Growth factor-like effects of lysophosphatidic acid, a novel lipid mediator (original) (raw)
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Lysophosphatidic acid as a phospholipid mediator: pathways of synthesis
FEBS Letters, 1997
From very recent studies, including molecular cloning of cDNA coding for membrane receptors, lysophosphatidic acid (LPA) reached the status of a novel phospholipid mediator with various biological activities. Another strong argument supporting this view was the discovery that LPA is secreted from activated platelets, resulting in its appearance in serum upon blood coagulation. The metabolic pathways as well as the enzymes responsible for LPA production are poorly characterized. However, a survey of literature data indicates some interesting issues which might be used as the basis for further molecular characterization of phospholipases A able to degrade phosphatidic acid.
Development of Our Current Understanding of Bioactive Lysophospholipids
Annals of the New York Academy of Sciences, 2006
Lysophosphatidic acid (LPA) serves as the prototypic lysophospholipid mediator that acts through G-protein-coupled receptors to evoke a host of responses in numerous target cells. The hormone-and growth-factor-like activities of LPA, mediated by distinct G proteins, were discovered about 10 years ago. Since then, considerable progress has been made in our understanding of LPA receptor signaling, culminating in the recent identification of a growing family of heptahelical receptors specific for LPA and the structurally related lysolipid, sphingosine-1-phosphate (S1P). In addition to stimulating G i-Rasmediated cell proliferation, LPA and S1P induce rapid G= 12/13-RhoAmediated cytoskeletal changes underlying such diverse responses as neurite retraction, cell rounding, and enhanced tumor cell invasiveness. LPA also triggers inhibition of gap-junctional communication. This overview focuses on how our understanding of LPA as an intercellular lipid mediator has developed during the last decade.
The Biochemical journal, 1992
Lysophosphatidic acid (LPA) is a simple phospholipid that possesses hormone- and growth-factor-like properties. LPA initiates its action by inducing GTP-dependent phosphoinositide hydrolysis and inhibiting adenylate cyclase [van Corven, Groenink, Jalink, Eichholtz & Moolenaar (1989) Cell 59, 45-54]. Here we show that LPA stimulates rapid breakdown of phosphatidylcholine (PC) in Rat-1 fibroblasts. LPA-induced PC breakdown occurs through activation of phospholipase D (PLD), as measured by the formation of free choline and phosphatidic acid and by transphosphatidylation in the presence of butan-1-ol. LPA also stimulates generation of diacylglycerol, but there is no detectable formation of phosphocholine, suggesting that a PC-specific phospholipase C (PLC) is not involved. The response to LPA was compared with that to endothelin, a potent inducer of phospholipid hydrolysis but a poor mitogen for Rat-1 cells. Our results indicate that: (1) LPA is less efficient than endothelin in inducin...
Archives of Biochemistry and Biophysics, 1996
Ether-linked lysophosphatidic acid, 1-alkyl-2-lyso-Intracellular Ca 2/ mobilization and the release of free sn-glycero-3-phosphate (ALPA), 4 is a lipid phosphoric fatty acids and inositol phosphates were not inhibited acid with an alkyl chain at the sn-1 position of the by pretreatment of platelets with pertussis toxin (PTX) phosphoglycerol backbone. ALPA can be derived from or the PAF receptor antagonist WEB 2086. Following naturally occurring bioactive phospholipids such as platelet stimulation with ALPA, tyrosine phosphoryla-1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelettion of proteins with apparent molecular masses of 65-95, 110-130, and 145-170 kDa was increased in a time-activating factor, PAF) following enzymatic cleavage of dependent manner, while phosphorylation of 40-to its choline and acetate groups. Phosphatidic acids (PA), 45-kDa proteins was decreased. One of the platelet propredominantly diacylglycerophosphates, are well esteins phosphorylated on tyrosine residues in response tablished as important intermediates in the biosyntheto ALPA was found to be PLC-g1. Exogenous [ 3 H]ALPA sis of glycerophospholipids (1). However, evidence has was metabolized primarily to [1-3 H]alkyl-2,3-diacylbeen presented that these compounds, particularly lyglycerol. The metabolic conversion of [ 3 H]ALPA insophosphatidic acids (LPAs), evoke a variety of biologivolved a dephosphorylation reaction, and the formacal responses suggesting at least that LPAs possess tion of the dephosphorylated product, [1-3 H]alkylsignaling capabilities (see Refs. 2, 3 for reviews). It has monoglycerol, was detected within 5 s. These data been demonstrated that extracellular acyl-LPA aggredemonstrate that an ether-linked lysophosphatidic 4 Abbreviations used: ALPA, alkyllysophosphatidic acid (1-hexade-
Clinical cancer research : an official journal of the American Association for Cancer Research, 2000
Ascitic fluid and plasma from ovarian cancer patients, but not from patients with nongynecological tumors, contain elevated levels of the bioactive phospholipid lysophosphatidic acid (LPA). We show that ovarian cancer cells constitutively produce increased amounts of LPA as compared with normal ovarian epithelium, the precursor of ovarian epithelial cancer, or breast cancer cells. In addition, LPA, but not other growth factors, increases LPA production by the OVCAR-3 ovarian cancer cell line but not by normal ovarian epithelium or breast cancer cell lines. We show that phospholipase D activity contributes to both constitutive and LPA-induced LPA production by ovarian cancer cells. Constitutive and LPA-induced LPA synthesis by ovarian cancer cells is differentially regulated with respect to the requirement of specific phospholipase A2 (PLA2) subgroups. Group IB (pancreatic) secretory PLA2 plays a critical role in both constitutive and LPA-induced LPA formation, whereas group IIA (syn...
