilibrium concentration of receptors in aggregates against the log of the free ligand concentration, the cross-linking curve, is symmetric and bell shaped. However, steady state cellular responses initiated through receptor cross-linking may have a different dependence on ligand concentration than the aggregated receptors that initiate and maintain these responses. The authors illustrate by considering the activation of the protein kinase Syk that rapidly occurs after high affinity receptors for IgE, FcεRI, are aggregated on the surface of mast cells and basophils. Using a mathematical model of Syk activation the authors investigate two effects, one straightforward and one less so, that result in Syk activation not qualitatively following the cross-linking curve. Model predictions show that if the mechanism by which Syk is fully activated involves the transphosphorylation of Syk by Syk, then Syk activation curves can be either bell shaped or double humped, depending on the cellular concentrations of Syk and FcεRI. The model also predicts that the Syk activation curve can be non-symmetric with respect to the ligand concentration. The cell can exhibit differential Syk activation at two different ligand concentrations that produce identical distributions of receptor aggregates that form and dissociate at the same rates. The authors discuss how, even though it is only receptor aggregates that trigger responses, differences in total ligand concentration can lead to subtle kinetic effects that yield qualitative differences in the levels of Syk activation.
authors.affiliation: Los Alamos National Laboratory, Theoretical Biology and Biophysics Group, Los Alamos, NM, USA. bxg@lanl.gov
authors.forename: Ambarish
authors.initials: A
authors.lastname: Nag
authors.forename: James R
authors.initials: JR
authors.lastname: Faeder
authors.forename: Byron
authors.initials: B
authors.lastname: Goldstein
mesh_terms: D000465:Algorithms; D002450:Cell Communication / Q000502:physiology*; D019295:Computational Biology; D003198:Computer Simulation; D006801:Humans; D007073:Immunoglobulin E / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism*; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D017455:Receptors, IgE / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017455:Receptors, IgE; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase