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At least 19 recordsLinked to original sources
PubMed1996

Raf-1 kinase possesses distinct binding domains for phosphatidylserine and phosphatidic acid. Phosphatidic acid regulates the translocation of Raf-1 in 12-O-tetradecanoylphorbol-13-acetate-stimulated Madin-Darby canine kidney cells.

Previous studies demonstrated that the cysteine-rich amino-terminal domain of Raf-1 kinase interacts selectively with phosphatidylserine (Ghosh, S., Xie, W. Q., Quest, A. F. G., Mabrouk, G. M., Strum, J. C., and Bell, R. M. (1994) J. Biol. Chem. 269, 10000-10007). Further analysis showed that full-length Raf-1 bound to both phosphatidylserine and phosphatidic acid (PA). Specifically, a carboxyl-terminal domain of Raf-1 kinase (RafC; residues 295 648 of human Raf-1) interacted strongly with phosphatidic acid. The binding of RafC to PA displayed positive cooperativity with Hill numbers between 3.3 and 6.2; the apparent Kd ranged from 4.9 +/- 0.6 to 7.8 +/- 0.9 mol % PA. The interaction of RafC with PA displayed a pH dependence distinct from the interaction between the cysteine-rich domain of Raf-1 and PA. Also, the RafC-PA interaction was unaffected at high ionic strength. Of all the lipids tested, only PA and cardiolipin exhibited high affinity binding; other acidic lipids were either ineffective or weakly effective. By deletion mutagenesis, the PA binding site within RafC was narrowed down to a 35-amino acid segment between residues 389 and 423. RafC did not bind phosphatidyl alcohols; also, inhibition of PA formation in Madin-Darby canine kidney cells by treatment with 1% ethanol significantly reduced the translocation of Raf-1 from the cytosol to the membrane following stimulation with 12-O-tetradecanoylphorbol-13-acetate. These results suggest a potential role of the lipid second messenger, PA, in the regulation of translocation and subsequent activation of Raf-1 in vivo.

Amino Acid Sequence↗
PubMed1989

Stimulation of phosphatidylinositol 4,5-bisphosphate phospholipase C activity by phosphatidic acid.

Phosphatidic acid was a potent activator of the phosphatidylinositol 4,5-bisphosphate (PtdIns-P2) phospholipase C activity associated with human platelet membranes. Lysophosphatidic acid was half as active as phosphatidic acid, and shortening the fatty acid chain reduced the effectiveness of the corresponding phosphatidic acid. Compounds lacking either the phosphate group (diacylglycerol or phorbol ester) or the fatty acid (glycerol phosphate) were not activators. When the negative charge was contributed by a carboxyl group (fatty acid or phosphatidylserine), stimulation of phospholipase C was weak but detectable. Structural analogs of phosphatidic acid (lipopolysaccharide, lipid A, and 2,3-diacylglucosamine 1-phosphate) were less effective but also enhanced PtdIns-P2 hydrolysis. Phosphatidic acid potentiated the activation of phospholipase C by alpha-thrombin, chelators, and guanine nucleotides. Phosphatidylinositol 4-phosphate and PtdIns-P2 were also effective activators of PtdIns-P2 degradation. Other phospholipids were without effect. The production of inositol 1,4,5-trisphosphate and diacylglycerol via the activation of phospholipase C provides a rationale for the cellular responses evoked by phosphatidic acid and the ability of this phospholipid to potentiate and initiate hormonal responses.

Blood Platelets↗
PubMed1988

In vivo studies on stereospecificity of the monoglyceride kinase, lysophosphatidic acid acyltransferase, phosphatidic acid phosphatase and CDP-diglyceride synthase of Streptococcus mutans BHT using the stereoisomers of the ether lipid, dodecylglycerol.

Streptococcus mutans BHT metabolizes radioactive 3-dodecyl-sn-glycerol (sn-3-DDG) almost exclusively to lysophosphatidic acid, phosphatidic acid and 1,3-diradyl-sn-glycerol, whereas the cells of this organism metabolize 1-dodecyl-sn-glycerol (sn-1-DDG) to all of the glycerol lipids of S. mutans BHT, with the largest amounts incorporated into phosphatidylglycerol and diradylglycerol (mostly the 1,2- but also the 1,3-isomer). (The common names of lipids, such as phosphatidic acid, are used in the broader sense to mean that the lipid may contain alkyl as well as acyl groups.) The addition of an equivalent amount of nonradioactive sn-3-DDG to radioactive sn-1-DDG causes more of the radioactivity to accumulate at phosphatidic acid. These results indicate that the monoglyceride kinase (EC 2.7.1.94), lysophosphatidic acid acyltransferase (EC 2.3.1.40) and the monoglyceride acyltransferase (EC 2.3.1.22) enzymatic reactions are not stereospecific, and that the CDP-diglyceride synthase (EC 2.7.7.41) and phosphatidic acid phosphatase (EC 3.1.3.4) metabolic steps are stereospecific in S. mutans BHT. The synthesis of phosphatidic acid and lysophosphatidic acid from sn-3-DDG provides a unique method for synthesizing these glycerol lipids with the uncommon stereochemical configuration in which the phosphate moiety is in the sn-1 position.