Pharmacological Characterization of Phospholipid Growth-Factor Receptors
Annals of the New York Academy of Sciences, 2006
The phospholipid growth-factor (PLGE) terminology is proposed to describe a group of endogenous glycerol- and sphingolipid mediators that regulate cell proliferation through plasma membrane receptors. In addition to LPA and SPP, multiple PLGFs are present in blood plasma and serum. PLGF activity is regulated by its stimulus-coupled production and by endogenous inhibitors. In addition to LPA and SPP, alkenyl-glycerophosphate, cyclic-phosphatidic acid, and sphingosylphosphorylcholine were detected in biological fluids using mass spectrometry. Heterologous desensitization studies indicate the expression of multiple LPA-activated receptors in a variety of cell types, which are differentially activated by the different PLGFs. Northern blot and RT-PCR results reinforce the coexpression of PSP24 alpha and different members of the EDG1-7 receptors in the same cell. Stable heterologous expression of the PSP24 alpha, EDG2, and EDG4 receptors in HEK293 cells show distinct PLGF specificities and dose-response properties for each receptor subtype. Thus, both the controlled availability of the different agonists/inhibitors and the regulated expression of their receptors regulate the biological effects of PLGFs.
Unfolding the Pathophysiological Role of Bioactive Lysophospholipids
Current Drug Targets - Immune, Endocrine & Metabolic Disorders, 2003
Lysophospholipids (LPLs), including glycerol-and sphingoid-based lipids, stimulate cell signaling and play important pathophysiological roles in humans and other animals. These LPLs include lysophosphatidic acid (LPA), lysophosphatidylinositol (LPI), lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), sphingosine-1-phosphate (S1P), and sphingosylphosphorylcholine (SPC). Analyses of LPLs in human body fluids from subjects with different pathophysiological conditions reveal not only the relevance of LPLs in human diseases, but also their potential application as biomarkers and/or therapeutic targets. In recent years, the identification and/or characterization of the plasma membrane receptors for LPLs and enzymes regulating the metabolism of LPLs have greatly facilitated our understanding of their role and signaling properties. In vitro and in vivo functional and signaling studies have revealed the broad and potent biological effects of LPLs and the mechanisms of LPL actions in different cellular systems. Development of specific antagonists for each of the LPL receptors will provide powerful tools for dissecting signaling pathways mediated by receptor subtypes. More importantly, these antagonists may serve as therapeutics for relevant diseases. Genetic depletion of LPL receptors in mice has provided and will continue to provide critical information on the pathophysiological roles of LPL receptors. It is important to further evaluate the significance of targeting these bioactive LPL receptors, their downstream signaling molecules, and/or metabolic enzymes in the treatment of cancers and other diseases.
Biochimica Et Biophysica Acta Lipids and Lipid Metabolism, 1984
A simple method of determination of phosphatidylinositol-specific phospholipase C activity in soluble platelet extracts has been devised. It is based on the use of a total lipid extract from rat liver microsomes incubated with (3H]inositol in the presence of MnCI,. Phosphatidylinositol hydrolysis can thus be detected by determining hydrosoluble radioactivity formed upon incubation with enzyme fractions. Owing to the presence of other phospholipids in the assay system, phospholipase C was inhibited. However, activity was restored by sodium deoxycholate (O.l%, w/v). Optimal conditions also included calcium (l-10 mM) and a pH between 5 and 7, allowing the detection of phospholipase C without the need for purifying the substrate. Using this simplified procedure, platelet phospholipase C was submitted to preparative electrofocusing and to gel filtration chromatography on Sephacryl S-200. Phospholipase C focused in one single peak at pH 6.1. An ikf, of 86 000 was found upon gel chromatography of a crude extract, against 68 000 when phospholipase C had been previously purified by electrofocusing. These data indicate that phospholipase C might be associated with lipids or with an IV, 20000 protein, the significance of which is discussed. Abbreviation: Pipes, piperazine-1,4-bis(2-ethane-sulfonic acid). 0005-2760/84/$03.00 0 1984 Elsevier Science Publishers B.V.