The Function of SWAP-70 in Mast Cells

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DESCRIPTION (provided by applicant): Mast cells play diverse and important roles in the mammalian immune system. Upon aggregation of the Fc-epsilonRI receptor, mast cells can degranulate and release histamine and other biologically active compounds. While beneficial in some instances, e.g. within the innate immune system, such reactions are also causing allergic reactions, including asthma and anaphylaxis. Aberrant proliferation of mast cells characterizes many mast cell tumors. Details of the signaling pathways that trigger mast cell degranulation need to be further defined. Protein SWAP-70, identified by us earlier from B cells, has signatures of a novel type of signal transducing protein, and is also expressed in mast cells. Mast cells derived from our recently generated SWAP-70 -/- mice show impaired Fc-epsilonRI-triggered degranulation. This proposal suggests an important contribution of protein SWAP-70 to mast cell biology, i.e. exocytosis. Specifically, we hypothesize that SWAP-70 through its newly determined Rac-specific guanosine nucleotide exchange activity is important for Fc-epsilonRI-triggered exocytosis in mast cells. Therefore, we aim at understanding the role and position of SWAP- 70 in the signaling pathway leading to Fc-epsilonRI-triggered exocytosis, and will explore how SWAP-70 itself is regulated. Towards this goal, we will apply a combination of biochemical and cellular approaches. The proposed experiments should yield key information on pathways regulating mast cell exocytosis, and will help understanding mast cell-associated diseases such as allergic reactions.