An Unusual Mechanism for Ligand Antagonism

Torigoe, Chikako; Inman, John K.; Metzger, Henry

doi:10.1126/science.281.5376.568

Cited by 152 publications

(158 citation statements)

References 40 publications

Supporting

Mentioning

150

Contrasting

Unclassified

Order By: Relevance

“…Signals downstream of aggregated Fc⑀RI appear to occur as a complex network sensitive to both the presence and the amount of an activated protein or generated lipid, as well as kinetic proofreading (42,43). Signal transduction in the RBL-2H3 cell is in part regulated by the shuttling of limited amounts of the Lyn kinase that initiates a cascade of phosphorylation events (44).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Rat Basophilic Leukemia-2H3 Mast Cell Secretion by a Constitutive Lyn Kinase Interaction with the High Affinity IgE Receptor (FcεRI)

Vonakis

Gibbons

Rotté

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

Signaling through the high affinity IgE receptor is initiated by noncovalently associated Lyn kinase, resulting in the secretion of inflammatory mediators from mast cells. A fraction of the total cellular Lyn is associated via its N-terminal unique domain with the cytoplasmic domain of the FcεRI β subunit before receptor aggregation. In the current study, we stably transfected the unique domain of Lyn into rat basophilic leukemia-2H3 mast cells and examined the consequences on FcεRI-induced signal transduction and mediator secretion to further define the role of the unique domain of Lyn in mast cell secretion. Tyrosine phosphorylation of FcεRI β and γ subunits was partially inhibited in the Lyn unique domain transfectants after Ag stimulation. Ag stimulation of Lyn unique domain transfectants was accompanied by enhanced phosphorylation of MEK and ERK-2, which are required for leukotriene C4 (LTC4) release, and production of LTC4 was increased 3- to 5-fold, compared with cells transfected with vector alone. Conversely, tyrosine phosphorylation of the adaptor protein Gab2, which is essential for mast cell degranulation, was inhibited after Ag stimulation of Lyn unique domain transfectants, and Ag-induced release of histamine was inhibited up to 48%. In rat basophilic leukemia-2H3 cells, Lyn thus plays a dual role by positively regulating FcεRI phosphorylation and degranulation while negatively regulating LTC4 production. This study provides further evidence that the constitutive interaction between the unique domain of Lyn and the FcεRI β subunit is a crucial step in the initiation of FcεRI signaling and that Lyn is limiting for FcεRI-induced secretion of inflammatory mediators.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of Rat Basophilic Leukemia-2H3 Mast Cell Secretion by a Constitutive Lyn Kinase Interaction with the High Affinity IgE Receptor (FcεRI)

Vonakis

Gibbons

Rotté

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…[106,107] Ligand-induced sequestering of key signaling proteins also can cause antagonist-or agonist-like effects. [108,109] Thus, rather than terming multivalent ligands agonists or antagonists, we refer to them as either multivalent effectors or inhibitors. [84] Inhibitors block receptor function and multivalent effectors activate cellular processes.…”

Section: Definitions Of Multivalent Ligand Structure and Functionmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

View full text Add to dashboard Cite

Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

show abstract

“…Although much is known about the role of Fc receptors (such as the high affinity receptor for IgE, Fc RI), TLRs, and a G protein-coupled receptors (2) on mast cell activation, the influence of the microenvironment in promoting mast cell responses is just beginning to be explored (3,4). Whether a stimulus induces mast cell granule exocytosis (5) and cytokine production or selectively induces just the latter has been demonstrated to be partly dependent on the strength of the stimulus (6,7). These studies showed that the cell's response is governed by kinetic proofreading parameters (molecular events) that must occur to achieve the particular response.…”

mentioning

confidence: 99%

Selective Activation of Fyn/PI3K and p38 MAPK Regulates IL-4 Production in BMMC under Nontoxic Stress Condition

Frossi

Rivera

Hirsch

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Mast cells have the ability to react to multiple stimuli, implicating these cells in many immune responses. Specific signals from the microenvironment in which mast cells reside can activate different molecular events that govern distinct mast cells responses. We previously demonstrated that hydrogen peroxide (H2O2) promotes IL-4 and IL-6 mRNA production and potentates FcεRI-induced cytokine release in rat basophilic leukemia RBL-2H3 cells. To further evaluate the effect of an oxidative microenvironment (which is physiologically present in an inflammatory site) on mast cell function and the molecular events responsible for mast cell cytokine production in this environment, we analyzed the effect of H2O2 treatment on IL-4 production in bone marrow-derived, cultured mast cells. Our findings show that nanomolar concentrations of H2O2 induce cytokine secretion and enhance IL-4 production upon FcεRI triggering. Oxidative stimulation activates a distinct signal transduction pathway that induces Fyn/PI3K/Akt activation and the selective phosphorylation of p38 MAP kinase. Moreover, H2O2 induces AP-1 and NFAT complexes that recognize the IL-4 promoter. The absence of Fyn and PI3K or the inhibition of p38 MAPK activity demonstrated that they are essential for H2O2-driven IL-4 production. These findings show that mast cells can respond to an oxidative microenvironment by initiating specific signals capable of eliciting a selective response. The findings also demonstrate the dominance of the Fyn/p38 MAPK pathway in driving IL-4 production.

show abstract

An Unusual Mechanism for Ligand Antagonism

Cited by 152 publications

References 40 publications

Regulation of Rat Basophilic Leukemia-2H3 Mast Cell Secretion by a Constitutive Lyn Kinase Interaction with the High Affinity IgE Receptor (FcεRI)

Regulation of Rat Basophilic Leukemia-2H3 Mast Cell Secretion by a Constitutive Lyn Kinase Interaction with the High Affinity IgE Receptor (FcεRI)

Synthetic Multivalent Ligands as Probes of Signal Transduction

Selective Activation of Fyn/PI3K and p38 MAPK Regulates IL-4 Production in BMMC under Nontoxic Stress Condition

Contact Info

Product

Resources

About