Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lysophosphatidic acid (LPA) is both a potential marker and a therapeutic target for ovarian cancer. It is critical to identify the sources of elevated LPA levels in ascites and blood of patients with ovarian cancer. We show here that human peritoneal mesothelial cells constitutively produce LPA, which accounts for a significant portion of the chemotactic activity of the conditioned medium from peritoneal mesothelial cells to ovarian cancer cells. Both production of LPA by peritoneal mesothelial cells and the chemotactic activity in the conditioned medium can be blocked by HELSS [an inhibitor of the calcium-independent phospholipase A(2) (iPLA(2))] and AACOCF(3) [an inhibitor of both cytosolic PLA(2) (cPLA(2)) and iPLA(2)]. Moreover, cell-based enzymatic activity assays for PLA(2) indicate that peritoneal mesothelial cells have strong constitutive PLA(2) activity. Receptors for LPA, LPA(2), and LPA(3) are involved in the conditioned medium-induced chemotactic activity. Invasion of ovarian cancer cells into peritoneal mesothelial cells has also been analyzed and shown to require PLA(2), LPA receptors, and the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase signaling pathway. Thus, we show here, for the first time, that human peritoneal mesothelial cells constitutively produce bioactive lipid signaling molecules, such as LPA, via iPLA(2) and/or cPLA(2) activities. Conditioned medium from peritoneal mesothelial cells stimulate migration, adhesion, and invasion of ovarian cancer cells, and may play similar roles in vivo.
 ...
PMID:Lysophosphatidic acid is constitutively produced by human peritoneal mesothelial cells and enhances adhesion, migration, and invasion of ovarian cancer cells. 1654 Jun 49

Within the kidney, angiotensin II type 2 (AT(2)) receptor mediates phospholipase A(2) (PLA(2)) activation, arachidonic acid release, epidermal growth factor (EGF) receptor transactivation, and mitogen-activated protein kinase activation. Arachidonic acid mimics this transactivation by an undetermined mechanism. The role of c-Src in mediating angiotensin II and arachidonic acid signaling was determined by employing immunocomplex kinase assay, Western blotting analysis, and protein immunoblotting on co-precipitated EGF receptor (EGFR) proteins and agarose conjugates of glutathione S-transferase fusion proteins containing the c-Src homology 2 (SH2) and SH3 domains. Angiotensin II induced extracellular signal-regulated kinase (ERK) activation in primary cultures of rabbit proximal tubule cells via the activation of c-Src and association of the EGFR with the c-Src SH2 domain, effects that were mimicked by arachidonic acid and its inactive analogue eicosatetraynoic acid. Inhibition of PLA(2) by mepacrine and methyl arachidonyl fluorophosphate, AT(2) receptor by PD123319, Src family kinases by, 1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d] pyrimidine (PP2) and c-Src by overexpression of a dominant-negative mutant of c-Src abrogated these effects. However, inhibitors of arachidonic acid metabolic pathways did not block these effects. The present work provides a new and novel paradigm for transactivation of a kinase receptor linked to a fatty acid, which may apply to activation of a variety of phospholipases and accompanying arachidonic acid release.
 ...
PMID:Arachidonic acid induces ERK activation via Src SH2 domain association with the epidermal growth factor receptor. 1659 96

The marine natural product scalaradial (SLD) is a potent inhibitor of secretory phospholipase A(2) (sPLA(2)). Our previous work has demonstrated that SLD inhibits epidermal growth factor receptor-mediated Akt phosphorylation, and this effect is independent of sPLA(2). Here we report the role of SLD in extracellular signal-regulated kinase (ERK)1/2 activation. SLD inhibited ERK1/2 phosphorylation within the first 15 min (early inhibition), then stimulated ERK1/2 phosphorylation after 15 min of SLD treatment (late stimulation) in BEL-7402 cells, displaying biphasic regulatory features. Other PLA(2) inhibitors such as the cytosolic and Ca(2+)-independent PLA(2) inhibitor methyl arachidonyl fluorophosphonate, and another sPLA(2) inhibitor, thioetheramide-phosphatidylcholine, only transiently inhibited ERK1/2 phosphorylation and did not display the stimulatory effect. The early inhibition of ERK1/2 phosphorylation by SLD was reversed by the PLA(2) metabolite arachidonic acid, while the late stimulation was abrogated by constitutively active myristolated-Akt. Furthermore, SLD dose- and time-dependently inhibited the phosphorylation of Raf-1 on Ser 259, which is an established event by which Akt inhibits ERK1/2 activation. Taken together, these data demonstrate a biphasic regulation of ERK1/2 phosphorylation by SLD in a time-dependent manner, i.e., early inhibition and late stimulation. The early inhibition of ERK1/2 phosphorylation is mediated by sPLA(2), at least in part, and the late stimulation is effected through SLD inhibition of Akt. These findings provide further insight into the mechanisms underlying the pharmacological effect of SLD.
 ...
PMID:Biphasic regulation of extracellular signal-regulated kinases by scalaradial, a secretory phospholipase A(2) inhibitor. 1676 Jun 75

