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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of microglia, the resident macrophages in the CNS, plays a significant role in neuronal death or degeneration in a broad spectrum of CNS disorders. Recent studies indicate that nanomolar concentrations of the serine protease, thrombin, can activate microglia in culture. However, in contrast to other neural cells responsive to thrombin, the participation of novel protease-activated receptors (PARs), such as the prototypic thrombin receptor PAR1, in thrombin-induced microglial activation was cast in doubt. In this report, by utilizing primary microglial cultures from PAR1 knockout (PAR1-/-) mice, application of the PAR1 active peptide TRAP-6 (SFLLRN) in comparison to a scrambled peptide (LFLNR), we have unambiguously demonstrated that murine microglia constitutively express PAR1 mRNA that is translated into fully functional protein. Activation of the microglial PAR1 induces a rapid cytosolic free [Ca2+]i increase and transient activation of both p38 and p44/42 mitogen-activated protein kinases. Moreover, although in part, this PAR1 activation directly contributes to thrombin-induced microglial proliferation. Furthermore, although not directly inducing tumor necrosis factor-alpha (TNF-alpha) release, PAR1 activation up-regulates microglial CD40 expression and potentiates CD40 ligand-induced TNF-alpha production, thus indirectly contributing to microglial activation. Taken together, these results demonstrate an essential role of PAR1 in thrombin-induced microglial activation. In addition, strategies aimed at blocking thrombin signaling through PAR1 may be therapeutically valuable for diseases associated with cerebral vascular damage and significant inflammation with microglial activation.
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PMID:Participation of protease-activated receptor-1 in thrombin-induced microglial activation. 1184 73

In vascular smooth muscle (VSM) and many other cells, G protein receptor-coupled activation of mitogen-activated protein kinases has been linked, in part, to increases in free intracellular Ca(2+). Previously, we demonstrated that ionomycin-, angiotensin II-, and thrombin-induced activation of extracellular signal-regulated kinase (ERK)1/2 in VSM cells was attenuated by pretreatment with KN-93, a selective inhibitor of the multifunctional Ca(2+)/calmodulin-dependent protein kinase (CaM kinase II). In the present study, we show that the Ca(2+)-dependent pathway leading to activation of ERK1/2 is preceded by nonreceptor proline-rich tyrosine kinase (PYK2) activation and epidermal growth factor (EGF) receptor tyrosine phosphorylation and is attenuated by inhibitors of src family kinases or the EGF receptor tyrosine kinase. Furthermore, we demonstrate that pretreatment with KN-93 or a CaM kinase II inhibitor peptide inhibits Ca(2+)-dependent PYK2 activation and EGF receptor tyrosine phosphorylation in response to ionomycin, ATP, and platelet-derived growth factor but has no effect on phorbol 12,13-dibutyrate- or EGF-induced responses. The results implicate CaM kinase II as an intermediate in the Ca(2+)/calmodulin-dependent activation of PYK2.
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PMID:CaM kinase II-dependent activation of tyrosine kinases and ERK1/2 in vascular smooth muscle. 1188 Feb 63

The authors previously found that pretreatment with a low dose of thrombin attenuates the brain edema induced by a large dose of thrombin or an intracerebral hemorrhage, and reduces infarct volume after focal cerebral ischemia (i.e., thrombin preconditioning). This study investigated whether thrombin preconditioning is caused by activation of the thrombin receptor, also called protease-activated receptor. In the in vivo studies, thrombin-induced brain tolerance was eliminated by RPPGF (Arg-Pro-Pro-Gly-Phe), a thrombin-receptor antagonist. Pretreatment with a thrombin-receptor agonist reduced the amount of edema induced by a large dose of thrombin infused into the ipsilateral basal ganglia 7 days later (81.3 +/- 0.7% vs. 82.6 +/- 0.8% in the control, P < 0.05). In the in vitro study, low doses of thrombin (1 or 2 U/mL) did not induce cell death. However, doses greater than 5 U/mL resulted in dose-dependent lactate dehydrogenase release (P < 0.01). Thrombin and thrombin receptor-activating peptide preconditioning reduced lactate dehydrogenase release induced by a high dose of thrombin (10 and 20 U/mL), whereas RPPGF blocked the effect of thrombin preconditioning in vitro. Western blots indicated that p44/42 mitogen-activated protein kinases were activated after thrombin preconditioning. Finally, inhibition of p44/42 mitogen-activated protein kinases activation by PD98059 abolished the thrombin-preconditioning effect. Results indicate that thrombin-induced brain tolerance is in part achieved through activation of the thrombin receptor. Activation of the thrombin receptor in the brain may be neuroprotective. The protective effect of thrombin preconditioning is achieved through the p44/42 mitogen-activated protein kinase signal-transduction pathway.
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PMID:Thrombin-receptor activation and thrombin-induced brain tolerance. 1191 11

