Phospholipase D/phosphatidic acid signal transduction: Role and physiological significance in lung |
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Authors: | Cummings Rhett Parinandi Narasimham Wang Lixin Usatyuk Peter Natarajan Viswanathan |
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Affiliation: | (1) Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA;(2) Department of Pulmonary and Critical Care Medicine, The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Room 4B.64, Baltimore MD, 21224, USA |
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Abstract: | Phospholipase D (PLD), a phospholipid phosphohydrolase, catalyzes the hydrolysis of phosphatidylcholine and other membrane phospholipids to phosphatidic acid (PA) and choline. PLD, ubiquitous in mammals, is a critical enzyme in intracellular signal transduction. PA generated by agonist- or reactive oxygen species (ROS)-mediated activation of the PLD1 and PLD2 isoforms can be subsequently converted to lysoPA (LPA) or diacylglycerol (DAG) by phospholipase A1/A2 or lipid phosphate phosphatases. In pulmonary epithelial and vascular endothelial cells, a wide variety of agonists stimulate PLD and involve Src kinases, p-38 mitogen activated protein kinase, calcium and small G proteins. PA derived from the PLD pathway has second messenger functions. In endothelial cells, PA regulates NAD[P]H oxidase activity and barrier function. In airway epithelial cells, sphingosine-1-phosphate and PA-induced IL-8 secretion and ERK1/2 phosphorylation is regulated by PA. PA can be metabolized to LPA and DAG, which function as first- and second-messengers, respectively. Signaling enzymes such as Raf 1, protein kinase C and type I phosphatidylinositol-4-phosphate 5-kinase are also regulated by PA in mammalian cells. Thus, PA and its metabolic products play a central role in modulating endothelial and epithelial cell functions. |
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Keywords: | phospholipase D phosphatidic acid secretion barrier function endothelium airway epithelium |
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