Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(1) Thrombin, a mitogen for human cultured airway smooth muscle (HASM), has many actions that have been attributed to activation of protease-activated receptor (PARs). However, the role of PARs in the proliferative action has not been clearly identified. Moreover, thrombin elicits cytokine production in a number of cell types, but these effects have not been characterized in human ASM. (2) Thrombin (0.03-3 U ml(-1))-stimulated increases in the levels of the pro-inflammatory and fibrogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF) were observed over the same concentration range observed for thrombin-stimulated mitogenesis. (3) Inhibition of thrombin proteolytic activity, with either D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK)- or hirudin-treated thrombin (0.3 U ml(-1)) or in the presence of the thrombin serine protease-selective inhibitor, SDZ 217-766 (0.15 micro M), reduced the thrombin-stimulated GM-CSF levels by 91+/-3, 65+/-12 and 83+/-9% (n=8, P<0.05), respectively. PPACK treatment, hirudin and SDZ 217-766 inhibited thrombin-stimulated increase in cell number by 70+/-8, 63+/-11 and 69+/-8%, respectively. (4) PAR-selective peptides SFLLRN (PAR1; 10 micro M), SLIGKV (PAR2; 10 micro M), GYPGQV (PAR4; 100 micro M) or the combination of SFLLRN and GYPGQV elicited mitogenic responses of only 15% of that to thrombin and surprisingly, had no effect on GM-CSF levels (n=8). Nevertheless, inhibition of thrombin responses by pertussis toxin (50 ng ml(-1)) suggests that the PAR-independent actions also involve a G-protein-coupled receptor. (5) PAR1 receptor expression was evident by immunohistochemistry and these receptors were coupled to increases in intracellular calcium, but not to the phosphorylation of ERK or the increases in cyclin D1 protein levels that are essential for cell proliferation. Cross-desensitization of intracellular calcium increases by thrombin and the PAR1-selective peptide provides evidence that the PAR1 receptor responds to both ligands. (6) The failure of PAR-selective peptides to mimic thrombin responses together with the inhibition of thrombin responses by serine protease inhibitors suggest the involvement of novel proteolytic receptor targets for thrombin-induced mitogenesis and cytokine production.
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PMID:Protease-activated receptor (PAR)-independent growth and pro-inflammatory actions of thrombin on human cultured airway smooth muscle. 1264 88

Cathepsin G is a neutrophil-derived serine protease that contributes to tissue damage at sites of inflammation. The actions of cathepsin G are reported to be mediated by protease-activated receptor (PAR)-4 (a thrombin receptor) in human platelets. This study provides the first evidence that cathepsin G promotes inositol 1,4,5-trisphosphate accumulation, activates ERK, p38 MAPK, and AKT, and decreases contractile function in cardiomyocytes. Because some cathepsin G responses mimic cardiomyocyte activation by thrombin, a role for PARs was considered. Cathepsin G markedly activates phospholipase C and p38 MAPK in cardiomyocytes from PAR-1-/- mice, but it fails to activate phospholipase C, ERK, p38 MAPK, or AKT in PAR-1- or PAR-4-expressing PAR-1-/- fibroblasts (which display robust responses to thrombin). These results argue that PAR-1 does not mediate the actions of cathepsin G in cardiomyocytes, and neither PAR-1 nor PAR-4 mediates the actions of cathepsin G in fibroblasts. Of note, prolonged incubation of cardiomyocytes with cathepsin G results in the activation of caspase-3, cleavage of FAK and AKT, sarcomeric disassembly, cell rounding, cell detachment from underlying matrix, and morphologic features of apoptosis. Inhibition of Src family kinases or caspases (with PP1 or benzyloxycarbonyl-VAD-fluoromethyl ketone, respectively) delays FAK and AKT cleavage and cardiomyocyte detachment from substrate. Collectively, these studies describe novel cardiac actions of cathepsin G that do not require PARs and are predicted to assume functional importance at sites of interstitial inflammation in the heart.
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PMID:Neutrophil cathepsin G promotes detachment-induced cardiomyocyte apoptosis via a protease-activated receptor-independent mechanism. 1270 81

