TRANSCELLULAR LEUKOTRIENE BIOSYNTHESIS AND INFLAMMATION

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DESCRIPTION (Adapted from applicant's abstract and specific aims): Lipoxygenase enzymes catalyze the formation of mono-(S) hydroxy-eicosatetraenoic acids (HETE). 5-lipoxygenase (5-LO) forms a chemically complex and potent family of lipid mediators designated leukotrienes which participate in the pathophysiology of pulmonary inflammatory disorders. The current model of leukotriene production in activated cells requires redistribution of 5-lipoxygenase from a soluble, cytosolic compartment to a membrane associated state where it engages an accessory protein, 5-lipoxygenase activating protein (FLAP). Molecular process which govern the activation and redistribution of 5-LO are poorly understood. Src homology (SH) domains are conserved intra-molecular amino acid sequences which mediate protein: protein interactions that are essential features of tyrosine kinase signal transduction pathways. The application hypothesize that lipoxygenases participate in cellular signal transduction pathways via intramolecular domains that mediate protein: protein interactions. The global hypothesis is that lipoxygenase enzymes have an important and previously unrecognized role in cellular activation that is independent of their enzymatic transformation of arachidonic acid into lipid mediators. The specific aims are to: 1) characterize protein: protein interactions between lipoxygenase enzymes and signaling proteins with SH3 domains; 2) characterize protein: protein interactions between lipoxygenase enzymes and cytoskeletal proteins; 3) characterize the effect of tyrosine kinases and mitogen-activated protein kinases on lipoxygenase enzymes; and 4) characterize 5-lipoxygenase as a GDP/GTP nucleotide exchange protein, or as a modulator of nucleotide exchange.