Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activators (tPA and uPA) are serine proteases that convert the circulating zymogen plasminogen to active plasmin and mediate fibrin degradation. These multifunctional proteins trigger various biological events such as extracellular matrix degradation, cell adhesion, migration, and proliferation, through not yet fully characterized mechanisms. We report that, in smooth muscle cells and ECV-304 carcinoma cells, tPA and ATF (the N-terminal catalytically inactive fragment of tPA) elicited DNA synthesis that requires activation of the sphingomyelin/ceramide/sphingosine-1-phosphate (Spm/Cer/S1P), signaling pathway and was blocked by D-erythro-2-(N-myristoylamino)-1-phenyl-propanol (D-MAPP) and N-N'-dimethyl sphingosine (DMS), two classical inhibitors of sphingosine-1-phosphate biosynthesis. Binding of tPA to its receptor uPAR triggered the coordinated activation of two key enzymes of the Spm/Cer/S1P pathway, the neutral sphingomyelinase and the sphingosine kinase-1 that was mediated by a common pertussis toxin (PTX)-sensitive mechanism. The tPA-induced sphingosine kinase-1 activation was mediated by Src, since it was inhibited by herbimycin A and in SrcK- cells (overexpressing a dominant negative kinase defective form of Src) and by ERK1/2 (early phase peaking at 15 min). Sphingosine kinase-1 activation was followed by a second phase of ERK1/2 phosphorylation (peaking at 120 min) and subsequent DNA synthesis, which were inhibited by D-MAPP and DMS, by anti-EGD-1 antibodies and in SrcK- cells (in which the mitogenic signaling was rescued by sphingosine-1-phosphate). Altogether, these data underline a pivotal role for the Spm/Cer/S1P pathway in the tPA-induced mitogenic signaling.
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PMID:The sphingomyelin/ceramide pathway is involved in ERK1/2 phosphorylation, cell proliferation, and uPAR overexpression induced by tissue-type plasminogen activator. 1523 24

The defining characteristic of a tumor cell is its ability to escape the constraints imposed by neighboring cells, invade the surrounding tissue and metastasize to distant sites. This invasive property of tumor cells is dependent on activation of proteinases at the cell surface. The serine proteinase plasmin is one of the key proteinases that participate in the pericellular proteolysis associated with the invasive program of tumor cells. The assembly of plasminogen and tissue plasminogen activator at the endothelial cell surface or on the fibrin clot provides a focal point for plasmin generation and therefore plays an important role in maintaining blood fluidity and promoting fibrinolysis. S100A10, a member of the S100 family of Ca2+-binding proteins, is a dimeric protein composed of two 11 kDa subunits. Typically, S100A10 is found in most cells bound to its annexin A2 ligand as the heterotetrameric (S100A10)2(annexin A2)2 complex, AIIt. In addition to an intracellular distribution, S100A10 is present on the extracellular surface of many cells. The carboxyl-terminal lysines of S100A10 bind tPA and plasminogen resulting in the stimulation of tPA-dependent plasmin production. Carboxypeptidases cleave the carboxyl-terminal lysines of S100A10, resulting in a loss of binding and activity. Plasmin binds to S100A10 at a distinct site and the formation of the S100A10-plasmin complex stimulates plasmin autoproteolysis thereby providing a highly localized transient pulse of plasmin activity at the cell surface. The binding of tPA and plasmin to S100A10 also protects against inhibition by physiological inhibitors, PAI-1 and alpha2-antiplasmin, respectively. S100A10 also colocalizes plasminogen with the uPA-uPAR complex thereby localizing and stimulating uPA-dependent plasmin formation to the surface of cancer cells. The loss of S100A10 from the extracellular surface of cancer cells results in a significant loss in plasmin generation. In addition, S100A10 knock-down cells demonstrate a dramatic loss in extracellular matrix degradation and invasiveness as well as reduced metastasis. Annexin A2 plays an important role in plasminogen regulation by controlling the levels of extracellular S100A10 and by acting as a plasmin reductase. The mechanism by which annexin A2 regulates the extracellular levels of S100A10 is unknown. This review highlights the important part that S100A10 plays in plasmin regulation and the role this protein plays in cancer cell invasiveness and metastasis.
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PMID:S100A10, annexin A2, and annexin a2 heterotetramer as candidate plasminogen receptors. 1557 70

