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PubMed2002

Regulation of phospholipase D activity by actin. Actin exerts bidirectional modulation of Mammalian phospholipase D activity in a polymerization-dependent, isoform-specific manner.

Many critical cellular processes, including proliferation, vesicle trafficking, and secretion, are regulated by both phospholipase D (PLD) and the actin microfilament system. Stimulation of human PLD1 results in its association with the detergent-insoluble actin cytoskeleton, but the molecular mechanisms and functional consequences of PLD-actin interactions remain incompletely defined. Biochemical and pharmacologic modulation of actin polymerization resulted in complex bidirectional effects on PLD activity, both in vitro and in vivo. Highly purified G-actin inhibited basal and stimulated PLD activity, whereas F-actin produced the opposite effects. Actin-induced modulation of PLD activity was independent of the activating stimulus. The efficacy and potency of the effects of actin were isoform-specific but broadly conserved among actin family members. Human betagamma-actin was only 45% as potent and 40% as efficacious as rabbit skeletal muscle alpha-actin, whereas its inhibitory profile was similar to the single actin species from the yeast, Saccharomyces cerevisiae. Use of actin polymerization-specific reagents indicated that PLD1 binds both monomeric G-actin, as well as actin filaments. These data are consistent with a model in which the physical state of the actin cytoskeleton is a critical determinant of its regulation of PLD activity.

Actins↗
PubMed2000

Purification of a low-molecular-weight phospholipase A(2) associated with soluble high-molecular-weight acidic proteins from rabbit nucleus pulposus and its comparison with a rabbit splenic group IIa phospholipase A(2).

An intervertebral disc is a large peice of avascular cartilage rich in proteoglycans and water consisting of gelatinous nucleus pulposus and fibrous annulus fibrosus. The soluble fraction of rabbit nucleus pulposus exhibited unusually high Ca(2+)-dependent phospholipase A(2) (PLA(2)) activity (about 70% of the total PLA(2) activity). The soluble PLA(2) activity was 6-7-fold higher than those of rabbit annulus fibrosus and spleen. The PLA(2) was bound to an anion-exchange column at pH 7.4, and eluted near the void volume as a broad peak on gel-filtration on a TSKgel SuperSW3000 column developed with a buffer containing 0.1-0.2 M salt. When the gel-filtration column was developed in the presence of 1 M salt, almost all the PLA(2) activity was eluted near the total available volume. The soluble PLA(2) was purified to near homogeneity. A Ca(2+)-dependent PLA(2) was also purified from the fractions extracted with 1 M KBr from nucleus pulposus. For comparison, we purified a Ca(2+)-dependent PLA(2) from the KBr fraction of spleen. The splenic PLA(2) was identical to a group IIa PLA(2), as judged from its N-terminal amino acid sequences and mass spectra. On SDS-polyacrylamide gel electrophoresis the enzymes purified from the soluble and KBr fractions of nucleus pulposus both gave a major 15. 7-kDa band at the same position as splenic group IIa PLA(2). These results suggest that group IIa PLA(2) is associated with soluble high-molecular-weight proteins, most likely proteoglycans, in the extracellular matrix of rabbit nucleus pulposus.

Amino Acid Sequence↗
PubMed2006

Sequences, geographic variations and molecular phylogeny of venom phospholipases and threefinger toxins of eastern India Bungarus fasciatus and kinetic analyses of its Pro31 phospholipases A2.

Eight phospholipases A2 (PLAs) and four three-finger-toxins (3FTx) from the pooled venom of Bungarus fasciatus (Bf) were previously studied and sequenced, but their expression pattern in individual Bf venom and possible geographic variations remained to be investigated. We herein analyze the individual venom of two Bf specimens from Kolkata (designated as KBf) to address this question. Seven PLAs and five 3FTx were purified from the KBf venoms, and respective cDNAs were cloned from venom glands of one of the snakes. Comparison of their mass and N-terminal sequence revealed that all the PLAs were conserved in both KBf venoms, but that two of their 3FTx isoforms were variable. When comparing the sequences of these KBf-PLAs with those published, only one was found to be identical to that of Bf Vb-2, and the other five were 94-98% identical to those of Bf II, III, Va, VI and XI-2, respectively. Notably, the most abundant PLA isoforms of Bf and KBf venoms contain Pro31 substitution. They were found to have abnormally low k(cat) values but high affinity for Ca2+. Phylogenetic analysis based on the sequences of venom group IA PLAs showed a close relationship between Bungarus and Australian and marine Elapidae. As the five deduced sequences of KBf-3FTx are only 62-82% identical to the corresponding Bf-3FTx from the pooled venom, the 3FTx apparently have higher degree of individual and geographic variations than the PLAs. None of the KBf-3FTx was found to be neurotoxic or very lethal; phylogenetic analyses of the 3FTx also revealed the unique evolution of Bf as compared with other kraits.

Amino Acid Sequence↗
PubMed1993

Arcanobacterium haemolyticum phospholipase D is genetically and functionally similar to Corynebacterium pseudotuberculosis phospholipase D.

Arcanobacterium haemolyticum, a pathogen of the human upper respiratory tract and other systems, has been reported to produce soluble toxins, including a phospholipase D (PLD). We confirmed production of PLD by this organism and cloned and sequenced pld. Arcanobacterial PLD (PLD-A) was found to be a protein of approximately 31.5 kDa with a pI of approximately 9.4. Cosmid cloning, followed by subcloning into phagemid pBluescriptIISK+, yielded Escherichia coli(pAh140), a recombinant with a gene product corresponding to PLD-A. Evidence of PLD activity was found by three assays in supernatant fluid of cultures of E. coli(pAh140) and A. haemolyticum, but not in E. coli(pBluescriptIISK+). Experiments to determine if this protein was secreted were not conducted, but previous work with PLD from Corynebacterium pseudotuberculosis suggested that the presence of the enzyme in culture supernatant fluids was due to lysis of E. coli rather than to active transport. Antibodies in polyclonal sera from goats immunized with native or recombinant PLD-A neutralized native and recombinant PLD-A activity, and antibodies against native or recombinant PLD from C. pseudotuberculosis (PLD-P) partially neutralized native and recombinant PLD-A. Antibodies prepared against recombinant PLD-A labelled both recombinant and native PLD-A in Western blots (immunoblots) and dot blots, but antibodies against PLD-P did not. Sequencing of the insert in pAh140 revealed an open reading frame of 930 bp coding for 309 amino acids, including a putative signal sequence of 26 amino acids (3.2 kDa, determined on the basis of homology with the 24-amino-acid signal sequence of pld from C. pseudotuberculosis bv. ovis) and the mature PLD protein (31.5 kDa). Sequence comparisons of coding regions revealed 65% DNA homology with pld genes from C. pseudotuberculosis and Corynebacterium ulcerans. Comparison of amino acid sequences revealed 64% homology of PLD-A both with PLD-P and with PLD produced by C. ulcerans.

Amino Acid Sequence↗
PubMed1998

Use of monoclonal antibodies to identify phospholipase C as the enterotoxic factor of the bifunctional hemolysin-phospholipase C molecule of Vibrio cholerae O139.

Two hybrid clones producing monoclonal antibodies (MAbs) raised against the purified enterotoxic hemolysin-phospholipase C (HlyPC) bifunctional molecule of a Vibrio cholerae O139 strain were used to study its enterotoxicity in relation to its hemolytic and enzymatic activities. Fab fragments of MAbs from ascites produced by the two hybrids neutralized the hemolytic activity of HlyPC, leaving the enzymatic activity unaffected. In ligated rabbit ileal loop and infant mouse intestine, the Fab fragments of the MAbs were not able to neutralize the enterotoxicity of HlyPC, suggesting that PC rather than Hly is the enterotoxic moiety of the molecule. The enterotoxicity of the purified PC molecule isolated from an Hly- spontaneous mutant of the HlyPC-producing parent strain further confirms this contention. The Hly molecule isolated from a PC- mutant was not diarrheagenic.

Animals↗
PubMed1991

Platelet-derived growth factor increases the in vivo activity of phospholipase C-gamma 1 and phospholipase C-gamma 2.

