LAT is essential for Fc epsilon RI-mediated mast cell activation

The linker molecule LAT is a substrate of the tyrosine kinases activated fo llowing TCR engagement of T cells. LAT is also expressed in platelets, NK, and mast cells. Although LAT-deficient mice contain normal numbers of mast cells, we found that LAT-deficient mice were resistant to IgE-mediated pass ive systemic anaphylaxis. LAT-deficient bone marrow-derived mast cells (BMM C) showed normal growth and development. Whereas tyrosine phosphorylation o f Fc epsilon RI, Syk, and Vav was intact in LAT-deficient BMMCs following F c epsilon RI engagement, tyrosine phosphorylation of SLP-76, PLC-gamma 1, a nd PLC-gamma 2 and calcium mobilization were dramatically reduced. LAT-defi cient BMMCs also exhibited profound defects in activation of MAPK, degranul ation, and cytokine production after Fc epsilon RI cross-linking. These res ults show that LAT plays a critical role in Fc epsilon RI-mediated signalin g in mast cells.