Membrane sidedness of biosynthetic pathways involved in the production of lysophosphatidic acid

Balle, François Le; Simon, Marie‐Pierre; Meijer, Sandra N.; Fourcade, Olivier; Chap, Hugues

doi:10.1016/s0065-2571(98)00024-7

Cited by 28 publications

(28 citation statements)

References 38 publications

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“…Secretory (Type II) PLA 2 is capable of generating LPA from microvesicles with increased membrane asymmetry (45). However, platelets isolated from mouse strains that are genetically deficient in sPLA 2 show apparently normal LPA production (44). Our results confirm that plasma is devoid of PA-specific PLA 2 activity (46).…”

Section: Figsupporting

confidence: 67%

“…Two markedly different sets of PLA 2 activities distinguished by their Ca 2ϩ requirements and pH optimums have been described in platelets (5, 18 -20, 42, 43). However, inhibitors of type I and II PLA 2 enzymes are without effect on LPA production from activated platelets (44). Secretory (Type II) PLA 2 is capable of generating LPA from microvesicles with increased membrane asymmetry (45).…”

Section: Figmentioning

confidence: 99%

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Multiple Mechanisms Linked to Platelet Activation Result in Lysophosphatidic Acid and Sphingosine 1-Phosphate Generation in Blood

Sano¹,

Baker²,

Virág³

et al. 2002

Journal of Biological Chemistry

243

239

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Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (Sph1P) production was examined in vitro under conditions that simulated blood clotting. Several approaches were utilized to elucidate the metabolic pathways. 1) Platelet phospholipids were labeled using [ 32 P]orthophosphate, and the production of [ 32 P]Sph1P and LPA was examined. Thrombin stimulation of platelets resulted in rapid secretion of Sph1P stored within the platelet. In contrast, LPA was neither stored within nor secreted from platelets. Nonetheless, extracellular levels of LPA gradually increased following stimulation. 2) Stable-isotope dilution mass spectrometry was used to quantify the molecular species of LPA generated from platelets in vitro. Only 10% of the LPA generated following thrombin stimulation was associated with platelets, the remaining 90% was contained within the extracellular medium. The acyl composition of LPA produced by platelets differed depending on the presence or absence of plasma in the incubation. 3) The fate of exogenously added fluorescent phospholipid analogs was determined. Incubation of [(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl-(NBD)-labeled phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine with the supernatant fractions from thrombin-stimulated platelets yielded no LPA production. However, these lipids were converted to the corresponding lysolipids by released PLA 1 and PLA 2 activities. When incubated with plasma or serum the NBD-labeled lysophospholipids were readily converted to LPA. Inhibitors of lysophospholipase D and the biological activity of LPA were detected in plasma. These results suggest that the bulk of LPA produced through platelet activation results from the sequential cleavage of phospholipids to lysophospholipids by released phospholipases A 1 and A 2 and then to LPA by plasma lysophospholipase D.Lysophosphatidic acid (LPA) 1 and sphingosine 1-phosphate (Sph1P) are phospholipid mediators with pleiotropic growth factor properties that elicit their actions via the activation of G protein-coupled receptors encoded by the endothelial differentiation gene family (1, 2). Several investigators have identified platelets as the source of Sph1P and LPA. However, contradictions exist in the literature concerning the mechanisms by which these mediators are generated. Although some investigators found no Sph1P generation in thrombin-activated platelets (3), others reported as much as 0.5 M Sph1P in human serum (4). Although it is generally agreed that LPA is generated in thrombin-activated platelets (3, 5, 6), the rate of production found at 0.02 nmol/min/10 9 platelet cannot account for the 5-10 M concentration detected in human serum (7). During the first hour of blood clotting the concentration of LPA increases ϳ300 nM; however, its production continues and an additional 5 M is added to serum during the first 24 h, a time course that is hard to reconcile with that of platelet activation and consequently of platelet only origin. Gerrard and Robinson (6) quantified the molecul...