Acyltransferases↗
PubMed1993

Calcium-independent activation of protein kinase C by the dianionic form of phosphatidic acid.

Phosphatidic acid in the form of small unilamellar vesicles has a dissociation constant of about 8.3 as determined by 31P nuclear magnetic resonance (NMR) spectroscopy. The activation of protein kinase C (PKC) by monovalent phosphatidic acid or phosphatidylserine occurs only in the presence of Ca2+. However, PKC activity on membranes of divalent anionic phosphatidic acid is independent of Ca2+ concentration.

Calcium↗
PubMed2000

Enhancement of the migration of metastatic human breast cancer cells by phosphatidic acid.

Phosphatidic acid (PA), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (SPP) are naturally occurring phospholipids which induce a variety of effects as extracellular messengers. In this study, we compared the effects of these phospholipid signaling molecules on the migration of invasive and noninvasive breast cancer cell lines, an index of the metastatic potential of these cells. As previously demonstrated, invasive MDA-MB-231 breast cancer cells exhibited increased constitutive (nonstimulated) migration in comparison to poorly invasive MCF-7 cells. Phosphatidic acid employed at nanomolar concentrations markedly potentiated migration of the invasive cells but had no effect on migration of either the noninvasive MCF-7 cells or nonneoplastic human epithelial cells. Lysophosphatidic acid and sphingosine 1-phosphate inhibited both the directed (chemotactic) and random (chemokinetic) migration of MDA-MB-231 cells. Experiments were undertaken to characterize the signaling pathway involved in constitutive and PA-stimulated migration of MDA-MB-231 cells. The tyrosine kinase inhibitors staurosporine and genistein inhibited constitutive and PA-induced migration in a dose-dependent manner, consistent with a role for tyrosine phosphorylation in the migratory response. In addition, the phosphatidylinositol (PI) 3' kinase inhibitors wortmannin and LY294002 strongly inhibited both the constitutive and PA-stimulated migration of the invasive breast cancer cells, indicating that PI-3' kinase plays an important role in the metastatic migration of breast cancer cells. Finally, PA-induced migration of MDA-MB-231 was markedly attenuated by pretreatment of cells with Clostridium difficile Toxin B, pertussis toxin and suramin, implying a role for a Gi receptor-dependent process involving activation of the small GTP-binding protein Rho. Since an enhanced ability to migrate heightens the metastatic potential of cells within solid tumors, our results suggest that the metastatic capabilities of breast cancer cells may be enhanced by a receptor-driven cellular process initiated by phosphatidic acid or related lipid phosphate messengers.

Breast Neoplasms↗
PubMed1998

Differential influence of rat liver fatty acid binding protein isoforms on phospholipid fatty acid composition: phosphatidic acid biosynthesis and phospholipid fatty acid remodeling.

The ability of two rat liver fatty acid binding protein (L-FABP) isoforms to influence microsomal phosphatidic acid biosynthesis, a key intermediate in glycerolipid formation, and phospholipid fatty acid remodeling was examined in vitro. Isoform I enhanced microsomal incorporation of [1-14C]-oleoyl-CoA into phosphatidic acid 7-fold while isoform II had no effect relative to basal. In contrast, isoform II enhanced microsomal incorporation of [1-14C]-palmitoyl-CoA into phosphatidic acid 4-fold while isoform I had no effect. These results suggest that each L-FABP isoform selectively utilized different acyl-CoAs for glycerol-3-phosphate esterification. Both isoforms stimulated phosphatidic acid formation by increasing glycerol-3-phosphate acyltransferase activity, not by increasing lysophosphatidic acid acyltransferase activity. Furthermore, the effects of L-FABP on phosphatidic acid biosynthesis could not be correlated with protection from acyl-CoA hydrolysis. L-FABP isoforms also influenced phospholipid fatty acid remodeling in a phospholipid-dependent manner. Isoform I preferentially enhanced oleate and palmitate esterification into phosphatidylethanol-amine, while isoform II stimulated esterification into phosphatidylcholine, phosphatidylserine and sphingomyelin. Taken together, these data demonstrated a unique role of each L-FABP isoform in modulating microsomally derived phospholipid fatty acid composition. (c) 1998 Elsevier Science B.V.