Upon binding to its cell surface receptor, platelet-derived growth factor (PDGF) causes the tyrosine phosphorylation of phospholipase C-gamma 1 (PLC-gamma 1) and stimulates the production of diacylglycerol and inositol 1,4,5-triphosphate. We showed that following stimulation by PDGF, rat-2 cells overexpressing PLC-gamma 1 display an increase in the levels of both tyrosine-phosphorylated PLC-gamma 1 and inositol phosphates compared with the parental rat-2 cells. This increased responsiveness to PDGF is a direct effect of PLC-gamma 1 overexpression, as a cell line expressing similar levels of an enzymatically inactive point mutant of PLC-gamma 1, PLC-gamma 1 335Q, did not show elevated inositol phosphate production in response to PDGF. Hematopoietic cells express PLC-gamma 2, a PLC isoform that is closely related to PLC-gamma 1. When rat-2 cells overexpressing PLC-gamma 2 were treated with PDGF, an increase in both the tyrosine phosphorylation and the in vivo activity of PLC-gamma 2 was observed. Aluminum fluoride (AIF4-), a universal activator of PLC linked to G-proteins, did not produce an increase in the levels of inositol phosphates in either of the overexpressing cell lines compared with parental rat-2 cells, demonstrating that PLC-gamma isoforms respond specifically to a receptor with tyrosine kinase activity.

Animals↗
PubMed2003

Role of phospholipase C-L2, a novel phospholipase C-like protein that lacks lipase activity, in B-cell receptor signaling.

Phospholipase C (PLC) plays important roles in phosphoinositide turnover by regulating the calcium-protein kinase C signaling pathway. PLC-L2 is a novel PLC-like protein which lacks PLC activity, although it is very homologous with PLC delta. PLC-L2 is expressed in hematopoietic cells, but its physiological roles and intracellular functions in the immune system have not yet been clarified. To elucidate the physiological function of PLC-L2, we generated mice which had a genetic PLC-L2 deficiency. PLC-L2-deficient mice grew with no apparent abnormalities. However, mature B cells from PLC-L2-deficient mice were hyperproliferative in response to B-cell receptor (BCR) cross-linking, although B2 cell development appeared to be normal. Molecular biological analysis revealed that calcium influx and NFATc accumulation in nuclei were increased in PLC-L2-deficient B cells. Extracellular signal-regulated kinase activity was also enhanced in PLC-L2-deficient B cells. These mice had a stronger T-cell-independent antigen response. These results indicate that PLC-L2 is a novel negative regulator of BCR signaling and immune responses.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Differential and nonredundant roles of phospholipase Cgamma2 and phospholipase Cgamma1 in the terminal maturation of NK cells.

NK cells play a central role in mediating innate immune responses. Activation of NK cells results in cytotoxicity, cytokine, and chemokine secretions. In this study, we show that in mice with targeted deletion of phospholipase Cgamma (PLCgamma)2, one of the key signal transducers, there are profound effects on the development and terminal maturation of NK cells. Lack of PLCgamma2 significantly impaired the ability of lineage-committed NK precursor cells to acquire subset-specific Ly49 receptors and thereby terminal maturation of NK cells. Overexpression of isozyme, PLCgamma1, in PLCgamma2-deficient NK cells resulted in the successful Ly49 acquisition and terminal maturation of the NK cells; however, it could only partially rescue NKG2D-mediated cytotoxicity with no cytokine production. Furthermore, PLCgamma2-deficient NK cells failed to mediate antitumor cytotoxicity and inflammatory cytokine production, displaying a generalized hyporesponsiveness. Our results strongly demonstrate that PLCgamma1 and PLCgamma2 play nonredundant and obligatory roles in NK cell ontogeny and in its effector functions.

Animals↗
PubMed1999

ADP ribosylation factor 1 mutants identify a phospholipase D effector region and reveal that phospholipase D participates in lysosomal secretion but is not sufficient for recruitment of coatomer I.