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Section: Figsupporting

confidence: 67%

Section: Figmentioning

confidence: 99%

Multiple Mechanisms Linked to Platelet Activation Result in Lysophosphatidic Acid and Sphingosine 1-Phosphate Generation in Blood

Sano¹,

Baker²,

Virág³

et al. 2002

Journal of Biological Chemistry

243

239

View full text Add to dashboard Cite

show abstract

“…For example, studies using inhibitors of PLA 2 isoforms have suggested that sPLA 2 -IB, Ca 2ϩ -independent PLA 2 , and cytosolic PLA 2 were partially involved in the LPA production of ovarian cancer cells (12,13). It was also proposed that sPLA 2 -IIA was able to produce LPA by hydrolyzing PA exposed on the cell surface after phospholipid scrambling (37) or by hydrolyzing PA on membrane microvesicles shed from erythrocytes (33).…”

Section: Discussionmentioning

confidence: 99%

A Novel Phosphatidic Acid-selective Phospholipase A1That Produces Lysophosphatidic Acid

Sonoda

Aoki

Hiramatsu

et al. 2002

Journal of Biological Chemistry

193

182

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Lysophosphatidic acid (LPA) is a lipid mediator with diverse biological properties, although its synthetic pathways have not been completely solved. We report the cloning and characterization of a novel phosphatidic acid (PA)-selective phospholipase A 1 (PLA 1 ) that produces 2-acyl-LPA. The PLA 1 was identified in the GenBank TM data base as a close homologue of phosphatidylserine (PS)-specific PLA 1 (PS-PLA 1 ). When expressed in insect Sf9 cells, this enzyme was recovered from the Triton X-100-insoluble fraction and did not show any catalytic activity toward exogenously added phospholipid substrates. However, culture medium obtained from Sf9 cells expressing the enzyme was found to activate EDG7/LPA 3 , a cellular receptor for 2-acyl-LPA. The activation of EDG7 was further enhanced when the cells were treated with phorbol ester or a bacterial phospholipase D, suggesting involvement of phospholipase D in the process. In the latter condition, an increased level of LPA, but not other lysophospholipids, was confirmed by mass spectrometry analyses. Expression of the enzyme is observed in several human tissues such as prostate, testis, ovary, pancreas, and especially platelets. These data show that the enzyme is a membrane-associated PA-selective PLA 1 and suggest that it has a role in LPA production.

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“…LPA is produced in membrane microvesicles from stimulated platelets, leukocytes, or tumor cells, and then is secreted outside on physiological activation, tissue injury, inflammation, and neoplasia (17,29,33). The principal effects of LPA are growth related, including induction of cellular proliferation, alterations in differentiation and survival, and suppression of apoptosis (see Ref.…”

mentioning

confidence: 99%

Enhancement of survival by LPA via Erk1/Erk2 and PI 3-kinase/Akt pathways in a murine hepatocyte cell line

Sautin

Crawford

Svetlov

2001

American Journal of Physiology-Cell Physiology

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In these models of hepatocellular injury, LPA prevented hepatocyte damage, suppressed apoptosis, and enhanced cell survival in a dose-dependent fashion. The protective effects of LPA were abolished by wortmannin and LY-294002, specific inhibitors of phosphatidylinositol 3-phosphate kinase (PI 3-kinase), and by PD-98059 and U-0126, inhibitors of MEK1/MEK2. In nontreated hepatocytes, LPA elicited a gradual and sustained increase in phosphorylation of Erk1/Erk2 over 180 min of stimulation and downstream phosphorylation of p90RSK and transcription factor Elk-1. In C. difficile toxin-treated cells, LPA-induced phosphorylation of Erk1/Erk2 was rapid but transient, while p90RSK and Elk-1 phosphorylation did not change significantly. LPA stimulated phosphorylation of Akt in a timedependent manner in both intact and toxin-treated AML12 hepatocytes. Wortmannin and LY-294002 abolished phosphorylation of Akt, further supporting activation of PI 3-kinase/Akt as a signaling pathway, which mediates hepatocyte protection by LPA. Taken together, these results demonstrate that LPA prevents cell apoptosis induced by C. difficile toxin and TNF-␣/ D-galactosamine in the AML12 murine hepatocyte cell line. Cell protection by LPA involves activation of the mitogen-activated protein kinase Erk1/Erk2 cascade and PI 3-kinase-dependent phosphorylation of Akt. lysophosphatidic acid; phosphatidylinositol-3-phosphate kinase; Clostridium difficile; mitogen-activated protein kinase

show abstract

Membrane sidedness of biosynthetic pathways involved in the production of lysophosphatidic acid

Cited by 28 publications

References 38 publications

Multiple Mechanisms Linked to Platelet Activation Result in Lysophosphatidic Acid and Sphingosine 1-Phosphate Generation in Blood

Multiple Mechanisms Linked to Platelet Activation Result in Lysophosphatidic Acid and Sphingosine 1-Phosphate Generation in Blood

A Novel Phosphatidic Acid-selective Phospholipase A1That Produces Lysophosphatidic Acid

Enhancement of survival by LPA via Erk1/Erk2 and PI 3-kinase/Akt pathways in a murine hepatocyte cell line

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