Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lipid growth factor lysophosphatidic acid (LPA) elicits multiple cellular responses, including cell growth and survival. LPA acts upon target cells by activating its cognate receptors, which belong to the G protein-coupled endothelial differentiation gene (EDG) family. To date, three known LPA receptors, termed LPA1, LPA2 and LPA3, have been molecularly characterized and cloned. Here, we review recent data describing the molecular steps involved in the LPA receptor-mediated activation of mitogenic extracellular signal-regulated kinase (ERK) pathway in prostate cancer. Induction of ERK by LPA proceeds via Gbetagamma-dependent activation of tyrosine kinases, including the epidermal growth factor (EGF) receptor and c-Src. Further, LPA-induced ERK activation involves matrix metalloproteinases (MMPs), which cause the release of active EGFR ligands. Finally, we present data demonstrating a correlation between the mitogenic effects of LPA and expression of the lp(A1) gene in the prostate cancer cells.
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PMID:Mitogenic action of LPA in prostate. 1206 37

Lysophosphatidic acid (LPA), a bioactive lipid produced by several cell types including postmitotic neurons and activated platelets, is thought to be involved in various biological processes, including brain development. Three cognate G protein-coupled receptors encoded by lpa(1)/lp(A1)/Edg-2/Gpcr26, lpa(2)/lp(A2)/Edg-4, and lpa(3)/lp(A3)/Edg-7 mediate the cellular effects of LPA. We have previously shown that deletion of lpa(1) in mice results in craniofacial dysmorphism, semilethality due to defective suckling behavior, and generation of a small fraction of pups with frontal hematoma. To further investigate the role of these receptors and LPA signaling in the organism, we deleted lpa(2) in mice. Homozygous knockout (lpa(2)((-/-))) mice were born at the expected frequency and displayed no obvious phenotypic abnormalities. Intercrosses allowed generation of lpa(1)((-/-)) lpa(2)((-/-)) double knockout mice, which displayed no additional phenotypic abnormalities relative to lpa(1)((-/-)) mice except for an increased incidence of perinatal frontal hematoma. Histological analyses of lpa(1)((-/-)) lpa(2)((-/-)) embryonic cerebral cortices did not reveal obvious differences in the proliferating cell population. However, many LPA-induced responses, including phospholipase C activation, Ca(2+) mobilization, adenylyl cyclase activation, proliferation, JNK activation, Akt activation, and stress fiber formation, were absent or severely reduced in embryonic fibroblasts derived from lpa(1)((-/-)) lpa(2)((-/-)) mice. Except for adenylyl cyclase activation [which was nearly abolished in lpa(1)((-/-)) fibroblasts], these responses were only partially affected in lpa(1)((-/-)) and lpa(2)((-/-)) fibroblasts. Thus, although LPA(2) is not essential for normal mouse development, it does act redundantly with LPA(1) to mediate most LPA responses in fibroblasts.
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PMID:Characterization of lpa(2) (Edg4) and lpa(1)/lpa(2) (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa(2). 1221 48

We investigated the mechanism of lysophosphatidic acid (LPA) signaling in ovarian theca cells and observed that stimulation with this bioactive lipid markedly enhanced Thr/Tyr phosphorylation of the MAPK ERK1/2. Activation of ERK was transient, showing a peak at 5 min that declined thereafter, and was not associated with a concomitant nuclear translocation of the enzyme, suggesting that a cytosolic tyrosine phosphatase may be responsible for switching off the signal. Epidermal growth factor (EGF)-induced activation of the enzyme in the same cell system was more rapid (peaking at 1 min), sustainable for at least 60 min, and could be suppressed by prior treatment with either pertussis toxin or a noncompetitive inhibitor of Ras acceptor protein, manumycin A. This functional inhibition of either Gi or Ras failed, however, to affect the LPA-induced ERK-phosphorylation. Surprisingly, functional inhibition of Rho-GTPase, in C3-exotoxin-lipofected cells, markedly reduced LPA-stimulated phosphorylation of ERK, without affecting the EGF-induced stimulation of MAPK. Theca cells labeled with anti-LPA1/edg2-type antibody showed a distinct cell surface labeling, which is reflected in the expression of (LPA1)-type LPA receptors at both mRNA and protein levels. The findings indicate that LPA transiently stimulates MAPK ERK in LPA1/edg2-expressing theca cells and suggest an alternative mechanism regulating the activation of ERK that differs from the canonical EGF-Ras-MAPK kinase pathway.
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PMID:Lysophosphatidic acid signals through mitogen-activated protein kinase-extracellular signal regulated kinase in ovarian theca cells expressing the LPA1/edg2-receptor: involvement of a nonclassical pathway? 1273 Mar 29

