Optimal aggregation of FcεRI with a structurally defined trivalent ligand overrides negative regulation driven by phosphatases.
ACS Chem Biol
; 9(7): 1508-19, 2014 Jul 18.
Article
em En
| MEDLINE
| ID: mdl-24784318
ABSTRACT
To investigate why responses of mast cells to antigen-induced IgE receptor (FcεRI) aggregation depend nonlinearly on antigen dose, we characterized a new artificial ligand, DF3, through complementary modeling and experimentation. This ligand is a stable trimer of peptides derived from bacteriophage T4 fibritin, each conjugated to a hapten (DNP). We found low and high doses of DF3 at which degranulation of mast cells sensitized with DNP-specific IgE is minimal, but ligand-induced receptor aggregation is comparable to aggregation at an intermediate dose, optimal for degranulation. This finding makes DF3 an ideal reagent for studying the balance of negative and positive signaling in the FcεRI pathway. We find that the lipid phosphatase SHIP and the protein tyrosine phosphatase SHP-1 negatively regulate mast cell degranulation over all doses considered. In contrast, SHP-2 promotes degranulation. With high DF3 doses, relatively rapid recruitment of SHIP to the plasma membrane may explain the reduced degranulation response. Our results demonstrate that optimal secretory responses of mast cells depend on the formation of receptor aggregates that promote sufficient positive signaling by Syk to override phosphatase-mediated negative regulatory signals.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Virais
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Imunoglobulina E
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Degranulação Celular
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Receptores de IgE
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Monoéster Fosfórico Hidrolases
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Mastócitos
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Antígenos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
ACS Chem Biol
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos