Protein-tyrosine kinases and adaptor proteins in FcepsilonRI-mediated signaling in mast cells.

Mast cells function as the initiator of the allergic reaction and play a role in the innate immune system. Aggregation of the high affinity IgE receptor (FcepsilonRI) on mast cells triggers degranulation with the release of chemical mediators such as histamine, production of cytokines and leukotrienes. FcepsilonRI signals by activating proximal non-receptor type of protein-tyrosine kinases, Lyn, Syk, Btk and Fyn. Activated tyrosine kinases then phosphorylate their specific substrates which include other enzymes and adaptor proteins and assemble these cytoplasmic signaling molecules for cellular activation. The adaptor proteins have multiple domains that allow binding to effector molecules and therefore act as positive or negative regulators controlling FcepsilonRI signaling. Deletion of the adaptor proteins such as LAT, SLP-76 or Gab2 resulted in decreased FcepsilonRI-mediated anaphylactic reaction in vivo. Functional analysis of adaptor proteins has raised the possibility that they may be new targets for the discovery of anti-allergic drugs.