Cellular components that functionally interact with signaling phospholipase A2s

Accumulating evidence has suggested that cytosolic phospholipase A2 (cPLA2) and several secretory PLA2 (sPLA2) isozymes are signaling PLA2s that are functionally coupled with downstream cyclooxygenase (COX) isozymes for prostaglandin (PG) biosynthesis. Arachidonic acid (AA) released by cPLA2 and sPLA2s is supplied to both COX-1 and COX-2 in the immediate, and predominantly to COX-2 in the delayed, PG-biosynthetic responses. Vimentin, an intermediate filament component, acts as a functional perinuclear adapter for cPLA2, in which the C2 domain of cPLA2 associates with the head domain of vimentin in a Ca2+-sensitive manner. The heparin-binding signaling sPLA2-IIA, IID and V bind the glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan glypican, which plays a role in sorting of these isozymes into caveolae and perinuclear compartments. Phospholipid scramblase, which facilitates transbilayer movement of anionic phospholipids, renders the cellular membranes more susceptible to signaling sPLA2s. There is functional cooperation between cPLA2 and signaling sPLA2s in that prior activation of cPLA2 is required for the signaling sPLA2s to act properly. cPLA2-derived AA is oxidized by 12/15-lipoxygenase, the products of which not only augment the induction of sPLA2 expression, but also cause membrane perturbation, leading to increased cellular susceptibility to the signaling sPLA2s. sPLA2-X, a heparin-non-binding sPLA2 isozyme, is capable of releasing AA from intact cells in the absence of cofactors. This property is attributed to its ability to avidly hydrolyze zwitterionic phosphatidylcholine, a major phospholipid in the outer plasma membrane. sPLA2-V can also utilize this route in several cell types. Taken together, the AA-releasing function of sPLA2s depends on the presence of regulatory cofactors and interfacial binding to membrane phospholipids, which differ according to cell type, stimuli, secretory processes, and subcellular distributions.