Lysophosphatidate (LPA) mediates multiple cellular responses via heterotrimeric G protein coupled LPA-1, LPA-2, and LPA-3 receptors. Many G protein-coupled receptors stimulate ERK following tyrosine phosphorylation of growth factor receptors; however, the mechanism(s) of transactivation of receptor tyrosine kinases are not well defined. Here, we provide evidence for the involvement of phospholipase D (PLD) in LPA-mediated transactivation of platelet-derived growth factor receptor-beta (PDGF-R beta). In primary cultures of human bronchial epithelial cells (HBEpCs), LPA stimulated tyrosine phosphorylation of PDGF-R beta and threonine/tyrosine phosphorylation of ERK1/2. The LPA-mediated activation of ERK and tyrosine phosphorylation of PDGF-R beta was attenuated by tyrphostin AG 1296, an inhibitor of PDGF-R kinase, suggesting transactivation of PDGF-R by LPA. Furthermore, LPA-, but not PDGF beta-chain homodimer-induced tyrosine phosphorylation of PDGF-R beta was partially blocked by pertussis toxin, indicating coupling of LPA-R(s) to Gi. Exposure of HBEpCs to LPA activated PLD. Butan-1-ol, which acts as an acceptor of phosphatidate generated by the PLD pathway, blocked LPA-mediated transactivation of PDGF-R beta. This effect was not seen with butan-3-ol, suggesting PLD involvement. The role of PLD1 and PLD2 in the PDGF-R beta transactivation by LPA was investigated by infection of cells with adenoviral constructs of wild type and catalytically inactive mutants of PLD. LPA activated both PLD1 and PLD2 in HBEpCs; however, infection of cells with cDNA for wild type PLD2, but not PLD1, increased the tyrosine phosphorylation of PDGF-R beta in response to LPA. Also, the LPA-mediated tyrosine phosphorylation of PDGF-R beta was attenuated by the catalytically inactive mutant mPLD2-K758R. Infection of HBEpCs with adenoviral constructs of wild type hPLD1, mPLD2, and the inactive mutants of hPLD1 and mPLD2 resulted in association of PLD2 wild type and inactive mutant proteins with the PDGF-R beta compared with PLD1. These results show for the first time that transactivation of PDGF-R beta by LPA in HBEpCs is regulated by PLD2.
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PMID:Involvement of phospholipase D2 in lysophosphatidate-induced transactivation of platelet-derived growth factor receptor-beta in human bronchial epithelial cells. 1289 Jun 82

Olfactory ensheathing cells (OECs) are a unique type of macroglia with axonal growth-promoting properties. However, our understanding of the factors that regulate OECs is at early stages. Lysophosphatidic acid (LPA) is a lipid that influences diverse functions in the nervous system. Recent studies suggest that glial cells, including astrocytes and Schwann cells, are important targets of LPA. However, the influences of LPA on OECs are not known. To address if LPA can influence OECs, we examined effects of LPA on the proliferation and migration of OECs and intracellular effector events. Initially, we observed that OECs expressed the genes for LPA1, LPA2, and LPA3 receptors. When OECs were treated with LPA, we observed stimulated proliferation and migration of OECs. Treatment of OECs with LPA also induced actin cytoskeleton reorganization and focal adhesion assembly. These effects of LPA were blocked by treatment with C3 exoenzyme or Y-27632, which inhibit Rho-GTPase and Rho-associated kinase, respectively. Effects of LPA on OEC proliferation were blocked by the MEK inhibitors PD098059 and U0126 and by the phosphotidylinositol 3-kinase (PI 3-K) inhibitors LY0294002 and wortmannin. These results show that LPA acts via Rho-GTPase, MAPK, and PI 3-K signaling cascades to influence OEC proliferation, migration, and cytoskeleton assembly.
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PMID:Lysophosphatidic acid regulates the proliferation and migration of olfactory ensheathing cells in vitro. 1295 54