The present study compared the effects of glucocorticoids on thrombin- and EGF-stimulated proliferation in human cultured airway smooth muscle (ASM) to identify pathways that may be differentially regulated by glucocorticoids. Mitogenic responses to thrombin were inhibited by extracellular-regulated kinase (ERK 1/2) and phosphoinositide 3-kinase (PI3K) inhibitors, whereas mitogenic responses to EGF were inhibited by ERK 1/2 and PI3K inhibitors as well as by the p38 mitogen activated protein kinase inhibitor, SB203580 (10 microM). Mitogenic responses to thrombin were more sensitive to inhibition by dexamethasone (Dex) or fluticasone propionate (FP) than were those to EGF. Elevated cyclin D1 protein and mRNA levels induced by thrombin and EGF were attenuated equally by glucocorticoids. The protein or mRNA levels of the cyclin-dependent kinase inhibitors (cdki) p21(Cip1), p27(Kip1) were unaffected by Dex treatment of ASM cells treated with mitogens. The resistance of EGF-induced proliferation to inhibition by glucocorticoids is not associated with a failure to regulate cyclin D1 induction, nor does it appear to be explained by differential regulation of the levels of the cdki's, p21(Cip1) and p27(Kip1).
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PMID:Differential inhibition of thrombin- and EGF-stimulated human cultured airway smooth muscle proliferation by glucocorticoids. 1274 33

To investigate the role of thrombin in regulating apoptosis, we have used CCl39 cells, a fibroblast cell line in which thrombin-induced cell proliferation has been extensively studied. Withdrawal of serum from CCl39 cells resulted in a rapid apoptotic response that was completely prevented by the inclusion of thrombin. The protective effect of thrombin was reversed by pertussis toxin, suggesting that cell-survival signalling pathways are activated via a G(i) or G(o) heterotrimeric GTPase. Serum-withdrawal-induced death required de novo gene expression and was preceded by the rapid de novo expression of the pro-apoptotic 'BH3-only' protein Bim (Bcl-2-interacting mediator of cell death). Thrombin strongly inhibited the up-regulation of both Bim protein and Bim mRNA. The ability of thrombin to repress Bim expression, and to protect cells from apoptosis, was reversed by U0126, a MEK1/2 [MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) 1/2] inhibitor, or LY294002, a phosphoinositide 3'-kinase (PI3K) inhibitor, suggesting that both the Raf-->MEK-->ERK1/2 and PI3K pathways co-operate to repress Bim and promote cell survival. A PAR1p (protease-activated receptor 1 agonist peptide) was also able to protect cells from serum-withdrawal-induced apoptosis, suggesting that thrombin acts via PAR1 to prevent apoptosis.
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PMID:Thrombin inhibits Bim (Bcl-2-interacting mediator of cell death) expression and prevents serum-withdrawal-induced apoptosis via protease-activated receptor 1. 1284 49

Glycoprotein (GP)IIb/IIIa inhibition may abolish activated leukocyte-induced platelet activation, in which leukocyte-released platelet-activating factor (PAF) is a major mediator. The present study thus investigated if and how GPIIb/IIIa inhibitors interfere with PAF-induced platelet activation. Platelet and leukocyte activation were monitored by flow cytometry and immunoblotting. GPIIb/IIIa inhibitors (c7E3, non-peptide SR121566, and MAb RFGP56) attenuated PAF-induced, but not adenosine diphosphate (ADP)- or thrombin receptor activating peptide (TRAP)-induced platelet P-selectin expression in whole blood. GPIIb/IIIa blockade enhanced ADP- or TRAP-induced leukocyte CD11b expression, but not the response to PAF. GPIIb/IIIa blockade attenuated PAF-induced, but enhanced ADP- or TRAP-induced platelet-leukocyte aggregation. Under the present experimental conditions, thromboxane A2 receptor antagonism did not significantly influence PAF-induced platelet activation, and GPIIb/IIIa inhibition did not interfere with calcium mobilization/influx in platelets. Protein kinase C (PKC) blockade inhibited PAF-induced platelet P-selectin expression, and PAF-induced PKC activity was reduced by GPIIb/IIIa inhibition. PAF (=1 micro m) did not induce MEK 1/2 or ERK 1/2 phosphorylation, whilst thrombin induced marked responses, which were enhanced by GPIIb/IIIa blockade. Thus, GPIIb/IIIa inhibition attenuates PAF-induced platelet activation via inhibiting PKC activity. GPIIb/IIIa blockade enhances thrombin-induced platelet MEK 1/2 and ERK 1/2 activation, and augments ADP- and TRAP-induced leukocyte activation by enhancing platelet-leukocyte aggregation.
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PMID:Glycoprotein IIb/IIIa inhibition attenuates platelet-activating factor-induced platelet activation by reducing protein kinase C activity. 1291 97