Acyl Coenzyme A↗
PubMed1986

Cholinergic stimulation of arachidonic acid and phosphatidic acid metabolism in C62B glioma cells.

Glioma C62B cells were incubated for 18 h with [1-14C]arachidonic acid. Most (80%) of the added [1-14C] arachidonic acid was taken into the intracellular pool; less than 1% of the intracellular [1-14C]arachidonic acid remained unesterified; the rest was present in glycerophospholipids. Acetylcholine stimulation of the prelabeled cells resulted in the rapid accumulation of free [1-14C]arachidonic acid, presumably liberated by hydrolysis from phospholipids. Labeled unesterified [1-14C]arachidonic acid peaked by 90 s and returned to basal levels by 5 min. Paralleling the transient increase of unesterified [1-14C]arachidonic acid were increases in level of radioactivity in an unidentified lipoxygenase metabolite of arachidonic acid and of radioactive phosphatidic acid. The release of arachidonic acid induced by acetylcholine or carbachol was blocked by muscarinic but not nicotinic receptor antagonists; adrenergic or histaminergic receptor agonists were ineffective at stimulating arachidonic acid liberation. In contrast to the transient effects of stimulation with cholinergic agonists, stimulation with the divalent cation ionophore A23187 resulted in a linear increase in the accumulation of liberated arachidonic acid for at least 1 h. Furthermore, the pattern of metabolites synthesized from arachidonic acid in response to ionophore stimulation was more complex than that observed following cholinergic stimulation and included also several metabolites derived from cyclooxygenase activity. We conclude that muscarinic receptor agonists rapidly induce specific changes in arachidonic acid and phosphatidic acid metabolism in a glioma cell line and suggest that similar responses may occur in glial cells and play a physiologically significant role in neural metabolism.

Acetylcholine↗
PubMed2001

Phospholipase A(2)-mediated fusion of neutrophil-derived membranes is augmented by phosphatidic acid.

Phosphatidic acid (PA), the product of phospholipase D (PLD) metabolism, is not only an important second messenger in neutrophil signal transduction but PA generation increases membrane fusogenicity. Following neutrophil stimulation, PA formation can be detected in azurophil, specific, and plasma membrane vesicle subcellular fractions, suggesting a potential role for PA formation in granule-plasma membrane fusion. Neutrophil stimulation also activates phospholipase A(2) (PLA(2)) and the release of arachidonic acid. In vitro fusion of plasma membrane vesicles and specific granules with complex liposomes were dependent on PLA(2) (<10 microM Ca(2+)) while the presence of PA in the liposomes augmented the effects of PLA(2). Azurophil granules were extremely resistant to fusion (no fusion at 12 mM Ca(2+) even in the presence of PLA(2)). However, in the presence of both PA and PLA(2) fusion could be detected at <5 microM Ca(2+), suggesting a direct role for phospholipid metabolism in neutrophil degranulation.

Cell Degranulation↗
PubMed1988

Activation of NADPH-dependent superoxide production in plasma membrane extracts of pig neutrophils by phosphatidic acid.

Phosphatidic acid (PA), a molecule that is rapidly produced by the stimulated turnover of phospholipids in a variety of cells including blood neutrophils, elicited NADPH-dependent superoxide anion (O2-) production in detergent extracts from membranes of resting pig neutrophils. The stimulatory effect of PA was independent of cytosolic factors, differing from arachidonic acid and sodium dodecyl sulfate which, on the contrary, absolutely required the presence of cytosol to elicit the same result. The O2(-)-forming activity of the detergent extract activable by PA, as that by sodium dodecyl sulfate and arachidonic acid plus cytosol, was found in the chromatographic fractions containing cytochrome b558 and presented a chromatographic profile identical to that of the activated NADPH oxidase, which was obtained from neutrophils prestimulated with phorbol 12-myristate 13-acetate. The PA-induced NADPH-dependent O2(-)-forming activity showed kinetic properties and sensitivity to the inhibitors similar to the classical ones of the activated neutrophil NADPH oxidase. The data suggest that, in this cell-free system, PA may stimulate O2- formation by direct interaction with latent NADPH oxidase of neutrophils or with some of its regulatory components.

Animals↗
PubMed1998

Regulation of PDE-4 cAMP phosphodiesterases by phosphatidic acid.