The small GTP-binding protein, ADP-ribosylation factor 1 (ARF1) is essential for the formation of coatomer-coated vesicles from the Golgi and is also an activator of phospholipase D (PLD). Moreover, ARF1-regulated PLD is part of the signal-transduction pathway that can lead to secretion. In this study, substitution and deletion mutants of ARF1 were tested for their ability to activate PLD. These map the PLD effector region of ARF1 to the alpha2 helix, part of the beta2-strand and the N-terminal helix and its ensuing loop. ARF mutants with an increased or decreased ability to activate PLD showed similar characteristics when tested for their ability to stimulate secretion from HL60 cells. ARF1, deleted of the N-terminal 17 amino acid residues (Ndel17), did not support PLD activity or secretion, and neither did it inhibit the activity of wild-type myristoylated ARF1 (myrARF1). In contrast, Ndel17 effectively competed with wild-type myrARF1 to prevent coatomer binding to membranes. This appears to define a structural role for Ndel17, as it can bind a high-molecular mass complex in cytosol. In addition, ethanol has no effect on recruitment of coatomer to membrane. We conclude that the function of ARF-regulated PLD is in the signal-transduction pathway leading to secretion of lysosomal granules, and not as an essential component of ARF1-mediated coatomer binding.

ADP-Ribosylation Factor 1↗
PubMed1991

Phospholipase C gamma complexes with ligand-activated platelet-derived growth factor receptors. An intermediate implicated in phospholipase activation.

Several steps implicated in platelet-derived growth factor (PDGF) receptor-coupled signaling are activated by PDGF exposure at 0-4 degrees C. These include receptor self-phosphorylation, physical association with and phosphorylation of phospholipase C gamma (PLC gamma). Reduced temperature blocks PDGF internalization, making it possible to dissociate bound PDGF after PLC gamma tyrosine phosphorylation. We addressed the functional consequences of PDGF dissociation from intact cell PDGF receptors. PDGF exposure at 0-4 degrees C for 15 min stimulated self-phosphorylation of a subpopulation of BALB/c 3T3 cell PDGF beta-type receptors (35%) and initiated subsequent inositol phosphate production. A small fraction of cellular PLC gamma (1-3%) coprecipitated with ligand-activated PDGF receptors; 3-5% of cellular PLC gamma acquired phosphotyrosine. The PLC gamma coprecipitating with PDGF receptors did not contain detectible phosphotyrosine. Phosphotyrosine antibody recovered similar amounts of PLC gamma from soluble and particulate fractions of PDGF-stimulated cells. Acid dissociation of bound PDGF from receptor caused rapid dephosphorylation of PDGF receptors and PCL gamma, and interrupted PLC gamma-PDGF receptor coprecipitation. Orthovanadate blocked tyrosine dephosphorylation of both PDGF receptors and PLC gamma and stabilized coprecipitation. Orthovanadate reversed the acid wash effect to abrogate PDGF-stimulated inositol phosphate production. PDGF receptor remains competent to coprecipitate with PLC gamma and stimulate PLC-mediated inositol phosphate production if PDGF-induced receptor phosphorylation is maintained. Formation of a coprecipitable PDGF receptor-PLC gamma complex appears required for PDGF-stimulated inositol phosphate production.

Blotting, Western↗
PubMed1991

Phospholipase D activation by platelet-activating factor, leukotriene B4, and formyl-methionyl-leucyl-phenylalanine in rabbit neutrophils. Phospholipase D activation is involved in enzyme release.

Lipid chemoattractants, such as platelet-activating factor and leukotriene B4, as well as the peptide chemoattractant FMLP, were found to stimulate [3H]phosphatidic acid ([3H]PA) formation in 1-O-[3H]octadecyl-lyso platelet-activating factor-labeled rabbit neutrophils. The stimulation of [3H]PA formation appears to result from the activation of phospholipase D (PLD), because in the presence of ethanol, chemoattractant stimulation produced [3H]phosphatidylethanol, the characteristic compound produced by PLD at the expense of [3H]PA formation. The PLD activation by all chemoattractants tested was primed by cytochalasin B and revealed a similar time dependence. However, lipid chemoattractants were less potent as compared with FMLP, and the maximal stimulation by the former was lower than that by the latter. From these results, it is concluded that the mechanism of PLD activation by lipid chemoattractants is similar to, but different from, that by FMLP. Cytochalasin B stimulated degranulation and [3H]PA formation in agonist-stimulated neutrophils, and their stimulations were well correlated. Ethanol inhibited both agonist-stimulated [3H]PA formation and degranulation in a concentration-dependent manner, but the inhibition in degranulation was much less than that in [3H]PA formation. These results suggest that PLD activation is involved in degranulation, but another signaling pathway may also be required for full stimulation of degranulation. When the radiolabeled neutrophils were stimulated by chemoattractants for 5 min, 1,2-[3H]diglyceride was found to accumulate. The accumulation was inhibited by either ethanol or the phosphatidate phosphohydrolase inhibitor propranolol, which indicates that PA produced by PLD can be converted to 1,2-diglyceride by phosphatidate phosphohydrolase. Under these conditions, propranolol did not inhibit degranulation stimulated by chemoattractants. These results indicate that PA produced by PLD is more important than its metabolite diglyceride for the degranulation of rabbit neutrophils.