Although the ability of G protein-coupled receptors to stimulate normal and aberrant cell growth has been intensely investigated, the precise nature of the molecular mechanisms underlying their transforming potential are still not fully understood. In this study, we have taken advantage of the potent mitogenic effect of thrombin and the focus-forming activity of one of its receptors, protease-activated receptor-1, to dissect how this receptor coupled to Galphai, Galphaq/11, and Galpha12/13 transduces signals from the membrane to the nucleus to initiate transcriptional events involved in cell transformation. Using endogenous and transfected thrombin receptors in NIH 3T3 cells, ectopic expression of muscarinic receptors coupled to Galphaq and Galphai, and chimeric G protein alpha subunits and murine fibroblasts deficient in Galphaq/11, and Galpha12/13, we show here that, although coupling to Galphai is sufficient to induce ERK activation, the ability to couple to Galphaq and/or Galpha13 is necessary to induce c-jun expression and cell transformation. Furthermore, we show that Galphaq and Galpha13 can initiate the activation of MAPK cascades, including JNK, p38, and ERK5, which in turn regulate the activity of transcription factors controlling expression from the c-jun promoter. We also present evidence that c-Jun and the kinases regulating its expression are integral components of the transforming pathway initiated by protease-activated receptor-1.
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PMID:Thrombin protease-activated receptor-1 signals through Gq- and G13-initiated MAPK cascades regulating c-Jun expression to induce cell transformation. 1295 41

Most tumors have constitutively active tissue factor on their surface, capable of generating thrombin in the surrounding environment, and thrombosis is associated with cancer. Thrombin is known to induce a malignant phenotype by enhancing tissue adhesion and cell growth in vitro and in vivo in mice. Because tumors require angiogenesis for growth, we examined whether thrombin induces neoangiogenesis in a physiologically intact in vivo model. Thrombin (0.1 U mL-1) induced neoangiogenesis in the chick chorioallantoic membrane over a 24-72-h period by approximately 2-3-fold. This was inhibited by the potent thrombin inhibitor, hirudin and shown to have its mode of action by ligation of the thrombin protease-activated receptor, PAR-1. The thrombin receptor activation peptide, SFLLRNPNDKYEPF (200 microm) also enhanced neoangiogenesis c. 2-3-fold. Thrombin-induced neoangiogenesis was accompanied by the induction of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) mRNA at 24-48 h (approximately 2-fold) as determined by semi-quantitative reverse transcriptase-polymerase chain reaction. Thrombin-induced neoangiogenesis was inhibited to baseline level by the specific angiogenesis receptor inhibitors KDR-Fc (vs. VEGF) and Tie-2-Fc (vs. Ang-1 and Ang-2), as well as the non-specific angiogenesis inhibitor thrombospondin-1. Thrombin-induced neoangiogenesis was also inhibited to baseline level by agents known to inhibit thrombin receptor signaling in other cells: G-coupled protein receptor inhibitor, pertussis toxin (40 pg per egg), protein kinase C inhibitor, bisindolylmaleimide (1 microm per egg), MAP kinase inhibitor, PD980598 (10 microm per egg) and PI3 kinase inhibitor, LY294002 (0.25 microm per egg). Thus angiogenesis is stimulated by thrombosis, which could help explain the enhancement of experimental tumorigenesis by thrombin.
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PMID:Thrombin induces neoangiogenesis in the chick chorioallantoic membrane. 1452 87

The influence of two peroxisome proliferator-activated receptor gamma (PPARgamma) ligands, a thiazolidinedione, rosiglitazone (RG) and the prostaglandin D2 metabolite 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) on the proliferation of human cultured airway smooth muscle (HASM) was examined. The increases in HASM cell number in response to basic fibroblast growth factor (bFGF, 300 pm) or thrombin (0.3 U ml-1) were significantly inhibited by either RG (1-10 microM) or 15d-PGJ2 (1-10 microM). The effects of RG, but not 15d-PGJ2, were reversed by the selective PPARgamma antagonist GW9662 (1 microM). Neither RG nor 15d-PGJ2 (10 microM) decreased cell viability, or induced apoptosis, suggesting that the regulation of cell number was due to inhibition of proliferation, rather than increased cell death. Flow-cytometric analysis of HASM cell cycle distribution 24 h after bFGF addition showed that RG prevented the progression of cells from G1 to S phase. In contrast, 15d-PGJ2 caused an increase in the proportion of cells in S phase, and a decrease in G2/M, compared to bFGF alone. Neither RG nor 15d-PGJ2 inhibited ERK phosphorylation measured 6 h post mitogen addition. The bFGF-mediated increase in cyclin D1 protein levels after 8 h was reduced in the presence of 15d-PGJ2, but not RG. Although both RG and 15d-PGJ2 can inhibit proliferation of HASM irrespective of the mitogen used, only the antiproliferative effects of RG appear to be PPARgamma-dependent. The different antimitogenic mechanisms of 15d-PGJ2 and synthetic ligands for PPARgamma may be exploited to optimise the potential for these compounds to inhibit airway remodelling in asthma. British Journal of Pharmacology (2004) 141, 517-525. doi:10.1038/sj.bjp.0705630
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PMID:PPAR gamma ligands, 15-deoxy-delta12,14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms. 1471 59

