Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ceramide and ceramide-1-phosphate are sphingolipid analogues of diacylglycerol and phosphatidate, respectively, and they are putative second messengers of agonist-stimulated sphingomyelin metabolism. The interactions of exogenous cell-permeable ceramides and ceramide-1-phosphates in modifying DNA synthesis and signal transduction were investigated in Rat-1 fibroblasts. C2- and C8-Ceramide-1-phosphates (N-acetylsphingosine-1-phosphate and N-octanoylsphingosine-1-phosphate, respectively) at 1-10 microM stimulated DNA synthesis and cell division. This effect was blocked by cell-permeable ceramides. C2-Ceramide stimulated the conversion of exogenous C8-ceramide-1-phosphate to C8-ceramide, with very little production of sphingosine or sphingosine-1-phosphate. This mechanism may be partly responsible for preventing the stimulation of DNA synthesis. Unlike phosphatidate or lyso-phosphatidate, concentrations of C8-ceramide-1-phosphate that stimulated DNA synthesis did not inhibit adenylate cyclase activity, nor did they increase the activities of phospholipase D or mitogen-activated protein kinases (42- and 44 kDa isoforms). Although ceramide-1-phosphate can be considered as an analogue of phosphatidate, the effects of this compound on signal transduction differ considerably from those of phosphatidate. This work demonstrates that short-chain ceramide-1-phosphates can be used as novel external agonists that can stimulate DNA synthesis. This effect can be counteracted by short-chain ceramides.
Mol Pharmacol 1995 May
PMID:Short-chain ceramide-1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides. 774 76

We examined the effect of endothelin-1 (ET-1) on phosphatidylcholine-hydrolyzing phospholipase D activity in osteoblast-like MC3T3-E1 cells. ET-1 stimulated the formation of choline (EC50 10 nM) as well as that of inositol phosphates (EC50 1.2 nM). The effects of ET-1 and 12-O-tetradecanoylphorbol-13-acetate, a protein kinase C-activating phorbol ester, were additive. Staurosporine enhanced the ET-1-induced formation of choline. NaF or pertussis toxin were ineffective. The results indicate that ET-1 activates phospholipase D independent of protein kinase C in osteoblast-like cells.
Mol Cell Endocrinol 1994 Nov
PMID:Effect of endothelin-1 on phospholipase D activity in osteoblast-like cells. 785 25

We demonstrated previously that v-Src activates a phospholipase D (PLD) activity (Song, J., Pfeffer, L.M., and Foster, D.A. (1991) Mol. Cell. Biol. 11, 4903-4908) and that this activation is dependent upon a G protein(s) (Jiang H., Alexandropoulos, K., Song, J., and Foster, D.A. (1994) Mol. Cell. Biol. 14, 3676-3682). An in vitro PLD assay was developed to study G protein involvement in v-Src-induced PLD activity. Maximal PLD activity in membranes isolated from v-Src-transformed cells was dependent upon both GTP and cytosol. In this report, we present three lines of evidence demonstrating that v-Src-induced PLD activity is mediated by Ras. First, a neutralizing Ras monoclonal antibody (Y13-259) inhibits PLD activity in membranes isolated from v-Src-transformed Balb/c 3T3 cells. Second, immobilized Ras protein depleted cytosol of the ability to stimulate PLD activity. This effect was dependent upon preloading immobilized Ras with GTP. Last, expression of a dominant negative Ras mutant in v-Src-transformed cells reduced PLD activity to the level observed in the nontransformed parental cells. These data establish a novel role for Ras in the regulation of PLD activity.
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PMID:Ras mediates the activation of phospholipase D by v-Src. 789 Jul 31

Phosphatidic acid has been proposed to contribute to the mitogenic actions of various growth factors. In 32P-labeled neonatal rat cardiac fibroblasts, 100 nM [Sar1]angiotensin II was shown to rapidly induce formation of 32P-phosphatidic acid. Levels peaked at 5 min (1.5-fold above control), but were partially sustained over 2 h. Phospholipase D contributed in part to phosphatidic acid formation, as 32P- or 3H-phosphatidylethanol was produced when cells labeled with [32P]H3PO4 or 1-O-[1,2- 3H]hexadecyl-2-lyso-sn-glycero-3-phosphocholine were stimulated in the presence of 1% ethanol. [Sar1]angiotensin II-induced phospholipase D activity was transient and mainly mediated through protein kinase C (PKC), since PKC downregulation reduced phosphatidylethanol formation by 68%. Residual activity may have been due to increased intracellular Ca2+, as ionomycin also activated phospholipase D in PKC-depleted cells. Phospholipase D did not fully account for [Sar1]angiotensin II-induced phosphatidic acid: 1) compared to PMA, a potent activator of phospholipase D, [Sar1]angiotensin II produced more phosphatidic acid relative to phosphatidylethanol, and 2) PKC downregulation did not affect [Sar1]angiotensin II-induced phosphatidic acid formation. The diacylglycerol kinase inhibitor R59949 depressed [Sar1]angiotensin II-induced phosphatidic acid formation by only 21%, indicating that activation of a phospholipase C and diacylglycerol kinase also can not account for the bulk of phosphatidic acid. Thus, additional pathways not involving phospholipases C and D, such as de novo synthesis, may contribute to [Sar1]angiotensin II-induced phosphatidic acid in these cells. Finally, as previously shown for [Sar1]angiotensin II, phosphatidic acid stimulated mitogen activated protein (MAP) kinase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1994 Dec 21
PMID:Angiotensin II induces phosphatidic acid formation in neonatal rat cardiac fibroblasts: evaluation of the roles of phospholipases C and D. 789 71

