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.

Department(s)

Chemical and Biochemical Engineering

Comments

ACS AuthorChoice -- This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Keywords and Phrases

2,4 Dinitrophenol; Df 3; Fc Epsilon Receptor I; Fc Receptor; Ligand; Protein Tyrosine Phosphatase SHP 1; Protein Tyrosine Phosphatase SHP 2; Unclassified Drug; Antigen; FcepsilonRI Protein, Rat; Fibritin Protein, Enterobacteria Phage T4; Immunoglobulin E; Immunoglobulin E Receptor; Ligand; Peptide; Phosphatase; Protein Tyrosine Phosphatase SHP 2; Virus Protein, Animal Cell; Article; Bacteriophage T4; Capping Phenomenon; Cell Membrane; Cross Linking; Endocytosis; Enzyme Localization; Fluorescence Imaging; Immunoelectron Microscopy; Mast Cell Degranulation; Molecular Model; Mouse; Nonhuman; Priority Journal; Receptor Binding; Signal Transduction; Animal; Chemical Structure; Chemistry; Cytology; Degranulation; Human; Immunology; Mast Cell; Rat, Animals; Antigens; Cell Degranulation; Humans; Immunoglobulin E; Ligands; Mast Cells; Models, Molecular; Peptides; Phosphoric Monoester Hydrolases; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Rats; Receptors, IgE; Signal Transduction; Viral Proteins

International Standard Serial Number (ISSN)

1554-8929

Document Type

Article - Journal

Document Version

Final Version

File Type

text

Language(s)

English

Rights

© 2014 American Chemical Society (ACS), All rights reserved.

PubMed ID

24784318

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