A perspective: Regulation of IgE receptor-mediated mast cell responses by a LAT-organized plasma membrane-localized signaling complex

Background: To understand how the high-affinity IgE receptor (Fc epsilon RI ) communicates with downstream effecters, we focused on exploring the funct ional importance of the Fc epsilon RI-mediated formation and localization o f a signaling complex that contains the hematopoietic cell-specific scaffol ding protein linker for activation of T cells (LAT) and the guanine nucleot ide exchange factor Vav1. Methods: Using the mast cell line RBL-2H3, we exp lored the localization of these proteins by confocal microscopy and cell fr actionation. Additionally, the mechanism of function and the importance of LAT and Vav1 to mast cells was studied in genetically disrupted mice and in mast cells derived from their bone marrow. Results: We found that LAT, Vav 1 and the adapter molecule SLP-76 associated in detergent-resistant microdo mains (lipid rafts) found in the plasma membrane upon Fc epsilon RI stimula tion. In the absence of LAT, mast cells showed a remarkable loss of the sec retory response and reduced cytokine responses. Vav1 deficiency also affect ed secretion, al though not to the extent of LAT deficiency, and inhibited IL-2 and IFN-gamma production. LAT- and Vav1-deficient mice showed reduced blood histamine levels after a systemic anaphylaxis challenge as compared t o their normal counterparts. Conclusions: The results demonstrate that LAT is a central mediator in IgE receptor signaling by regulating multiple sign aling pathways that affect mast cell degranulation and cytokine production. Vav1, a component of this LAT-containing signaling complex, regulates a sp ecific subset of these responses. Copyright (C) 2001 S. Karger AG,Basel.