The Journal of Experimental Medicine
ThymUS '08
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Published 2 September 2003. doi:10.1084/jem.20030574
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© Rockefeller University Press, 0022-1007/2003/9/831 $5.00
The Journal of Experimental Medicine, Volume 198, Number 5, 831-843

The Four Distal Tyrosines Are Required for LAT-dependent Signaling in Fc{varepsilon}RI-mediated Mast Cell Activation

Shin-ichiroh Saitoh1, Sandra Odom2, Gregorio Gomez2, Connie L. Sommers1, Howard A. Young3, Juan Rivera2 and Lawrence E. Samelson1

1 Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute
2 Molecular Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
3 Laboratory of Experimental Immunology, National Cancer Institute-Frederick, Frederick, MD 21702

Address correspondence to L.E. Samelson, Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892. Phone: (301) 496-9683; Fax: (301) 496-8479; email: samelson{at}helix.nih.gov

The linker for activation of T cells (LAT) is an adaptor protein critical for Fc{varepsilon}RI-mediated mast cell activation. LAT is a substrate of the tyrosine kinases activated after TCR and Fc{varepsilon}RI engagement. After phosphorylation of the cytosolic domain of LAT, multiple signaling molecules such as phospholipase C–{gamma}1, Grb2, and Gads associate with phosphorylated LAT via their SH2 domains. The essential role of the four distal tyrosines in TCR-mediated signaling and T cell development has been demonstrated by experiments using LAT-deficient cell lines and genetically modified mice. To investigate the role of these four tyrosines of LAT in Fc{varepsilon}RI-mediated mast cell activation, bone marrow–derived mast cells from LAT-deficient mice were infected with retroviral vectors designed to express wild-type or mutant LAT. Examination of bone marrow–derived mast cells expressing various tyrosine to phenylalanine mutants in LAT demonstrates a differential requirement for these different binding sites. In these studies, assays of biochemical pathways, degranulation, and cytokine and chemokine release were performed. Finally, the role of these tyrosines was also evaluated in vivo using genetically modified animals. Deletion of all four distal tyrosines, and in particular, loss of the primary phospholipase C–{gamma}-binding tyrosine had a significant effect on antigen-induced histamine release.

Key Words: signal transduction • adapter molecules • phosphorylation • Fc epsilon receptor • anaphylaxis


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