The ras oncogenes are among those most frequently found in human cancers. Blocking Ras farnesylation is a promising strategy for arresting cancer growth. Ras activates several signaling pathways with key roles in cellular proliferation, invasion, metastasis and angiogenesis. Furthermore, proteolytic activities of matrix proteinases such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) are regulated by Ras isoforms. Thus, we investigated the effects of SCH-66336, a farnesyltransferase inhibitor, on secretion of components of the plasminogen activation system as well as on the gelatinases MMP-2 and MMP-9, which play pivotal roles in matrix remodeling. SCH-66336 up to 5 microM did not significantly alter the viability of prostate (PC-3) and renal (Caki-1) cancer cells incubated in serum-depleted medium. SCH-66336 partly inhibited the processing of H-Ras, while levels of mature N-Ras and K-Ras remained unaffected. Under these noncytotoxic conditions, uPA and tPA levels were lowered in culture medium but raised in cell lysates, suggesting inhibition of trafficking pathways. In contrast, SCH-66336 had no effect on uPAR expression or on secreted PAI-1 levels. As expected, the reduction of uPA and tPA activities by SCH-66336 inhibited the conversion of plasminogen to plasmin by about 25% in PC-3 cells. SCH-66336 also inhibited the levels of secreted pro-MMP-2 and pro-MMP-9 as well as the release of their inhibitors TIMP-1 and TIMP-2. SCH-66336 decreased both the adhesion and even more so the migration of PC-3 cells on gelatin. Thus, SCH-66336 inhibited farnesylation in both cancer cell types, and H-Ras functions should be reduced by the drug. In addition, the lower levels of secreted proteinases in the presence of SCH-66336 suggest that reduced matrix remodeling and cell migration should occur in treated tumors.
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PMID:Farnesyltransferase inhibitor SCH-66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration. 1560 18

The hepatocyte growth factor (HGF) is a multifunctional cytokine that is produced as latent scHGF (single chain HGF). Various proteases reportedly cleave scHGF to generate the active two-chain form (HGF), including u-PA (urokinase-type plasminogen activator), t-PA (tissue-type plasminogen activator), kallikrein, Factor XIa, Factor XIIa, HGF activator and matriptase. Considerable evidence indicates that, in vivo, u-PA activates scHGF in the liver; however, the in vivo results have not been uniformly supported by in vitro experiments. We now report that cleavage of scHGF by high-molecular-mass u-PA (abbreviated u-PA throughout) is sensitive to ionic strength. scHGF cleavage by u-PA was accelerated as the ionic strength was decreased. This result was equivalent irrespective of whether the predominant anion was chloride or acetate. Lmw-u-PA (low-molecular-mass u-PA) was ineffective at cleaving scHGF, regardless of ionic strength. Although scHGF shares homology with plasminogen, EACA (-amino-caproic acid) did not regulate u-PA-mediated scHGF cleavage. Soluble HGF receptor (MET) and soluble u-PAR (u-PA receptor) inhibited the scHGF cleavage. These results support a model in which the ability of u-PA to activate scHGF in vivo may be highly dependent on local conditions within the extracellular space.
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PMID:Activation of hepatocyte growth factor by urokinase-type plasminogen activator is ionic strength-dependent. 1586 63

The pathogenesis of vascular tumors such as angiosarcomas is poorly understood. Cadherin expression inversely correlates with tumor malignancy and the endothelial specific VE-cadherin is low or absent in angiosarcomas, suggesting an inhibitory role for this protein in tumor progression. In this paper we report that PmyT VE-cadherin null (VEC null) endothelial cells form larger vascular tumors in nude mice when injected subcutaneously as compared to isogenic VE-cadherin positive (VEC pos) cells. This effect requires the association of beta-catenin to VEcadherin, since a VE-cadherin mutant lacking the domain responsible for beta-catenin binding (Deltabetacat) cannot rescue the phenotype. In VEC null cells beta-catenin is phosphorylated and partly degraded. N-cadherin is increased and detected at junctions. VEC null cells also present an altered fibrinolytic activity with increases in tPA, uPA, uPAR and a strong reduction in PAI-1, which may be correlated to the high incidence of abrupt hemorrhages in VEC null tumors. Overall, these data strongly suggest that downregulation of VE-cadherin in endothelial tumors may have important consequences for tumor growth and bleeding complications.
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PMID:Downregulation of vascular endothelial-cadherin expression is associated with an increase in vascular tumor growth and hemorrhagic complications. 1596 86

Early signs of inflammatory demyelination include entry of fibrin(ogen) into the central nervous system (CNS), which is normally excluded by the blood-brain barrier, and up-regulation of components of the plasminogen activator system. Using mice deficient in tissue-type plasminogen activator (tPA-/-) and urokinase plasminogen activator receptor (uPAR-/-), we investigated the involvement of the PA system on the clinical and pathological features of experimental allergic encephalomyelitis, an animal model of multiple sclerosis. tPA-/- mice suffered an early and a more severe acute disease characterized by incomplete recovery when compared to wild-type controls, with significantly higher CNS levels of plasminogen activator inhibitor-1. This correlated with fibrin accumulation, which co-localized with nonphosphorylated neurofilament on thickened axons in experimental allergic encephalomyelitis tissue. In contrast, uPAR-/- mice had a delayed, less acute disease reflected in delayed infiltration of inflammatory cells. These animals developed chronic disease as a result of steadily increased inflammation, increased levels of urokinase-type plasminogen activator (uPA), and greater degree of demyelination. Thus, the plasminogen activator system can modulate both inflammatory and degenerative events in the CNS through the respective effects of tPA and uPAR on fibrinolysis and cell adhesion/migration, manipulation of which may have therapeutic implications for multiple sclerosis.
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PMID:A role for the plasminogen activator system in inflammation and neurodegeneration in the central nervous system during experimental allergic encephalomyelitis. 1604 38

