Phospholipase D: role in signal transduction and membrane traffic.

The activation of phospholipase D (PLD) in response to cell stimulation by extracellular signal molecules is a widespread phenomenon. A variety of extracellular signal molecules cause a rapid and dramatic stimulation of PLD activity. G proteins and protein kinases appear to be involved in the receptor-mediated regulation of PLD. There is indirect evidence for the existence of multiple PLD subtypes, both membrane-associated and cytosolic. Recent studies indicate that PLD activities require a lipid cofactor, phosphatidylinositol 4,5-bisphosphate (PIP2). Addition of PIP2 at physiological concentrations stimulates both membrane-associated and partially purified PLD activity. Other acidic phospholipids have little or no effect. Neomycin, a high affinity ligand of PIP2, inhibits membrane PLD activity, presumably by binding to endogenous PIP2. A monoclonal antibody to phosphatidylinositol 4-kinase inhibits PIP2 synthesis in permeabilized U937 cells and blocks PLD activation by GTP gamma S and TPA. These results indicate that PIP2 synthesis is required for G protein- and protein kinase C-mediated activation of PLD in the cells. Recent evidence has implicated PLD and phosphoinositide kinases in vesicular trafficking. The main lipid mediator produced by PLD, phosphatidic acid, could regulate membrane traffic events by direct regulation of target proteins involved in vesicle targeting, docking and fusion. In addition, under certain circumstances, the formation of phosphatidic acid may lead to changes in lipid bilayer properties that would facilitate vesicle budding and fusion events in the course of intracellular membrane traffic.