Phosphodiesterase (PDE)4 inhibition attenuates neutrophilic inflammation in chronic obstructive pulmonary disease. The objective of the present study was to examine the efficacy and mechanism by which PDE4 inhibition blocks adhesion of beta(2)-integrin to an endothelial counterligand. Neutrophils (polymorphonuclear leukocytes (PMNs)) were isolated from humans receiving no medication. Adhesion was analysed by myeloperoxidase activity. The effects of cilomilast+/-salmeterol on the following were determined: 1) surface CD11b expression; 2) adhesion; 3) intracellular cyclic adenosine monophosphate (cAMP) concentration; and 4) extracellular signal-regulated kinase (ERK)-1/2-mediated group IVA-phospholipase A(2) (gIVA-PLA(2)) phosphorylation caused by leukotriene (LT)B(4) or tumour necrosis factor (TNF)-alpha activation. Either cilomilast or rolipram+/-salmeterol caused concentration-related blockade of LTB(4)-induced adhesion to counterligand, but had no effect on TNF-alpha-activated PMNs. A comparable increase in intracellular cAMP concentration for PMNs activated with LTB(4) and TNF-alpha was caused by 1 muM cilomilast and 0.1 microM salmeterol. Upregulation of surface CD11b expression and ERK-1/2 phosphorylation were blocked by cilomilast or rolipram+/-salmeterol for PMNs activated by LTB(4), but not for cells stimulated by TNF-alpha. Cilomilast+/-salmeterol also blocked gIVA-PLA(2) phosphorylation caused by LTB(4) but not TNF-alpha. In conclusion, the current study demonstrates that both leukotriene B(4) and tumour necrosis factor-alpha upregulate cyclic adenosine monophosphate. However, cyclic adenosine monophosphate does not block beta(2)-integrin adhesion caused by tumour necrosis factor-alpha. It was concluded that tumour necrosis factor-alpha prevents inhibition of extracellular signal-regulated kinase-1/2-mediated group IVA-phospholipase A(2) activation, which is essential for beta(2)-integrin adhesion in polymorphonuclear leukocytes.
 ...
PMID:Phosphodiesterase 4 inhibition of beta2-integrin adhesion caused by leukotriene B4 and TNF-alpha in human neutrophils. 1680 66

Gonadotropin-releasing hormone (GnRH) is the first key hormone of reproduction. GnRH analogs are extensively used in in vitro fertilization, and treatment of sex hormone-dependent cancers, due to their ability to bring about 'chemical castration'. The interaction of GnRH with its cognate type I receptor (GnRHR) in pituitary gonadotropes results in the activation of Gq/G(11), phospholipase Cbeta (PLCbetaI), PLA(2), and PLD. Sequential activation of the phospholipases generates the second messengers inositol 1, 4, 5-trisphosphate (IP(3)), diacylglycerol (DAG), and arachidonic acid (AA), which are required for Ca(2+) mobilization, the activation of various protein kinase C isoforms (PKCs), and the production of prostaglandin (PG) and other metabolites of AA, respectively. PKC isoforms are the major mediators of the downstream activation of a number of mitogen-activated protein kinase (MAPK) cascades by GnRH, namely: extracellular signal-regulated kinase (ERK), jun-N-terminal kinase (JNK), and p38MAPK. The activated MAPKs phosphorylate both cytosolic and nuclear proteins to initiate the transcriptional activation of the gonadotropin subunit genes and the GnRHR. While Ca(2+) mobilization has been found to initiate rapid gonadotropin secretion, Ca(2+), together with various PKC isoforms, MAPKs and AA metabolites also serve as key nodes, in the GnRH-stimulated signaling network that enables the gonadotropes to decode GnRH pulse frequencies and translating that into differential gonadotropin synthesis and release. Even though pulsatility of GnRH is recognized as a major determinant for differential gonadotropin subunit gene expression and gonadotropin secretion very little is yet known about the signaling circuits governing GnRH action at the 'Systems Biology' level. Direct apoptotic and metastatic effects of GnRH analogs in gonadal steroid-dependent cancers expressing the GnRHR also seem to be mediated by the activation of the PKC/MAPK pathways. However, the mechanisms dictating life (pituitary) vs. death (cancer) decisions made by the same GnRHR remain elusive. Understanding these molecular mechanisms triggered by the GnRHR through biochemical and 'Systems Biology' approaches would provide the basis for the construction of the dynamic connectivity maps, which operate in the various cell types (endocrine, cancer, and immune system) targeted by GnRH. The connectivity maps will open a new vista for exploring the direct effects of GnRH analogs in tumors and the design of novel combined therapies for fertility control, reproductive disorders and cancers.
 ...
PMID:Signaling by G-protein-coupled receptor (GPCR): studies on the GnRH receptor. 1870 85