Phosphatidic acid (PA) has been previously shown to activate specifically some of the isoforms of type 4 cylic nucleotide phosphodiesterases (PDE-4) in an acellular system. In the present work, we have investigated the mechanism of PA-activating effect by using a recombinant PA-sensitive isoform, PDE-4D3. The enzyme was specifically activated by acidic phospholipids, but not by zwitterionic phospholipids or anionic detergents. The importance of the role of PA acidic groups in the activation process was confirmed by studying the influence of pH and ionic strength on activation. Crosslinking experiments suggested that PA might influence the ability of PDE-4D3 to form dimers. Binding studies performed with radiolabeled PA showed that PA binds to a PDE-4D3 preparation in a saturable manner. Specifically bound PA was displaced by anionic, but not by zwitterionic phospholipids. With a preparation of PDE-4B2, a PDE-4 isoform insensitive to PA activation, PA binding was only displaced by high concentrations of unlabeled PA, suggesting that high-affinity PA binding sites are only present on PDE-4D3. These data support the hypothesis that PA-activating effect depends on direct binding of the effector on specific sites carried by the PDE-4D3 protein.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Signaling functions of phosphatidic acid.

Phosphatidic acid (PA) has emerged as a new class of lipid mediators involved in diverse cellular functions in plants, animals, and microorganisms. Considerable progress has been made recently on the production, cellular function, and mode of action of PA in the cell. The cellular levels of PA undergo dynamic changes in response to developmental and environmental stimuli. The production of signaling PA is mediated by families of multiple enzymes that regulate the timing, location, amount, and molecular species of PA. A number of PA target proteins have been identified, which include proteins involved in phosphorylation and dephosphorylation of proteins and lipids, as well as in G protein regulation, vesicular trafficking, and metabolism. PA mediates cellular functions through different modes of action, such as membrane tethering, modulation of enzymatic activities, and/or structural effects on cell membranes. The regulatory processes in which PA has been implicated include signaling pathways in cell growth, proliferation, reproduction, and responses to hormones and biotic and abiotic stresses.

Animals↗
PubMedDate not supplied

Growth factor-like action of phosphatidic acid.

Phosphatidic acid (PA), an intriguing phospholipid that is rapidly produced during receptor-stimulated breakdown of phosphoinositides, has often been proposed to function as a Ca2+ ionophore in activated cells. The PA-ionophore hypothesis is supported by the fact that exogenously applied PA stimulates Ca2+ uptake in various cells and can evoke Ca2+-mediated physiological responses, but it is not known whether PA accumulation affects cytoplasmic free Ca2+ concentration ([Ca2+]i). Here we report that PA elicits a transient rise in [Ca2+]i in cultured cells, not by stimulating Ca2+ influx, but, surprisingly, by releasing Ca2+ from intracellular stores. We further show that PA evokes growth factor-like effects in that it raises cytoplasmic pH, induces expression of the c-fos and c-myc proto-oncogenes and stimulates DNA synthesis. Our results indicate that, unlike an ionophore, PA acts by triggering the hydrolysis of phosphoinositides, with consequent formation of second messengers such as inositol trisphosphate signalling Cai2+ release. Furthermore, our data strengthen the notion that any Ca2+-mobilizing stimulus acting through phospholipase C may ultimately function as a growth factor.

Calcium↗
PubMed1980

Rapid acylation and deacylation of arachidonic acid into phosphatidic acid of horse neutrophils.

Horse neutrophils incorporate exogenous [14C]arachidonate into phosphatidic acid very rapidly. This acylation of phosphatidate with arachidonate is followed quickly and spontaneously by its deacylation. This transient formation of arachidonyl-phosphatidate, which reflects a rapidly turning over pool of arachidonate-associated lipid, is not observed with stearic acid or other phospholipids or triglycerides. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylinosinositol, and triglycerides are slowly but increasingly labeled with time. Ionophore A23187 (10 microM) stimulates the extent of labeling of phosphatidate while decreasing the labeling of all the other phospholipids and triglycerides. Phosphatidate is not transiently labeled with [14C]stearate of (32P)orthophosphate, either in the presence or absence of ionophore A23187. When cells are prelabeled for 2 h with very high quantities of (32P)orthophosphate a very substantial fraction (i.e. 20 to 30%) of the phospholipid radioactivity is associated with phosphatidic acid. However, on addition of exogenous arachidonate, there is no increase in [32P]phosphatidate in these prelabeled cells. Thus, the entire phosphatidate molecule does not appear to be turned over during the process described above. Inhibitors of cyclooxygenase and lipoxygenase activities such as BW755C, nordihydroguaiaretic acid, and low concentrations of indomethacin do not affect the labeling of phospholipids. However, eicosatetraynoic acid, an analog of arachidonate, and high concentration (0.1 mM) of indomethacin can block [14C]arachidonate incorporation into lipids. The rapid turnover of the 2-acyl position in phosphatidate might be related to a specific process of fatty acid mobilization within neutrophils.

