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.
Department of Pharmacology, W 1345 BSTWR, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Mark
M
Rizzo
Guillermo
G
Romero
D000818:Animals; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010712:Phosphatidic Acids / Q000096:biosynthesis* / Q000378:metabolism* / Q000502:physiology; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology
D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D010712:Phosphatidic Acids; D020928:Mitogen-Activated Protein Kinases; D010739:Phospholipase D