Normal glomerular filtration depends on the combined properties of the three layers of glomerular capillary wall: glomerular endothelial cells (GEnC), basement membrane, and podocytes. Podocytes produce endothelial factors, including angiopoietin 1 (ang1), and vascular endothelial growth factor (VEGF), whereas GEnC express their respective receptors Tie2 and VEGFR2 in vivo. As ang1 acts to maintain the endothelium in other vascular beds, regulating some actions of VEGF, these observations suggest a mechanism whereby podocytes may direct the unique properties of the glomerular endothelium. This interaction was investigated by studies on the barrier properties of human GEnC in vitro. GEnC were examined for expression of endothelium-specific markers by immunofluorescence and Western blotting and for typical responses to TNF-alpha by a cell-based immunoassay. Expression of angiopoietin and VEGF receptors was examined similarly. Barrier properties of GEnC monolayers cultured on porous supports were investigated by measurement of transendothelial electrical resistance (TEER) and passage of labeled albumin. Responses to a cAMP analogue and thrombin were examined before those to ang1 and VEGF. Results confirmed the endothelial origin of GEnC and their expression of Tie2 and VEGFR2. GEnC formed monolayers with a mean TEER of 30 to 40 Omega/cm(2). The cAMP analogue and thrombin increased and decreased TEER by 34.4 and 14.8 Omega/cm(2), respectively, with corresponding effects on protein passage. Ang1 increased TEER by 11.4 Omega/cm(2) and reduced protein passage by 45.2%, whereas VEGF reduced TEER by 12.5 Omega/cm(2) but had no effect on protein passage. Both ang1 and VEGF modulate GEnC barrier properties, consistent with potential in vivo roles; ang1 stabilizing the endothelium and resisting angiogenesis while VEGF induces the high permeability to water, characteristic of the glomerular endothelium.
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PMID:Angiopoietin 1 and vascular endothelial growth factor modulate human glomerular endothelial cell barrier properties. 1497 58

Phosphorylation of extracellular signal-regulated kinases (ERK 1/2) represents a converging intracellular signalling pathway which is involved in the modulation of gene transcription and may contribute to the feed-back regulation of neurotransmitter receptor functioning. The purpose of the current study was to investigate the serotonin-mediated phosphorylation of ERK 1/2 in platelets from patients (n = 17) with panic disorder, with respect to healthy volunteers (n = 17). Patients presented a severe symptomatology as assessed by the self-report rating scales for panic-agoraphobic (PAS-SR) and mood (MOOD-SR) spectrum, and by Clinical Global Impression Severity Scale (CGI-S). In platelets from healthy volunteers, serotonin induced a rapid increase of ERK 1/2 phosphorylation with a transient monophasic kinetic. The dose-response curves showed this effect was concentration dependent with an average of the EC(50) value of 22.8 +/- 2.4 microM. Platelet pre-incubation with 5HT(1A) and 5HT(2A) antagonists, pindobind and ritanserin, significantly inhibited serotonin-mediated kinase activation with an EC(50) of 3.2 +/- 0.2 and 1.99 +/- 0.08 nM, respectively, suggesting an involvement of these specific receptor subtypes in serotonin-mediated response. Furthermore, the 5HT(1A) and 5HT(2A) agonists, 8-hydroxy-N,N-dipropyl-aminotetralin (8OH-DPAT) and 1-(2,5-dimethoxy)-4-iodophenyl-2-aminopropane (DOI), were able to modulate ERK 1/2 phosphorylation in a concentration-dependent manner with an EC(50) value of 3.1 +/- 0.2 and 76 +/- 4.5 nM, respectively. ERK 1/2 phosphorylation was not observed after serotonin treatment of platelets from drug-free panic disorder patients, suggesting an alteration in intracellular phosphorylative pathways. Since ERK 1/2 responsiveness to other stimulus, such as collagen and thrombin, was comparable in platelets from healthy volunteers and patients, our results suggested that a specific alteration of serotonergic system occurred in panic disorder. Further studies to investigate 5HT(1A) and 5HT(2A) receptor expression and threonine phosphorylation levels showed that, nevertheless no significant differences in the receptor expression levels were detected, an increase of both 5HT receptor phosphorylation, on threonine residues, occurred in platelet from panic patients with respect to controls, suggesting that a reduction of serotonin receptor functioning was involved in the loss of serotonin responsiveness in panic.
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PMID:Serotonin-mediated phosphorylation of extracellular regulated kinases in platelets of patients with panic disorder versus controls. 1501 78


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