An unusual mechanism for ligad antagonism
ABSTRACT The ratio of late to early events stimulated by the mast cell receptor for immunoglobulin E (IgE) correlated with the affinity of a ligand for the receptor-bound IgE. Because excess receptors clustered by a weakly binding ligand could hoard a critical initiating kinase, they prevented the outnumbered clusters engendered by the high-affinity ligands from launching the more complete cascade. A similar mechanism could explain the antagonistic action of some peptides on the activation of T cells.
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- "There is increasing evidence that ITAM-coupled activating receptors also contribute to inhibitory signaling (Fig. 3). This was first demonstrated in mast cell experiments that compared engagement of IgE-Fc1R receptors by low versus high affinity haptens (Torigoe et al. 1998). "
ABSTRACT: The response of innate immune cells to growth factors, immune complexes, extracellular matrix proteins, cytokines, pathogens, cellular damage, and many other stimuli is regulated by a complex net of intracellular signal transduction pathways. The majority of these pathways are either initiated or modulated by Src-family or Syk tyrosine kinases present in innate cells. The Src-family kinases modulate the broadest range of signaling responses, including regulating immunoreceptors, C-type lectins, integrins, G-protein-coupled receptors, and many others. Src-family kinases also modulate the activity of other kinases, including the Tec-family members as well as FAK and Pyk2. Syk kinase is required for initiation of signaling involving receptors that utilize immunoreceptor tyrosine activation (ITAM) domains. This article reviews the major activating and inhibitory signaling pathways regulated by these cytoplasmic tyrosine kinases, illuminating the many examples of signaling cross talk between pathways.Cold Spring Harbor perspectives in biology 11/2010; 3(3). DOI:10.1101/cshperspect.a002352 · 8.23 Impact Factor
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- "In Figure 2, we can compare the cellular responses that the model predicts for slowly and rapidly dissociating ligands. The comparison is controlled, as in experimental comparisons (Liu et al., 2001; Torigoe et al., 1998), in that the ligands differ intrinsically only in the dissociation rate constant that characterizes ligand-receptor binding and the concentrations of the two ligands are such that receptor aggregation is the same in each case at equilibrium . As can be seen, after a transient, Syk autophosphorylation is more extensive when signaling is stimulated by the slowly-dissociating ligand, which is consistent with the model of McKeithan (1995). "
ABSTRACT: Many activities of cells are controlled by cell-surface receptors, which in response to ligands, trigger intracellular signaling reactions that elicit cellular responses. A hallmark of these signaling reactions is the reversible nucleation of multicomponent complexes, which typically begin to assemble when ligand-receptor binding allows an enzyme, often a kinase, to create docking sites for signaling molecules through chemical modifications, such as tyrosine phosphorylation. One function of such docking sites is the co-localization of enzymes with their substrates, which can enhance both enzyme activity and specificity. The directed assembly of complexes can also influence the sensitivity of cellular responses to ligand-receptor binding kinetics and determine whether a cellular response is up- or downregulated in response to a ligand stimulus. The full functional implications of ligand-stimulated complex formation are difficult to discern intuitively. Complex formation is governed by conditional interactions among multivalent signaling molecules and influenced by quantitative properties of both the components in a system and the system itself. Even a simple list of the complexes that can potentially form in response to a ligand stimulus is problematic because of the number of ways signaling molecules can be modified and combined. Here, we review the role of multicomponent complexes in signal transduction and advocate the use of mathematical models that incorporate detail at the level of molecular domains to study this important aspect of cellular signaling.Biotechnology and Bioengineering 12/2003; 84(7):783-94. DOI:10.1002/bit.10842 · 4.16 Impact Factor
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- "Indeed, this has been demonstrated to be the case, as G protein coupled receptors form different signaling complexes from those of receptor tyrosine kinases or cytokine receptors, although many components may be shared in common (Miller and Lefkowitz, 2001). However, differences in signal generation can also be much more subtly regulated because in many cases a given stimulus (ligand, which refers to Ag/IgE interactions in the case of FcεRI) can elicit different cell responses depending on its concentration and/or affinity (Chang et al., 1997; Torigoe et al., 1998). We will not dwell on the effects of affinity of an Ag as this is briefly covered in Dr. Metzger's presentation in this issue. "
ABSTRACT: The generation of signals following engagement of cell surface receptors is an ordered process that requires tight regulation as spurious signals could result in unwanted, and possibly deleterious, cellular responses. Like other cell surface receptors, stimulation of a mast cell via the high affinity IgE receptor (FcepsilonRI) causes multiple biochemical events that ultimately result in cell activation and effector responses. Recently, our knowledge of how these events are ordered has increased. We now have identified some of the molecules involved, how they are organized into macromolecular complexes by FcepsilonRI stimulation, and the role of some of the constituents of these macromolecular signaling complexes in mast cell effector responses. In brief, we review the knowledge on macromolecular signaling complexes used by FcepsilonRI in mast cell activation and provide our view on the regulation of signal generation and its effect on mast cell activation.Molecular Immunology 10/2002; 38(16-18):1253-8. DOI:10.1016/S0161-5890(02)00072-X · 3.00 Impact Factor