Animals↗
PubMed1991

Divergent regulation of phospholipase C-alpha and phospholipase C-gamma transcripts during activation of a human T cell line.

Ligand-induced activation of T cells results in stimulation of phosphatidylinositol-specific phospholipase C (PI-PLC). A structurally diverse family of PI-PLC isoforms has recently been defined, and more than one isoform is frequently coexpressed in a single cell or tissue, suggesting that different forms may play distinct roles in cellular activation, proliferation, or differentiation. We show here that both PLC-alpha and PLC-gamma are expressed in rat splenic T cells and in Jurkat cells (a human T cell line). Activation of Jurkat cells with the combination of PMA and PHA leads to increased expression of PLC-alpha message and decreased expression of PLC-gamma message after 4 h of stimulation. The increase in PLC-alpha transcripts was detectable at 4 h, maximal at 6 h, and remained elevated for at least 24 h. The decrease in PLC-gamma message was transient, with a maximal effect at 4 h, and a return to basal levels by 6 h. Changes in PI-PLC transcripts were also induced by the combination of PMA and the calcium ionophore, ionomycin. These data demonstrate that the expression of transcripts for PLC-alpha and PLC-gamma can be differentially regulated during a cellular response, and raise the possibility that these two isoforms of PI-PLC subserve distinct functions in T cell activation.

Cell Line↗
PubMed1987

Identification of polyphosphoinositide-specific phospholipase C and its resolution from phosphoinositide-specific phospholipase C from human platelet extract.

Sonicated platelet extract, obtained after high-speed centrifugation, was fractionated by phosphocellulose chromatography, and assayed for phosphodiesteric cleavage of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-biphosphate (PIP2) using (i) single bilayer vesicles from total platelet membrane lipids and (ii) single bilayer vesicles from individual pure lipids. When total platelet lipids were used as the substrate, two clear-cut, but incompletely resolved, peaks of phosphoinositide-specific phospholipase C (PI-PLC) were detected; one of these activities hydrolysed PIP alone, whereas the second peak hydrolysed all three phosphoinositides. When pure phosphoinositides were used as the substrate, three distinct peaks of PI-PLC were observed; two of these peak activities correspond to the peaks when assays were conducted with total platelet membrane lipids. The third peak of activity hydrolysed PIP2 and PIP, but not PI. These results clearly show that there exist PIP/PIP2-specific PLC enzymes that do not act on PI, and escaped detection thus far because of the general practice of using PI as the substrate to monitor PI-PLC activities. I propose that these PIP/PIP2-specific PLC enzymes are the real candidates that respond to agonist occupation of receptors on the cell surface to generate the two putative second messengers inositol triphosphate and diacylglycerol.

Blood Platelets↗
PubMed1993

Dissociation of the pore-forming and phospholipase D activities stimulated via P2z purinergic receptors in BAC1.2F5 macrophages. Product inhibition of phospholipase D enzyme activity.

