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Vonakis, BM, Gibbons, SP Jr, Rotté, MJ, Brothers, EA, Kim, SC, Chichester, K and MacDonald, SM (2005) Regulation of rat basophilic leukemia-2H3 mast cell secretion by a constitutive Lyn kinase interaction with the high affinity IgE receptor (Fc epsilon RI). J. Immunol. 175:4543-54
Signaling through the high affinity IgE receptor is initiated by noncovalently associated Lyn kinase, resulting in the secretion of inflammatory mediators from mast cells. A fraction of the total cellular Lyn is associated via its N-terminal unique domain with the cytoplasmic domain of the Fc epsilonRI beta subunit before receptor aggregation. In the current study, we stably transfected the unique domain of Lyn into rat basophilic leukemia-2H3 mast cells and examined the consequences on Fc epsilonRI-induced signal transduction and mediator secretion to further define the role of the unique domain of Lyn in mast cell secretion. Tyrosine phosphorylation of Fc epsilonRI beta and gamma subunits was partially inhibited in the Lyn unique domain transfectants after Ag stimulation. Ag stimulation of Lyn unique domain transfectants was accompanied by enhanced phosphorylation of MEK and ERK-2, which are required for leukotriene C4 (LTC4) release, and production of LTC4 was increased 3- to 5-fold, compared with cells transfected with vector alone. Conversely, tyrosine phosphorylation of the adaptor protein Gab2, which is essential for mast cell degranulation, was inhibited after Ag stimulation of Lyn unique domain transfectants, and Ag-induced release of histamine was inhibited up to 48%. In rat basophilic leukemia-2H3 cells, Lyn thus plays a dual role by positively regulating Fc epsilonRI phosphorylation and degranulation while negatively regulating LTC4 production. This study provides further evidence that the constitutive interaction between the unique domain of Lyn and the Fc epsilonRI beta subunit is a crucial step in the initiation of Fc epsilonRI signaling and that Lyn is limiting for Fc epsilonRI-induced secretion of inflammatory mediators.
Animals; Calcium/metabolism; Cell Line, Tumor; Cell Membrane/physiology; Enzyme Precursors/physiology; Histamine/metabolism; Intracellular Signaling Peptides and Proteins; Kinetics; Leukemia, Basophilic, Acute/metabolism; Mast Cells/enzymology; Mast Cells/secretion; Mice; Phosphoproteins/physiology; Phosphorylation; Protein Structure, Tertiary/genetics; Protein-Tyrosine Kinases/physiology; Rats; Receptors, IgE/metabolism; Signal Transduction/physiology; Transfection; Tumor Necrosis Factor-alpha/biosynthesis; Tyrosine/metabolism; src-Family Kinases/genetics; src-Family Kinases/physiology