Microglia, the major immune effector cells in the CNS, become activated when the brain suffers injury. In this study, we observed that prothrombin, a zymogen of thrombin, induced NO release and mRNA expression of inducible NO synthase, IL-1beta, and TNF-alpha in rat brain microglia. The effect of prothrombin was independent of the protease activity of thrombin since hirudin, a specific inhibitor of thrombin, did not inhibit prothrombin-induced NO release. Furthermore, factor Xa enhanced the effect of prothrombin on microglial NO release. Kringle-2, a domain of prothrombin distinct from thrombin, mimicked the effect of prothrombin in inducing NO release and mRNA expression of inducible NO synthase, IL-1beta, and TNF-alpha. Prothrombin and kringle-2 both triggered the same intracellular signaling pathways. They both activated mitogen-activated protein kinases and NF-kappaB in a similar pattern. NO release stimulated by either was similarly reduced by inhibitors of the extracellular signal-regulated kinase pathway (PD98059), p38 (SB203580), NF-kappaB (N-acetylcysteine), protein kinase C (Go6976, bisindolylmaleimide, and Ro31-8220), and phospholipase C (D609 and U73122). These results suggest that prothrombin can activate microglia, and that, in addition to thrombin, kringle-2 is a domain of prothrombin independently capable of activating microglia.
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PMID:Prothrombin kringle-2 activates cultured rat brain microglia. 1202 83

The signaling pathways that lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) use to activate Akt in ovarian cancer cells are investigated here. We show for the first time, with the use of both pharmacological and genetic inhibitors, that the kinase activity and S473 phosphorylation of Akt induced by LPA and S1P requires both mitogen-activated protein (MAP) kinase kinase (MEK) and p38 MAP kinase, and MEK is likely to be upstream of p38, in HEY ovarian cancer cells. The requirement for both MEK and p38 is cell type- and stimulus-specific. Among 12 cell lines that we tested, 11 respond to LPA and S1P and all of the responsive cell lines require p38 but only nine of them require MEK. Among different stimuli tested, platelet-derived growth factor stimulates S473 phosphorylation of Akt in a MEK- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1-stimulated Akt S473 phosphorylation require p38 but not MEK. Insulin, on the other hand, stimulates Akt S473 phosphorylation independent of both MEK and p38 in HEY cells. T308 phosphorylation stimulated by LPA/S1P requires MEK but not p38 activation. MEK and p38 activation were sufficient for Akt S473 but not T308 phosphorylation in HEY cells. In contrast to S1P and PDGF, LPA requires Rho for Akt S473 phosphorylation, and Rho is upstream of phosphatidylinositol 3-kinase (PI3-K). LPA/S1P-induced Akt activation may be involved in cell survival, because LPA and S1P treatment in HEY ovarian cancer cells results in a decrease in paclitaxel-induced caspase-3 activity in a PI3-K/MEK/p38-dependent manner.
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PMID:Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific. 1218 43

Although microglial cells are thought to play a beneficial role in the regeneration and plasticity of the central nervous system (CNS), recent studies have indicated that at least some molecules released by microglia may be harmful in acute brain insults and neurodegenerative diseases. Therefore, the pathways mediating the synthesis and release of these neurotoxic compounds are of importance. p38 and p44/42 families of mitogen-activated protein kinases (MAPKs) in microglia respond strongly to various extracellular stimuli, such as ATP, thrombin, and beta-amyloid, a peptide thought to be responsible for the neuropathology in Alzheimer's disease. In this review we describe in vivo evidence implicating that p38 and p44/42 MAPKs may play a critical role in harmful microglial activation in acute brain injury, such as stroke, and in more chronic neurodegenerative diseases, such as Alzheimer's disease. We also clarify the extracellular signals responsible for activation of p38 and p44/42 MAPK in microglia and review the responses so far reported to be mediated by these kinases.
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PMID:Role of p38 and p44/42 mitogen-activated protein kinases in microglia. 1237 5

Elucidating the factors that inhibit the increase in airway smooth muscle (ASM) mass may be of therapeutic benefit in asthma. Here, we investigated whether interferon-gamma (IFN-gamma), a potent inducer of growth arrest in various cell types, regulates mitogen-induced ASM cell proliferation. IFN-gamma (1-100 U/ml) was found to markedly decrease both DNA synthesis and ASM cell number induced by the mitogens epidermal growth factor (EGF) and thrombin. Interestingly, IFN-gamma had no effect on mitogen-induced activation of three major mitogenic signaling pathways, phosphatidylinositol 3-kinase, p70(S6k), or mitogen-activated protein kinases. Mitogen-induced expression of cell cycle regulator cyclin D1 was increased by IFN-gamma, whereas no effect was observed on degradation of p27(Kip1). Expression array analysis of 23 cell cycle-related genes showed that IFN-gamma inhibited EGF-induced increases in E2F-1 expression, whereas induction of c-myc, cyclin D2, Egr-1, and mdm2 were unaffected. Induction of E2F-1 protein and Rb hyperphosphorylation after mitogen stimulation was also suppressed by IFN-gamma. In addition, IFN-gamma decreased activation of cdk2 and expression of cyclin E, upstream signaling molecules responsible for Rb hyperphosphorylation in the late G1 phase. IFN-gamma also increased levels of IFI 16 protein, whose mouse homolog p202 has been associated with growth inhibition. Together, our data indicate that IFN-gamma is an effective inhibitor of ASM cell proliferation by blocking transition from G1-to-S phase by acting at two different levels: modulation of cdk2/cyclin E activation and inhibition of E2F-1 gene expression.
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PMID:IFN-gamma inhibits human airway smooth muscle cell proliferation by modulating the E2F-1/Rb pathway. 1258 5