Lysophosphatidic acid (LPA) is a locally produced bioactive phospholipid which is involved in tissue repair. The objective of this study was to determine whether dental pulp tissue also responds to the phospholipid. Effects of LPA on proliferation, differentiation, and mitogen-activated protein kinase (MAPK) signaling of dental pulp fibroblasts (DPF) were examined in vitro. We report that DPF express LPA receptors LPA1, LPA2, and LPA3 and respond to the ligand with increased mitogenic activity. Involvement of extracellular signal-regulated kinase, p38 MAPK, and c-Jun NH(2)-terminal kinase in LPA signaling could be demonstrated by use of specific inhibitors and detection of the phosphorylation status of the kinases. An increased mitogenic activity paralleled a decreased number of alkaline-phosphatase-positive cells and expression levels of dentin sialophosphoprotein and osteocalcin. Together, these results suggest that dental pulp fibroblasts can respond to LPA, a process that may play a role in pulp tissue repair.
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PMID:Dental pulp fibroblasts contain target cells for lysophosphatidic Acid. 1515 58

HBEpCs (human bronchial epithelial cells) contribute to airway inflammation by secreting a variety of cytokines and chemokines in response to allergens, pathogens, viruses and environmental toxins and pollutants. The potent neutrophil chemoattractant, IL-8 (interleukin-8), is a major cytokine secreted by HBEpCs. We have recently demonstrated that LPA (lysophosphatidic acid) stimulated IL-8 production in HBEpCs via protein kinase C delta dependent signal transduction. However, mechanisms of IL-8 expression and secretion are complex and involve multiple protein kinases and transcriptional factors. The present study was undertaken to investigate MAPK (mitogen-activated protein kinase) signalling in the transcriptional regulation of IL-8 expression and secretion in HBEpCs. Exposure of HBEpCs to LPA (1 microM) enhanced expression and secretion of IL-8 by 5-8-fold and stimulated threonine/tyrosine phosphorylation of ERK (extracellular-signal-regulated kinase), p38 MAPK and JNK (c-Jun N-terminal kinase). The LPA-induced secretion of IL-8 was blocked by the p38 MAPK inhibitor SB203580, by p38 MAPK siRNA (small interfering RNA), and by the JNK inhibitor JNK(i) II, but not by the MEK (MAPK/ERK kinase) inhibitor, PD98059. LPA enhanced the transcriptional activity of the IL-8 gene; that effect relied on activation of the transcriptional factors NF-kappaB (nuclear factor kappaB) and AP-1 (activator protein-1). Furthermore, SB203580 attenuated LPA-dependent phosphorylation of IkappaB (inhibitory kappaB), NF-kappaB and phospho-p38 translocation to the nucleus, NF-kappaB transcription and IL-8 promoter-mediated luciferase reporter activity, without affecting the JNK pathway and AP-1 transcription. Similarly, JNK(i) II only blocked LPA-mediated phosphorylation of JNK and c-Jun, AP-1 transcription and IL-8 promoter-mediated luciferase reporter activity, without blocking p38 MAPK-dependent NF-kappaB transcription. Additionally, siRNA for LPA(1-3) receptors partially blocked LPA-induced IL-8 production and activation of MAPKs. The LPA1 and LPA3 receptors, as compared with LPA2, were most efficient in transducing LPA-mediated IL-8 production. These results show an independent role for p38 MAPK and JNK in LPA-induced IL-8 expression and secretion via NF-kappaB and AP-1 transcription respectively in HBEpCs.
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PMID:Transcriptional regulation of lysophosphatidic acid-induced interleukin-8 expression and secretion by p38 MAPK and JNK in human bronchial epithelial cells. 1619 69

Rat primary chondrocytes express the lysophosphatidic acid (LPA) receptor, LPA1, LPA3, but not LPA2. When chondrocytes were stimulated with LPA, phospholipase C-mediated cytosolic calcium increase was dramatically induced. LPA also stimulated two kinds of mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK) and p38 kinase in chondrocytes. In terms of the LPA-mediated functional modulation of chondrocytes, LPA stimulated cellular proliferation. We examined the signaling pathways involved in LPA-mediated cellular proliferation. LPA-induced chondrocyte proliferation was almost completely blocked by 2'-amino-3'-methoxyflavone (PD98059) but not by 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), suggesting that ERK activity is essentially required for the process. Pertussis toxin almost completely inhibited the LPA-induced cellular proliferation and ERK activation, indicating the role of G(i/o) protein(s) in the processes. This study demonstrates the physiological role of LPA on the modulation of rat primary chondrocyte proliferation, and the crucial role played by ERK in the process.
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PMID:Lysophosphatidic acid stimulates cell proliferation in rat chondrocytes. 1624 72

