Pharmacological importance of phospholipase D and phosphatidic acid in the regulation of the mitogen-activated protein kinase cascade

The stimulation of cells with many extracellular agonists leads to the activation of phospholipase (PL)D. PLD metabolizes phosphatidylcholine to generate phosphatidic acid (PA). Neither the mechanism through which cell surface receptors regulate PLD activation nor the functional consequences of PLD activity in mitogenic signaling are completely understood. PLD is activated by protein kinase C, phospholipids, and small GTPases of the ADP-ribosylation factor and Rho families, but the mechanisms linking cell surface receptors to the activation of PLD still require detailed analysis. Furthermore, the latest data on the functional consequences of the generation of cellular PA suggest an important role for this lipid in the regulation of membrane traffic and on the activation of the mitogen-activated protein kinase cascade. This review addresses these issues, examining some novel models for the physiological role of PLD and PA and discussing their potential usefulness as specific targets for the development of new therapies. (C) 2002 Elsevier Science Inc. All rights reserved.