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Molecular and Cellular Biology, April 2003, p. 2395-2406, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2395-2406.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Structural Requirements of SLP-76 in Signaling via the High-Affinity Immunoglobulin E Receptor (Fc{varepsilon}RI) in Mast Cells

Alexander Kettner,1,2 Vadim Pivniouk,1,2 Lalit Kumar,1,2 Hervé Falet,3,4 Jeng-Shin Lee,5,6 Richard Mulligan,5,6 and Raif S. Geha1,2*

Division of Immunology, Children's Hospital,1 Division of Hematology, Brigham and Women's Hospital,3 Harvard Institute of Human Genetics,5 Departments of Pediatrics,2 Medicine,4 Genetics, Harvard Medical School, Boston, Massachusetts 021156

Received 29 July 2002/ Returned for modification 5 November 2002/ Accepted 14 January 2003

The adapter SLP-76 plays an essential role in Fc{varepsilon}RI signaling, since SLP-76-/- bone marrow-derived mast cells (BMMC) fail to degranulate and release interleukin-6 (IL-6) following Fc{varepsilon}RI ligation. To define the role of SLP-76 domains and motifs in Fc{varepsilon}RI signaling, SLP-76-/- BMMC were retrovirally transduced with SLP-76 and SLP-76 mutants. The SLP-76 N-terminal and Gads binding domains, but not the SH2 domain, were critical for Fc{varepsilon}RI-mediated degranulation and IL-6 secretion, whereas all three domains are essential for T-cell proliferation following T-cell receptor (TCR) ligation. Unexpectedly, the three tyrosine residues in SLP-76 critical for TCR signaling, Y112, Y128, and Y145, were not essential for IL-6 secretion, but were required for degranulation and mitogen-activated protein kinase activation. Furthermore, a Y112/128F SLP-76 mutant, but not a Y145F mutant, strongly reconstituted mast cell degranulation, suggesting a critical role for Y145 in Fc{varepsilon}RI-mediated exocytosis. These results point to important differences in the function of SLP-76 between T cells and mast cells.

* Corresponding author. Mailing address: Division of Immunology, 300 Longwood Ave., Boston, MA 02115. Phone: (617) 355-7603. Fax: (617) 739-3145. E-mail: raif.geha{at}tch.harvard.edu.

Molecular and Cellular Biology, April 2003, p. 2395-2406, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2395-2406.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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