Many G protein-coupled receptors can couple to multiple G proteins to convey their intracellular signaling cascades. The receptors for lysophosphatidic acid (LPA) possess this ability. LPA receptors are important mediators of a wide variety of biological actions including cell migration, proliferation and survival which are processes that can all have a considerable impact on vascular smooth muscle (VSM) and blood vessels. To date, confirmation of G proteins involved has mostly relied on the inhibition of Gi-mediated signaling via pertussis toxin (PTx). We were interested in the specific involvement of LPA-Gq-mediated signaling therefore we isolated aorta VSM cells (VSMCs) from transgenic mice that express a peptide inhibitor of Gq, GqI, exclusively in VSM. We detected both LPA1 and LPA2 receptor expression in mouse VSM whereas LPA1 and LPA3 were expressed in rat VSM. SM22-GqI did not alter LPA-induced migration but it was sufficient to attenuate LPA-induced proliferation. GqI expression also attenuated LPA-induced ERK1/2 and Akt activation by 40-50%. To test the feasibility of this peptide as a potential therapeutic agent, we also generated adenovirus encoding the GqI. Transient expression of GqI was capable of inhibiting both LPA-induced migration and proliferation of VSMCs isolated from rat and mouse. Furthermore, ERK activation in response to LPA was also attenuated in VSMCs with Adv-GqI. Therefore, LPA receptors couple to Gq in VSMC and mediate migration and proliferation which may be mediated through activation of ERK1/2 and Akt. Our data also suggest that both chronic and transient expression of the GqI peptide is an effective strategy to lower Gq-mediated LPA signaling and may be a successful therapeutic strategy to combat diseases with enhanced VSM growth such as occurs following angioplasty or stent implantation.
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PMID:Vascular smooth muscle migration and proliferation in response to lysophosphatidic acid (LPA) is mediated by LPA receptors coupling to Gq. 1650 75

Stimulation of freshly isolated rat hepatocytes with lysophosphatidic acid (LPA) resulted in LPA1 receptor-mediated and nitricoxide-dependent up-regulation of the immediate early genes iNOS (inducible nitric-oxide synthase (NOS)) and mPGES-1 (microsomal prostaglandin E synthase-1). Because LPA is a ligand for both cell surface and intracellular receptor sites and a potent endothelial NOS (eNOS) activator, we hypothesized that NO derived from activated nuclearized eNOS might participate in gene regulation. Herein we show, by confocal microscopy performed on porcine cerebral endothelial cells expressing native LPA1-receptor and eNOS and on HTC4 rat hepatoma cells co-transfected with recombinant human LPA1-receptor and fused eNOS-GFP cDNA, a dynamic eNOS translocation from peripheral to nuclear regions upon stimulation with LPA. Nuclear localization of eNOS and its downstream effector, soluble guanylate cyclase, were demonstrated in situ in rat liver specimens by immunogold labeling using specific antibodies. Stimulation of this nuclear fraction with LPA and the NO donor sodium nitroprusside resulted, respectively, in increased production of nitrite (and eNOS phosphorylation) and cGMP; these separate responses were also correspondingly blocked by NOS inhibitor L-NAME and soluble guanylate cyclase inhibitor ODQ. In addition, sodium nitroprusside evoked a sequential increase in nuclear Ca2+ transients, activation of p42 MAPK, NF-kappaB binding to DNA consensus sequence, and dependent iNOS RNA. This study describes a hitherto unrecognized molecular mechanism by which nuclear eNOS through ensuing NO modulates nuclear calcium homeostasis involved in gene transcription-associated events. Moreover, our findings strongly support the concept of the nucleus as an autonomous signaling compartment.
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PMID:Nitric oxide signaling via nuclearized endothelial nitric-oxide synthase modulates expression of the immediate early genes iNOS and mPGES-1. 1657 49


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