Co-aggregation of FcγRII with FcεRI on human mast cells inhibits antigen-induced secretion and involves SHIP-Grb2-Dok complexes Journal Article
| Authors: | Kepley, C. L.; Taghavi, S.; Mackay, G.; Zhu, D.; Morel, P. A.; Zhang, K.; Ryan, J. J.; Satin, L. S.; Zhang, M.; Pandolfi, P. P.; Saxon, A. |
| Article Title: | Co-aggregation of FcγRII with FcεRI on human mast cells inhibits antigen-induced secretion and involves SHIP-Grb2-Dok complexes |
| Abstract: | Signaling through the high affinity IgE receptor FcεRI on human basophils and rodent mast cells is decreased by co-aggregating these receptors to the low affinity IgG receptor FcγRII. We used a recently described fusion protein, GE2, which is composed of key portions of the human γl and the human ε heavy chains, to dissect the mechanisms that lead to human mast cell and basophil inhibition through co-aggregation of FcγRII and FcεRI. Unstimulated human mast cells derived from umbilical cord blood express the immunoreceptor tyrosine-based inhibitory motif-containing receptor FcγRII but not FcγRI or FcγRIII. Interaction of the mast cells with GE2 alone did not cause degranulation. Co-aggregating FcεRI and FcγRII with GE2 1) significantly inhibited IgE-mediated histamine release, cytokine production, and Ca2+ mobilization, 2) reduced the antigen-induced morphological changes associated with mast cell degranulation, 3) reduced the tyrosine phosphorylation of several cellular substrates, and 4) increased the tyrosine phosphorylation of the adapter protein downstream of kinase 1 (p62dok; Dok), growth factor receptor-bound protein 2 (Grb2), and SH2 domain containing inositol 5-phosphatase (SHIP). Tyrosine phosphorylation of Dok was associated with increased binding to Grb2. Surprisingly, in non-stimulated cells, there were complexes of phosphorylated SHIP-Grb2-Dok that were lost upon IgE receptor activation but retained under conditions of Fcε-Fcγ co-aggregation. Finally, studies using mast cells from Dok-1 knock-out mice showed that IgE alone triggers degranulation supporting an inhibitory role for Dok degranulation. Our results demonstrate how human FcεRI-mediated responses can be inhibited by co-aggregation with FcγRIIB and implicate Dok, SHIP, and Grb2 as key intermediates in regulating antigen-induced mediator release. |
| Keywords: | signal transduction; controlled study; protein expression; protein phosphorylation; unclassified drug; dna binding protein; human cell; dna-binding proteins; proteins; metabolism; cell structure; phosphatase; protein; protein interaction; phosphorylation; physiology; rna binding protein; rna-binding proteins; blood; immunology; immunoglobulin heavy chain; antigen; hybrid protein; antigens; adaptor proteins, signal transducing; phosphoproteins; umbilical cord blood; fc receptor; cytokine production; receptors, igg; rodentia; signal transducing adaptor protein; phosphoric monoester hydrolases; biological organs; phosphoprotein; knockout mouse; cell secretion; grb2 adaptor protein; growth factor receptor bound protein 2; immunoglobulin e; cells; degranulation; protein aggregation; mast cell; mast cells; histamine; histamine release; calcium mobilization; receptors, ige; agglomeration; alcohols; basophil; inppl1 protein, human; cell degranulation; mediator release; receptor aggregation; humans; human; priority journal; article; human mast cells; dok protein; fc receptor ii; fc receptor iii; ge2 protein; high affinity receptor for immunoglobulin e; immunoglobulin e receptor; protein ship; ship grb2 dok protein complex; dok1 protein, human; grb2 protein, human; basophil degranulation; mast cell degranulation; capping phenomenon |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 279 |
| Issue: | 34 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2004-08-20 |
| Start Page: | 35139 |
| End Page: | 35149 |
| Language: | English |
| DOI: | 10.1074/jbc.M404318200 |
| PROVIDER: | scopus |
| PUBMED: | 15151996 |
| DOI/URL: | |
| Notes: | J. Biol. Chem. -- Cited By (since 1996):67 -- Export Date: 16 June 2014 -- CODEN: JBCHA -- Source: Scopus |
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