Glioblastoma multiforme is an invasive primary brain tumor, which evades the current standard treatments. The invasion of glioblastoma cells into healthy brain tissue partly depends on the proteolytic and nonproteolytic activities of the plasminogen activator system proteins, including the urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), and a receptor for uPA (uPAR). Here we show that sphingosine-1-phosphate (S1P) and the inflammatory mediator interleukin-1 (IL-1) increase the mRNA and protein expression of PAI-1 and uPAR and enhance the invasion of U373 glioblastoma cells. Although IL-1 enhanced the expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, down-regulation of SphK1 had no effect on the IL-1-induced uPAR or PAI-1 mRNA expression, suggesting that these actions of IL-1 are independent of S1P production. Indeed, the S1P-induced mRNA expression of uPAR and PAI-1 was blocked by the S1P(2) receptor antagonist JTE013 and by the down-regulation of S1P(2) using siRNA. Accordingly, the inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 and Rho-kinase, two downstream signaling cascades activated by S1P(2), blocked the activation of PAI-1 and uPAR mRNA expression by S1P. More importantly, the attachment of glioblastoma cells was inhibited by the addition of exogenous PAI-1 or siRNA to uPAR, whereas the invasion of glioblastoma cells induced by S1P or IL-1 correlated with their ability to enhance the expression of PAI-1 and uPAR. Collectively, these results indicate that S1P and IL-1 activate distinct pathways leading to the mRNA and protein expression of PAI-1 and uPAR, which are important for glioblastoma invasiveness.
 ...
PMID:Sphingosine-1-phosphate and interleukin-1 independently regulate plasminogen activator inhibitor-1 and urokinase-type plasminogen activator receptor expression in glioblastoma cells: implications for invasiveness. 1881 34

Low-density lipoprotein receptor-related protein 1 (LRP1) functions in endocytosis and intracellular signaling for a variety of structurally diverse ligands. Although LRP1 has been implicated in several aspects of neuronal function, molecular mechanisms underlying the activity of neuronal LRP1 remain unclear. Here, we describe a signaling pathway whereby LRP1 transactivates Trk receptors. Binding of tissue-type plasminogen activator or alpha(2)-macroglobulin (alpha(2)M) to LRP1 resulted in Src family kinase (SFK) activation and SFK-dependent Trk receptor transactivation in PC12 cells and neurons. Trk receptor transactivation was necessary for activation of Akt and extracellular signal-regulated kinase and for neurite outgrowth downstream of LRP1. Injection of the LRP1-binding domain of alpha(2)M into rat dorsal root ganglia induced Trk receptor phosphorylation, which was blocked by receptor-associated protein, an antagonist of ligand binding to LRP1. Trk receptor transactivation provides a mechanism by which diverse LRP1 ligands may show neurotrophic activity.
 ...
PMID:Ligand binding to LRP1 transactivates Trk receptors by a Src family kinase-dependent pathway. 1940 92

