HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 34, 35139-35149, August 20, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/34/35139    most recent M404318200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kepley, C. L. Articles by Saxon, A. Search for Related Content PubMed PubMed Citation Articles by Kepley, C. L. Articles by Saxon, A. Social Bookmarking                      What's this?

Co-aggregation of FcRII with FcRI on Human Mast Cells Inhibits Antigen-induced Secretion and Involves SHIP-Grb2-Dok Complexes^*

Christopher L. Kepley, Sharven Taghavi, Graham Mackay¶, Daocheng Zhu||, Penelope A. Morel**, Ke Zhang||, John J. Ryan, Leslie S. Satin, Min Zhang, Pier P. Pandolfi¶¶, and Andrew Saxon||

From the Departments of Internal Medicine, Biology, and Pharmacology and Toxicology, Virginia Commonwealth University Health Systems, Richmond, Virginia 23298, the ^¶Department of Pharmacology, University of Melbourne, Melbourne, Australia 3010, the ^**Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, the ^¶¶Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and the ^||Department of Medicine, University of California, Los Angeles, California 90033

Signaling through the high affinity IgE receptor FcRI on human basophils and rodent mast cells is decreased by co-aggregating these receptors to the low affinity IgG receptor FcRII. We used a recently described fusion protein, GE2, which is composed of key portions of the human 1 and the human heavy chains, to dissect the mechanisms that lead to human mast cell and basophil inhibition through co-aggregation of FcRII and FcRI. Unstimulated human mast cells derived from umbilical cord blood express the immunoreceptor tyrosine-based inhibitory motif-containing receptor FcRII but not FcRI or FcRIII. Interaction of the mast cells with GE2 alone did not cause degranulation. Co-aggregating FcRI and FcRII 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 (p62^dok; 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 Fc-Fc 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 FcRI-mediated responses can be inhibited by co-aggregation with FcRIIB and implicate Dok, SHIP, and Grb2 as key intermediates in regulating antigen-induced mediator release.

Received for publication, April 19, 2004

^* This work was supported in part by National Institutes of Health Grants P50 HL56384, RO1-AI15251, RO1 GM49814, RO3 TW00440, and RO1 AI42204. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by an American Lung Association grant and by a Parker B. Francis Fellowship in Pulmonary Research. To whom correspondence should be addressed: Dept. of Internal Medicine, Division of Rheumatology, Allergy, and Immunology, P. O. Box 263, MCV Station, Richmond, VA 23298. Tel.: 804-828-9685; Fax: 804-828-0283; E-mail: clkepley{at}mail1.vcu.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Li, A. Gustchina, J. Alexandratos, A. Wlodawer, S. Wunschmann, C. L. Kepley, M. D. Chapman, and A. Pomes Crystal Structure of a Dimerized Cockroach Allergen Bla g 2 Complexed with a Monoclonal Antibody J. Biol. Chem., August 15, 2008; 283(33): 22806 - 22814. [Abstract] [Full Text] [PDF]

				I. Bachelet, A. Munitz, B. Berent-Maoz, D. Mankuta, and F. Levi-Schaffer Suppression of Normal and Malignant Kit Signaling by a Bispecific Antibody Linking Kit with CD300a J. Immunol., May 1, 2008; 180(9): 6064 - 6069. [Abstract] [Full Text] [PDF]

				T. Hiragun, Z. Peng, and M. A. Beaven Cutting Edge: Dexamethasone Negatively Regulates Syk in Mast Cells by Up-Regulating Src-Like Adaptor Protein J. Immunol., August 15, 2006; 177(4): 2047 - 2050. [Abstract] [Full Text] [PDF]

				I. Bachelet, A. Munitz, A. Moretta, L. Moretta, and F. Levi-Schaffer The Inhibitory Receptor IRp60 (CD300a) Is Expressed and Functional on Human Mast Cells J. Immunol., December 15, 2005; 175(12): 7989 - 7995. [Abstract] [Full Text] [PDF]

				I. Boulay, J.-G. Nemorin, and P. Duplay Phosphotyrosine Binding-Mediated Oligomerization of Downstream of Tyrosine Kinase (Dok)-1 and Dok-2 Is Involved in CD2-Induced Dok Phosphorylation J. Immunol., October 1, 2005; 175(7): 4483 - 4489. [Abstract] [Full Text] [PDF]

				G. Gomez, C. D. Ramirez, J. Rivera, M. Patel, F. Norozian, H. V. Wright, M. V. Kashyap, B. O. Barnstein, K. Fischer-Stenger, L. B. Schwartz, et al. TGF-{beta}1 Inhibits Mast Cell Fc{epsilon}RI Expression J. Immunol., May 15, 2005; 174(10): 5987 - 5993. [Abstract] [Full Text] [PDF]

				T. Hiragun, Z. Peng, and M. A. Beaven Dexamethasone Up-Regulates the Inhibitory Adaptor Protein Dok-1 and Suppresses Downstream Activation of the Mitogen-Activated Protein Kinase Pathway in Antigen-Stimulated RBL-2H3 Mast Cells Mol. Pharmacol., March 1, 2005; 67(3): 598 - 603. [Abstract] [Full Text] [PDF]