Phospholipase D-mediated hydrolysis of phosphatidylcholine: role in cell signalling.
Studies carried out in many laboratories have demonstrated the activation of phospholipase D (PLD) by a variety of receptor agonists and in many cell types. The signal-dependent formation of phosphatidic acid (PA), by PLD-catalyzed hydrolysis of phosphatidylcholine (PC), may represent a novel and ubiquitous signal transduction pathway in mammalian cells. The mode(s) of coupling between agonist receptors and PLD activation are not well understood. Studies utilizing NIH-3T3 fibroblasts indicated that PLD activation by different mitogens involves distinct mechanisms. Protein kinase C (PKC) seems to play a role both as a mediator and as a modulator of PLD activation. The role of PKC was further examined in Swiss/3T3-derived fibroblasts which stably overexpress PKC-alpha. In these cells, both basal and agonist-stimulated PLD activity are higher than in control cells. In vitro analysis of PLD activity in detergent-solubilized cell membranes, utilizing exogenous C6-NBD-PC as fluorescent substrate, showed nearly 2-fold higher activity in membranes from cells that overexpress PKC-alpha. These results suggest that PKC-alpha may play a role in regulating PLD expression. The PLD product PA was identified as a precursor of 'late phase' diacylglycerol which, at least in some cases, was temporally correlated and causally related to the sustained activation of PKC. However, PA may itself act as an intracellular messenger in its own right, although immediate targets for its action have not yet been identified. Activation of phosphoinositide-phospholipase C, PLD and phospholipase A2 seems to comprise a signaling cascade which is typically utilized by most (if not all) Ca(2+)-mobilizing agonists.
Liscovitch
M
M
Department of Hormone Research, Weizmann Institute of Science, Rehovot, Israel.
Ben-Av
P
P
Danin
M
M
Faiman
G
G
Eldar
H
H
Livneh
E
E
D016475:3T3 Cells / Q000201:enzymology; D000818:Animals; D004789:Enzyme Activation; D006868:Hydrolysis; D051379:Mice; D010712:Phosphatidic Acids / Q000502:physiology; D010713:Phosphatidylcholines / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D010712:Phosphatidic Acids; D010713:Phosphatidylcholines; D011493:Protein Kinase C; D010739:Phospholipase D