Regulation of phospholipase D signalling by phosphoinositides

Abstract In addition to their function as precursors for second-messenger generation by phospholipase C (PLC) and phosphoinositide 3-kinase (PI 3-kinase), phosphoinositides play important roles as ligands responsible for membrane localization and/or regulation of a growing number of proteins that are involved in many different aspects of cell regulation (1). This review focuses on phosphoinositides as regulators of phosphatidylcholine (PC)-specific phospholipase D (PLD). These are widely expressed enzymes that have been identified in bacteria, yeasts, plants, and mammals (2–4). PLD catalyses the hydrolysis of PC and generates phosphatidic acid (PA), which is almost certainly a lipid mediator in its own right and can serve as the precursor for the synthesis of a number of well-established bioactive lipids including lyso-phosphatidic acid (LPA) and diacylglycerol (DAG) (5, 6). Regulation of PLD activity is complex and growing experimental evidence points to roles for these enzymes in both receptor-dependent intracellular signalling and in control of vesicular transport (7). The common involvement of PLD suggests that these processes may be linked in some previously unappreciated manner. The major challenge to the field continues to be the definition of the molecular mechanisms involved in regulation of signalling and membrane movement by PLD.