LT biosynthesis and assembly. Upon cellular activation of a mast cell or macrophage by IgE-antigen complexes or other stimuli, a cascade of cell activation events results in LT biosynthesis. A concomitant rise in free calcium induces translocation of cPLA2 to intracellular membranes, where it releases arachidonic acid. In parallel, 5-LO is phosphorylated by MAP kinase kinase and traffics through the nuclear pore to the nucleus (possibly in association with NF-κB) or directly to the outer nuclear envelope. 5-LO then associates with the nuclear membrane, and possibly with FLAP. FLAP facilitates arachidonic acid presentation to 5-LO and subsequent conversion of arachidonic acid to LTA4. LTA4 interacts with LTA4 hydrolase to form LTB4, or with LTC4 synthase to form LTC4. The synthesis of LTs A4, B4, and C4probably takes place within the lumen of, or in close proximity to, the nuclear membranes. However, for clarity they are shown here throughout the cytosol. FLAP is present on both the inner and the outer nuclear envelope, but LTC4 synthase is exclusively expressed on the outer nuclear membrane and ER.