The activation of human platelets by a variety of agonists is accompanied by the phosphorylation of the extracellular signal-regulated kinase (ERK) isoforms of mitogen-activated protein (MAP) kinases. However, the role(s) of, and the substrate(s) for, these enzymes in platelet function remain unclear. Studies on ERKs in platelets have relied on pharmacological tools, including an inhibitor of ERK activation, U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene]. In the present study, the effects of U0126 and its "inactive" analogue, U0125 [1,4-diamino-2,3-dicyano-1,4-bis(phenylthio)butadiene], on human platelet aggregation and MAP kinase activity were examined. Several agonists with a variety of signaling pathways were studied including thrombin, a thromboxane analogue, arachidonic acid, collagen, calcium ionophores, and the phorbol ester phorbol myristate acetate (PMA). U0126, at concentrations consistent with inhibition of the isolated enzyme, inhibited ERK phosphorylation, and therefore MEK activation, in response to each agonist. Under such conditions, U0126 did not affect the phosphorylation of a second MAP kinase, p38(MAPK); however, platelet aggregation was also unaffected. Higher concentrations of U0126, and of U0125, inhibited platelet aggregation in response to collagen and PMA with no effect on that induced by the other agonists. These results dissociate ERK activation from platelet aggregation, suggesting an alternative role for ERKs in platelet function. In addition, the effects of higher concentrations of U0126 are likely due to an action on protein kinase C, likely unrelated to ERK inhibition, suggesting that the inhibitor concentration is crucial to the interpretation of such studies.
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PMID:Inhibition of the MEK/ERK pathway has no effect on agonist-induced aggregation of human platelets. 1269 65

Sphingosine 1-phosphate (S1P), a bioactive lipid, is produced and stored in platelets and is released from activated platelets during blood coagulation activation. Thrombin, which is also generated during blood coagulation, has been shown to induce tissue factor (TF), the initiator of blood coagulation, in endothelial cells (ECs); however, the effect of S1P on this process is not evaluated. Here we demonstrated that S1P strongly potentiated thrombin-induced TF expression in ECs and that S1P itself did not induce TF expression. Among signaling lipids, platelet-activating factor slightly enhanced thrombin-induced TF expression; other lipids, including lysophosphatidic acid, lysophosphatidylcholine, sphingosine, and C2-ceramide exert no effect on TF expression. S1P enhanced TF expression at the transcriptional level, possibly via promoting the activation of transcription factors nuclear factor-kappaB (NF-kappaB) and Egr-1. Thrombin weakly and S1P strongly activated extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein (MAP) kinase and, in the presence of both stimulants, enhanced and sustained activation of this kinase was observed. The ERK1/2-specific inhibitor PD98059 significantly inhibited enhanced TF expression induced by both stimulants but only weakly inhibited thrombin-induced TF expression, thus indicating the requirement of the ERK1/2 pathway in synergistic induction of TF expression. In addition, we found that thrombin and S1P rapidly up-regulated the expression of S1P receptors, endothelial differentiation gene-1 (EDG-1) and EDG-3, thereby suggesting that the effect of S1P on TF expression and other EC functions may be enhanced by thrombin and S1P itself. The present data reveal the synergistic effect of S1P on thrombin-induced TF expression in ECs, which may promote further thrombin and S1P generation, thus propagating a positive feedback reaction.
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PMID:Synergistic effect of sphingosine 1-phosphate on thrombin-induced tissue factor expression in endothelial cells. 1273 Jan

Endothelial permeability depends on the integrity of intercellular junctions as well as actomyosin-based cell contractility. Rho GTPases have been implicated in signalling by many vasoactive substances including thrombin, tumour necrosis factor alpha (TNF-alpha), bradykinin, histamine, lysophosphatidic acid (LPA), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF). Two Rho family GTPases, Rho and Rac, have emerged as key regulators acting antagonistically to regulate endothelial barrier function: Rho increases actomyosin contractility, which facilitates breakdown of intercellular junctions, whereas Rac stabilizes endothelial junctions and counteracts the effects of Rho. In this review, we present evidence for the opposing effects of these two regulatory proteins and discuss links between them and other key signalling molecules such as cyclic AMP (cAMP), cyclic GMP (cGMP), phosphatidylinositide 3-kinases (PI3Ks), mitogen-activated protein kinases (MAPKs), and protein kinases C (PKCs). We also discuss strategies for targeting Rho GTPase signalling in therapies for diseases involving altered endothelial permeability.
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PMID:Rho GTPases and the regulation of endothelial permeability. 1274 59


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