We have previously reported that the occupancy of P2z purinergic receptors in BAC1.2F5 macrophages stimulates both the formation of nonselective membrane pores/channels and a novel phospholipase D (PLD) activity. In the present study, the relationship between these two P2z receptor-mediated responses was investigated. In [3H]oleic acid-labeled macrophages, isoosmotic replacement of extracellular Na+ with choline completely abolished 3'-O-(4-benzoyl)benzoyl-ATP (BzATP)-stimulated [3H]phosphatidylethanol ([3H]PEt) accumulation. This inhibitory effect of choline was mimicked when Na+ was replaced with other amine-containing cations (N-methylglucamine, ethanolamine, Tris+), but not with inorganic cations (K+, Li+). In contrast, substitution of Na+ with choline (or other cationic amines) did not prevent BzATP-induced Ca2+ influx and membrane depolarization. Thus, choline, which enters the cells through the BzATP-induced pores, can act to inhibit P2z receptor-stimulated PLD activity but not pore formation. The two responses also exhibit differential sensitivities to the pH of the incubation medium, to depletion of intracellular ATP, and to chronic phorbol ester treatment. These observations indicate that P2z receptor-mediated pore formation can be functionally uncoupled from the activation of PLD. However, both pore formation and PLD activity are similarly inhibited when the cells are: 1) partially desensitized by previous treatment with P2z agonists and 2) preincubated with 2',3'-dialdehyde-ATP or 4',4'-diisothiocyanostilbene-2,2'-disulfonate. This suggests that these two distinct responses are mediated by the same, or similar, P2z receptors.

Adenosine Triphosphate↗
PubMed1993

Association of tyrosine and serine kinases with the B cell surface antigen CD20. Induction via CD20 of tyrosine phosphorylation and activation of phospholipase C-gamma 1 and PLC phospholipase C-gamma 2.

CD20 is a B cell-specific 35/37 kDa integral membrane protein which modulates proliferation and differentiation of normal resting B cells when stimulated by CD20 antibodies. An increase in c-myc mRNA levels occurs within hours after treatment of resting B cells with CD20 mAb; however earlier events in the CD20 signal transduction pathway have not been described. Here we demonstrate that anti-CD20 mediated induction of c-myc mRNA is inhibited by the tyrosine kinase inhibitor herbimycin A, that CD20 is associated with both tyrosine and serine kinase activity, and that tyrosine phosphorylation of multiple substrates is induced within minutes upon ligation of CD20 with mAb. Association of the tyrosine and serine kinases with CD20 was stable in lysis buffer containing 1% NP40 and 0.25% deoxycholate. Under the same conditions, antibodies against several other B cell surface molecules failed to co-precipitate tyrosine kinase activity, however, a serine kinase was precipitated by the anti-CD19 mAb, B43. Both phospholipase C-gamma 1 and -gamma 2 were phosphorylated on tyrosine after cross-linking of CD20-bound mAb, and this correlated with increases in intracellular calcium that were partially resistant to depletion of extracellular calcium with EGTA. The pattern of tyrosine phosphorylated proteins observed in whole cell lysates after anti-CD20 cross-linking appeared to be a subset of those induced by anti-IgM; however, differences in phosphoproteins induced by anti-IgM and anti-CD20 were detected using a fynSH2-fusion protein.

Antigens, CD↗
PubMed1998

Phospholipase D and phosphatidic acid enhance the hydrolysis of phospholipids in vesicles and in cell membranes by human secreted phospholipase A2.

Phosphatidyl-choline (PC) vesicles and normal cell membranes are resistant to hydrolysis by human group II secreted PLA2, an enzyme that can attain high concentrations in extracellular fluids during many inflammatory processes. This highly cationic enzyme (pI>10.5) has a marked preference for anionic phospholipid interfaces, normally present within the cell. Therefore, the ability of one such anionic phospholipid, phosphatidic acid (PA), to enhance the activity of this enzyme has been investigated in detail. Results using model membrane vesicles and a continuous fluorescence assay highlight the ability of low molar proportions of PA to stimulate vesicle hydrolysis and this stimulation with increasing PA was parallelled by enhanced interfacial binding. In contrast, no productive binding of this enzyme could be detected to the surface of pure PC vesicles. The enhancement of hydrolysis in the presence of PA could also be achieved by prior treatment of pure PC vesicles with PLD, an effect that was dependent on the concentration of PLD and the duration of exposure to this enzyme. The fluorescence assay also allowed cell membranes and whole cells to be used as substrates and whereas such membrane presentations were refractory to hydrolysis by the human enzyme, prior treatment with PLD allowed hydrolysis using concentrations of this PLA2 that would be found extracellularly under inflammatory conditions. These results highlight the potential for PA, generated at the surface of the cell membrane, to be hydrolysed by extracellular human sPLA2 with the generation of lysophosphatidic acid and other lipid mediators and provides one possible mechanism whereby this human sPLA2 could become pro-inflammatory.

Calcium↗