Although the molecular bases of its actions remain debated, tissue-type plasminogen activator (tPA) is a paradoxical brain protease, as it favours some learning/memory processes, but increases excitotoxic neuronal death. Here, we show that, in cultured cortical neurons, tPA selectively promotes NR2D-containing N-methyl-D-aspartate receptor (NMDAR)-dependent activation. We show that tPA-mediated signalling and neurotoxicity through the NMDAR are blocked by co-application of an NR2D antagonist (phenanthrene derivative (2S(*), 3R(*))-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid, PPDA) or knockdown of neuronal NR2D expression. In sharp contrast with cortical neurons, hippocampal neurons do not exhibit NR2D both in vitro and in vivo and are consequently resistant to tPA-promoted NMDAR-mediated neurotoxicity. Moreover, we have shown that activation of synaptic NMDAR prevents further tPA-dependent NMDAR-mediated neurotoxicity and sensitivity to PPDA. This study shows that the earlier described pro-neurotoxic effect of tPA is mediated by NR2D-containing NMDAR-dependent extracellular signal-regulated kinase activation, a deleterious effect prevented by synaptic pre-activation.
 ...
PMID:NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity. 1991 Oct 10

Oral squamous cell carcinoma (OSCC) has 50% 5-year survival rate, highlighting our limited understanding of the molecular events that contribute to disease progression. Microarray analyses of primary oral tumors have identified urinary-type plasminogen activator (uPA) and its receptor (uPAR) as key genes associated with human OSCC progression. The uPAR functions as both a proteinase receptor and an integrin ligand, modifying proteolysis, migration, integrin signaling, and cellular transcription. In the current study, uPAR expression levels were modified in OSCC cells followed by analysis of tumor growth in an in vivo orthotopic xenograft model and by transcriptional profiling. Overexpression of uPAR resulted in more infiltrative and less differentiated tumors, with ill-defined borders, cytologic atypia, and enhanced vascularity. Analysis of serial sections of both murine experimental tumors and microarrayed human OSCC showed a statistically significant association between uPAR and alpha(3) integrin colocalization in areas exhibiting extracellular signal-regulated kinase phosphorylation, suggesting that uPAR/alpha(3) integrin interaction potentiates extracellular signal-regulated kinase signaling in vivo. This is supported by cDNA microarray analysis, which showed differential expression of 148 genes (113 upregulated and 35 downregulated). Validation of gene expression changes in human OSCC using immunohistochemistry and quantitative real-time PCR showed increased growth factors, proteinases/inhibitors, and matrix components in uPAR-overexpressing tumors. Together, these results support a model wherein increased uPAR expression promotes alpha(3)beta(1) integrin association, resulting in increased mitogen-activated protein kinase signaling and transcriptional activation, leading to the formation of more aggressive tongue tumors. This combined approach has efficacy to identify additional biomarkers and/or prognostic indicators associated with aggressive human OSCC.
 ...
PMID:Urinary-type plasminogen activator receptor/alpha 3 beta 1 integrin signaling, altered gene expression, and oral tumor progression. 2014 38

Prevotella intermedia is an important periodontal pathogen that induces various inflammatory and immune responses. In this study, we investigated the effects of P. intermedia on the plasminogen system in human periodontal ligament (hPDL) cells and explored the signaling pathways involved. Using semi-quantitative reverse transcription (RT)-PCR and quantitative real-time RT-qPCR, we demonstrated that P. intermedia challenge increased tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor (PAI)-2 expression in a concentration- and time-dependent manner, but exerted no influence on urokinase-type plasminogen activator and PAI-1mRNA expression in hPDL cells. Prevotella intermedia stimulation also enhanced tPA protein secretion as confirmed by enzyme-linked immunosorbent assay. Western blot results revealed that P. intermedia treatment increased phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase (p38). ERK, JNK and protein kinase C inhibitors significantly attenuated the P. intermedia-induced tPA and PAI-2 expression. Furthermore, p38 and phosphatidylinositol 3-kinase inhibitors markedly decreased PAI-2 expression, whereas they showed no or little inhibition on tPA expression. In contrast, inhibition of protein kinase A greatly enhanced the upregulatory effect of P. intermedia on tPA and PAI-2 expression. Our results suggest that P. intermedia may contribute to periodontal tissue destruction by upregulating tPA and PAI-2 expression in hPDL cells via multiple signaling pathways.
 ...
PMID:Prevotella intermedia stimulates tissue-type plasminogen activator and plasminogen activator inhibitor-2 expression via multiple signaling pathways in human periodontal ligament cells. 2131 33


<< Previous 1 2 3 Next >>