Mast cells play important roles in inflammation andMast cells are bone marrow-derived granulocytes that reside close to blood vessels and peripheral nerves and below epithelial cell surfaces exposed to external environments, including the respiratory and gastrointestinal tracts and skin (1, 62). While mast cell activation can cause allergic reactions and potentially life-threatening anaphylaxis, these cells also play a critical protective function against infection by parasites and bacteria (17,40). Mast cells and basophils, which are highly related cells that circulate in the bloodstream, have cytoplasms full of granules containing preformed mediators, including histamine, serotonin, heparin, tryptases, and other enzymes that, upon release, cause rapid changes in the surrounding tissues via changes in vascular permeability, growth factor activity, and remodeling of the extracellular matrix (62). In addition, activated mast cells also synthesize and secrete lipid mediators, including leukotrienes and prostaglandins, which are products of the lipooxygenase and cyclooxygenase pathways, respectively. The major leukotriene produced by mast cells is leukotriene C 4 (LTC 4 ); upon release, LTC 4 is converted to LTD 4 and LTE 4 , leading to prolonged bronchoconstriction, increased bronchial mucus production, increased venular permeability and arterial constriction, and cutaneous wheal-and-flare responses. The secretion of prostaglandin D 2 by activated mast cells inhibits platelet aggregation and promotes the recruitment of neutrophils (40). Mast cells are also a rich source of cytokines, including interleukin 2 (IL-2), IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, gamma interferon, tumor necrosis factor alpha (TNF-␣), and granulocyte-monocyte colony-stimulating factor, and of chemokines, such as monocyte chemoattractant protein 1 and macrophage inhibitory proteins 1␣ and 1. The secretion of these factors at later times after mast cell activation leads to changes in the growth, activation, and motility of leukocytes and lymphocytes (62).Mast cells and basophils play a role in immune surveillance and can recognize antigens via cell-associated immunoglobulin E (IgE) bound to its high-affinity receptor (FcεRI). FcεRI is composed of a predominantly extracellular ␣ chain that binds the Fc portion of IgE, a tetramembrane-spanning  subunit, and a dimeric ␥ chain. The  and ␥ chains possess important signaling motifs that are composed of twice-repeated YxxL sequences flanking seven variable residues and that are called immunoreceptor tyrosine-based activation motifs (ITAMs) (12). ITAMs are also found in the B-cell antigen receptor, T-cell receptor signaling subunits (46), and the glycoproteinVI (GPVI) receptor for collagen on platelets (61). Upon activation, these receptors are recruited to specialized cholesterolrich regions of the plasma membrane that are called lipid rafts (also called glycolipid-enriched membrane domains or detergent-resistant membranes) and that allow for the compartmentalization of proteins involved in signali...