Lactoferrin-binding or -associated proteins were identified in Treponema pallidum subspecies pallidum and Treponema denticola by affinity column chromatography using human lactoferrin and detergent-solubilized, radiolabelled spirochaetes. Two discrete polypeptides of T. pallidum with masses of 45 and 40 kDa and a broad band from 29-34 kDa exhibited association with human apo- and partially ferrated lactoferrin. T. denticola produced two proteins that associated with a lactoferrin affinity matrix (50 and 35 kDa). T. pallidum and T. denticola did not associate with soluble, human transferrin in parallel experiments. Soluble human lactoferrin competed with all lactoferrin-associated proteins from T. pallidum and T. denticola in competitive-binding assays. However, the T. denticola proteins dissociated from a lactoferrin-affinity matrix in the presence of differing concentrations of unlabelled, soluble lactoferrin competitor. Treatment with phospholipase D altered migration of the diffuse 29-34 kDa band of T. pallidum suggesting that the polypeptide was lipid-modified. Each of the lactoferrin-binding proteins from T. pallidum and T. denticola reacted with pooled rabbit syphilitic antisera. The lactoferrin-binding proteins of T. pallidum reacted with human sera from patients at all stages of syphilis. In addition, a monoclonal antibody generated against the 45 kDa polypeptide of T. pallidum crossreacted with the 29-34 kDa protein.
Mol Microbiol 1994 May
PMID:Identification of lactoferrin-binding proteins from Treponema pallidum subspecies pallidum and Treponema denticola. 793 85

The chromosomal gene encoding the phospholipase D from Corynebacterium pseudotuberculosis (biovar ovis) isolate Whetten 1 was replaced with an allele containing a nonsense mutation. The virulence of the mutant strain (W1.31r1) and the isogenic parental strain were then compared by inoculation of goats. The wild-type strain caused abscessation at the site of infection, which then spread to the regional lymph node, while W1.31r1 had a reduced ability to establish a primary infection and was incapable of dissemination. Our results confirm that phospholipase D is a virulence determinant of C. pseudotuberculosis that increases the persistence and spread of the bacteria within the host.
Mol Microbiol 1994 Jun
PMID:Targeted mutagenesis of the phospholipase D gene results in decreased virulence of Corynebacterium pseudotuberculosis. 793 99

Activation of the M3 muscarinic receptor in 1321N1 human astrocytoma cells leads to increased phospholipase D (PLD)-catalyzed hydrolysis of phosphatidylcholine, which is maximal within 1 min of exposure to agonist. Studies examining the kinetics of phosphatidylethanol formation indicate that there is no further PLD activation beyond this time. Thrombin, a mitogen for quiescent 1321N1 cells, also activates PLD only transiently. The PLD response does not recover for up to 1 hr and cells that have been exposed to carbachol or thrombin do not respond to subsequent challenge with the heterologous agonist. In contrast to the desensitization observed with agonists, phorbol-12-myristate-13-acetate induces a sustained stimulation of PLD. In addition, cells pretreated with carbachol or thrombin show a normal response to phorbol-12-myristate-13-acetate, suggesting that the enzymatic activity of PLD is not compromised. Guanosine-5'-O-(3-thio)triphosphate activation of PLD in cell-free homogenates is also unaffected by prior treatment of the cells with agonist. Agonist-stimulated PLD activation in 1321N1 cells is mediated by protein kinase C (PKC). Thrombin and carbachol cause comparable changes in redistribution of both PKC-alpha and PKC-epsilon. The increase in membrane-associated PKC-alpha is transient and is reinitiated by addition of the heterologous agonist, whereas PKC-epsilon remains membrane associated for at least 60 min and is not further increased by addition of the heterologous agonist. We suggest that desensitization of PLD activation results from the down-regulation of an as yet undefined mediator required for agonist receptor coupling to PLD and that PKC-epsilon might participate in this down-regulation.
Mol Pharmacol 1994 Sep
PMID:Rapid heterologous desensitization of muscarinic and thrombin receptor-mediated phospholipase D activation. 793 19

