An Unusual Mechanism for Ligand Antagonism

Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA.
Science (Impact Factor: 33.61). 08/1998; 281(5376):568-72. DOI: 10.1126/science.281.5376.568
Source: PubMed


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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    • "To our knowledge, this is the first study of an explicit spandrel structuring a complex signalling phenotype. The principles described can be applied to many processes, such as immune recognition by TCRs [13] or FcRIs [4] . Similar feed-forward/feedback mechanisms have been described in antagonism of Hh signalling [20], and underlie non monotonic responses in endocrine signalling [12] [21]. "
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    ABSTRACT: Recent works in quantitative evolution have shown that biological structures are constrained by selected phenotypes in unexpected ways . This is also observed in simulations of gene network evolution, where complex realistic traits naturally appear even if they have not been explicitly selected . An important biological example is the absolute discrimination between different ligand "qualities", such as immune decisions based on binding times to T cell receptors (TCRs) or Fc$\epsilon$RIs. In evolutionary simulations, the phenomenon of absolute discrimination is not achieved without detrimental ligand antagonism: a "dog in the manger" effect in which ligands unable to trigger response prevent agonists to do so. A priori it seems paradoxical to improve ligand discrimination in a context of increased ligand antagonism, and how such contradictory phenotypes can be disentangled is unclear. Here we establish for the first time a direct mathematical causal link between absolute discrimination and ligand antagonism. Inspired by the famous discussion by Gould and Lewontin, we thus qualify antagonism as a "phenotypic spandrel": a phenotype existing as a necessary by-product of another phenotype. We exhibit a general model for absolute discrimination, and further show how addition of proofreading steps inverts the expected hierarchy of antagonism without fully cancelling it. Phenotypic spandrels reveal the internal feedbacks and constraints structuring response in signalling pathways, in very similar way to symmetries structuring physical laws.
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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). "
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    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.
    Preview · Article · Nov 2010 · Cold Spring Harbor perspectives in biology
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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). "
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    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.
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