Acylation↗
PubMed2005

Lysophosphatidic acid increases phosphatidic acid formation, phospholipase D activity and degranulation by human neutrophils.

I-oleoyl-sn-glycero-3-phosphate, a lysophosphatidic acid (LPA), in serum is a biologically active lipid and has multiple functions depending on the cell types. Several studies have shown that LPA stimulates phospholipase D (PLD) activity in fibroblasts and prostate cancer cells in culture. PLD plays a central role in regulating neutrophil functions. One of the functions of the lipid product, phosphatidic acid (PA), of PLD action in neutrophils is to promote degranulation. In the present study, we examined the effect of LPA on PLD activity and degranulation by human neutrophils. The results show that exogenous LPA increased PA formation, PLD activity and degranulation by human neutrophils in a time and concentration dependent manner. These findings suggest that LPA released from activated platelets during blood clotting may participate in bacterial killing and wound healing process. On the other hand, augmented LPA production might be involved in inflammation, causing damage of the host tissues.

Glucuronidase↗
PubMed1992

Mitogenic action of lysophosphatidic acid and phosphatidic acid on fibroblasts. Dependence on acyl-chain length and inhibition by suramin.

Lysophosphatidic acid (LPA) is a naturally occurring phospholipid with growth-factor-like activities [van Corven, Groenink, Jalink, Eichholtz & Moolenaar (1989) Cell 45, 45-54]. We have examined various structural analogues of LPA for their ability to stimulate DNA synthesis in quiescent fibroblasts. When the acyl-chain length is varied, the rank order of mitogenic potency is: 1-oleoyl LPA congruent to 1-palmitoyl LPA greater than 1-myristoyl LPA greater than 1-lauroyl LPA greater than 1-decanoyl LPA; the last compound shows almost no activity over the concentration range tested (1-100 microM). An ether-linked LPA (1-O-hexadecylglycerol 3-phosphate) has much decreased mitogenic activity as compared with the ester-linked analogue at concentrations less than 25 microM, and becomes cytotoxic at higher concentrations. Hexadecylphosphate, which lacks a glycerol backbone, has negligible activity. On a molar basis, diacyl phosphatidic acid (PA) is about equally potent as the corresponding LPA analogue, showing similar acyl-chain-length dependence; the data argue against the possibility that the mitogenic action of PA is due to contaminating traces of LPA. Although the short-chain analogues of LPA and PA fail to antagonize the action of long-chain (L)PAs, the polyanionic drug suramin inhibits LPA- and PA-induced, DNA synthesis in a reversible and dose-dependent manner, at concentrations [IC50 (concn. giving 50% inhibition) approximately 70 microM] that do not affect epidermal-growth-factor-induced DNA synthesis. Suramin appears to act in the early G0/G1 phase of the cell cycle, blocking immediate responses to LPA such as phosphoinositide hydrolysis. We conclude that both LPA and PA can function as growth-promoting phospholipids, with the fatty acid chain length being a major determinant of mitogenic potency.

Animals↗
PubMed1977

Site of synthesis of phosphatidic acid and diacyglycerol in spinach chloroplasts.

The enzymatic synthesis of lysophosphatidic acid, phosphatidic acid, monoacylglycerol and diacylglycerol from sn-[14C]glycerol 3-phosphate occurs in purified chloroplasts. The results indicate that: (1) the chloroplast extract contains a soluble acylase (acyl-CoA: sn-glycerol 3-phosphate acyltransferase); (2) the envelope fraction contains an acyl-CoA synthetase, a bound acylase (acyl-CoA: acyl-sn glycerol 3-phosphate acyltransferase) and a phosphatidic acid phosphatase; without chloroplast extract in the incubation medium, the envelope is unable to incorporate sn-glycerol 3-phosphate into phosphatidic acid and diacylglycerol; addition of chloroplast extract to the incubation medium induced a fast increase of the incorporation of sn-glycerol 3-phosphate into phosphatidic acid and diacylglycerol; thylakoids being unable to incorporate sn-glycerol 3-phosphate (in presence or absence of soluble chloroplast extract in the incubation medium) our results indicate that the envelope of spinach chloroplast is the site of phosphatidic acid and diacylglycerol synthesis; (3) diacylglycerol actively synthesized by the envelope is also the substrate for the first galactosylation enzyme.

Acyltransferases↗