ADP-ribosylation factor 1 (ARF-1) is a member of a family of small G-proteins that regulate both intracellular vesicle transport and phospholipase D activity. Crystals of ARF-1 suitable for X-ray diffraction analysis have been grown in the presence of GDP by the hanging drop vapour diffusion method. Crystals grow in space group C2 with cell dimensions a = 122.36 A, b = 45.01 A, c = 91.96 A and beta = 133.62 degrees and diffract to at least 2.3 A resolution. A second crystal form has been characterized (space group C2, a = 69.70 A, b = 45.25 A, c = 60.45 A, beta = 109.6 degrees) but does not grow reproducibly.
J Mol Biol 1994 Dec 16
PMID:Crystallization and preliminary X-ray diffraction studies on ADP-ribosylation factor 1. 799 Jan 46

A substantial body of research implicates L-cysteine sulfinic acid (L-CSA) as a neurotransmitter. However, all physiological actions of L-CSA that have been pharmacologically characterized are mediated by cross-activation of glutamate receptors, and no receptor has been identified that is primarily activated by L-CSA. We report that a receptor exists in adult rat hippocampus that is activated by L-CSA but is insensitive to several other endogenous excitatory amino acids (EAAs), including L-glutamate, L-aspartate, and L-homocysteic acid. This receptor is coupled to an increase in the activity of phospholipase D (PLD). The L-CSA-induced PLD response is not blocked by ionotropic glutamate receptor antagonists but is mimicked by the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid. The agonist pharmacology of the PLD-coupled response is generally similar to that of mGluRs but clearly differs from that of any particular mGluR that has been characterized to date. Furthermore, this receptor is not significantly blocked by (RS)-alpha-methyl-4-carboxyphenylglycine, which blocks a variety of mGluR-mediated responses. L-CSA has little effect on mGluRs coupled to phosphoinositide hydrolysis or the potentiation of cAMP responses in adult hippocampus, indicating that L-CSA is not a broad mGluR agonist. It is commonly thought that EAAs act on the same receptor families, all of which use glutamate as their primary agonist. However, the finding that L-CSA acts on a glutamate-insensitive receptor suggests that different receptor families might exist for different EAAs.
Mol Pharmacol 1994 Jun
PMID:L-cysteine sulfinic acid as an endogenous agonist of a novel metabotropic receptor coupled to stimulation of phospholipase D activity. 802 10

We have investigated the activation of phospholipase D (PLD) by sphingosine and its derivatives in bovine pulmonary artery endothelial cells (BPAEC) prelabeled with [32P]orthophosphate or [32P]lyso phospholipids. Sphingosine, in a dose- and time-dependent manner, stimulated the hydrolysis of [32P]phosphatidylcholine (PC) resulting in the production of [32P]phosphatidic acid (PA), suggesting PLD activation. In the presence of ethanol (150 mM), the accumulation of [32P]phosphatidylethanol was also observed. The sphingosine-induced stimulation of PLD activity was not affected by treatment with the protein kinase C (PKC) inhibitor staurosporine or by down-regulation of PKC with TPA and was independent of extracellular Ca2+, suggesting that the PLD activation was independent of PKC and Ca2+. Chelation of intracellular Ca2+ with BAPTA actually potentiated the sphingosine-stimulated [32P]PC hydrolysis. Furthermore, the activation of PLD by sphingosine was not abolished by treatment of BPAEC with either cholera or pertussis toxin, indicating noninvolvement of toxin-sensitive G-proteins. In addition to hydrolysis of [32P]PC, sphingosine also stimulated PLD-mediated hydrolysis of [32P]phosphatidylethanolamine and [32P]phosphatidylinositol. Among the various sphingoid compounds, in addition to sphingosine, only sphingosine-1-phosphate (Sph-1-P) activated the endothelial cell PLD. The effect of sphingosine and Sph-1-P on PA phosphatase (PA Pase) activity was tested using [3H]glycerol-labeled PA. The Mg(2+)-independent and membrane-associated PA Pase activity was inhibited by sphingosine (IC50 = 200 microM) but not by Sph-1-P. This implies that sphingosine and Sph-1-P share a similar PLD-stimulating property but differ in their PA Pase inhibitory activity.
Am J Respir Cell Mol Biol 1994 Aug
PMID:Activation of endothelial cell phospholipase D by sphingosine and sphingosine-1-phosphate. 804 83


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