The high affinity receptor for IgE (FcepsilonRI) is central to allergic reactions. It is a tetrameric structure (alphabetagamma2) when expressed on mast cells and basophils. The a chain is solely responsible for binding the ligand IgE while the beta and gamma chains are involved in signaling. Aggregation of FcepsilonRI by IgE and the corresponding multivalent antigen induces the release of allergy mediators and proinflammatory cytokines. One of the critical events that connect FcepsilonRI aggregation with mediator and cytokine secretion is Ca2+ mobilization. Ca2+ mobilization is comprised of Ca2+ release from intracellular stores, and Ca2+ entry from the extracellular milieu. The role played by phospholipase Cgamma in contributing to Ca2+ release from intracellular stores is well documented. It produces the second messenger 1,4,5-triphosphate (IP3) that binds to IP3 receptors, thereby inducing Ca2+ release from intracellular stores. A few years ago we showed that, in addition to the well known role played by phospholipase Cgamma, sphingosine 1-phosphate (S1P) was critical in Ca2+ release induced by FcepsilonRI. S1P is produced by the action of a sphingosine kinase activity on sphingosine. Two sphingosine kinases have been cloned but they have not been shown to be involved in the Ca2+ release induced by FcepsilonRI aggregation. In this proposal our central hypothesis is that FceRI-dependent Ca2+ release requires both PLCgamma and PI3KC2beta activation and that PI3KC2beta plays a major role in mast cell function. We present preliminary data showing that PI3KC2beta possesses SK activity, is activated after FcepsilonRI aggregation, and contributes significantly to Ca2+ release.
In Aim 1 we will elucidate the mechanisms of FcepsilonRI-mediated activation of the PI3KC2beta sphingosine kinase activity.
In Aim 2 we will dissect the structural requirements underlying the sphingosine kinase function of PI3KC2beta.
In Aim 3 we will elucidate the role of sphingosine kinase function of PI3KC2beta in mast cell development and mast cell function in vitro and in vivo using mice with a mast cell specific PI3KC2beta deficiency. All together, the proposed experiments will provide a comprehensive characterization of PI3KC2beta and its sphingosine kinase activity, and define its role in mast cell physiology.
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