Alveolar osteitis (AO) is characterized by excess fibrinolysis, leading to early dissociation of the clot that normally follows tooth extraction. Nonetheless, scarce information is available on the fibrinolytic system in AO. In this study, we report on the differential composition of postextraction wound healing tissue and of peri-alveolar gingival epithelium from normal healing and AO patients in terms of plasminogen activators, plasminogen activator inhibitor-type 1, and urokinase-type plasminogen activator receptor. Plasminogen activators were studied by overlay zymography, western blotting, and enzyme-linked immunosorbent assay (ELISA). Plasminogen activator inhibitor-type 1 and urokinase receptor were measured by ELISA. In AO, the fibrinolytic activity of wound healing tissue was accounted for by an increase ( approximately 85%) of urokinase-type plasminogen activator, whereas tissue-type plasminogen activator was unchanged. Plasminogen activator inhibitor-type 1 showed a 6.7-fold increase in AO. These results point to key roles of urokinase in AO hyper-fibrinolysis and of plasminogen activator inhibitor type-1 in slowing down the healing response. Peri-alveolar gingival epithelium in AO showed an overall decrease of all the components of the fibrinolytic system, including the urokinase receptor, which indicates a decrease of the migration properties of epithelial cells.
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PMID:Plasminogen activators and inhibitor type-1 in alveolar osteitis. 1718 32

Interstitial fibrosis is a universal feature of progressive kidney disease. Urokinase-type plasminogen activator (uPA) is thought to participate for several reasons: 1) uPA is produced predominantly in kidney, 2) its inhibitor plasminogen activator inhibitor-1 (PAI-1) is a strong promoter of interstitial fibrosis, whereas its receptor (uPAR) attenuates renal fibrosis, 3) uPA reduces fibrosis in liver and lung, and 4) uPA can activate hepatocyte growth factor (HGF), a potent antifibrotic growth factor. The present study tested the hypothesis that endogenous uPA reduces fibrosis severity by investigating the unilateral ureteral obstruction (UUO) model in wild-type (WT) and uPA-/- mice. Several outcomes were measured: renal collagen 3-21 days after UUO, macrophage accumulation (F4/80 Western blotting), interstitial myofibroblast density (alpha-smooth muscle actin immunostaining), and tubular injury (E-cadherin and Ksp-cadherin Western blotting). None of these measures differed significantly between WT and uPA-/- mice. uPA genetic deficiency was not associated with compensatory changes in renal uPAR mRNA levels, PAI-1 protein levels, or tissue plasminogen activator activity levels after UUO. Despite the known ability of uPA to activate latent HGF, immunoblotting failed to detect significant differences in levels of the active HGF alpha-chain and phosphorylated cMET (the activated HGF receptor) between the WT and uPA-/- groups. These findings suggest that the profibrotic actions of PAI-1 are uPA independent and that an alternative pathway must activate HGF in kidney. Finally, these results highlight a significant organ-specific difference in basic fibrogenic pathways, as enhanced uPA activity has been reported to attenuate pulmonary and hepatic fibrosis.
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PMID:Endogenous urokinase lacks antifibrotic activity during progressive renal injury. 1749 93

Fibrinolysis is regulated by specific molecular interactions between its main components. Activation of plasminogen by tissue-type plasminogen activator (t-PA) is enhanced in the presence of fibrin or at the endothelial cell surface. Urokinase-type plasminogen activator (u-PA) binds to a specific cellular u-PA receptor (u-PAR), resulting in enhanced activation of cell-bound plasminogen. Inhibition of fibrinolysis occurs at the level of plasminogen activation or at the level of plasmin. Assembly of fibrinolytic components at the surface of fibrin results in fibrin degradation. Assembly at the surface of cells provides a mechanism for generation of localized cell-associated proteolytic activity. This review includes novel proteins such a thrombin-activatable fibrinolysis inhibitor (TAFI) and discusses new insights into molecular mechanisms obtained from the rapidly growing knowledge of crystal structures of proteins.
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PMID:New insights into the molecular mechanisms of the fibrinolytic system. 1898 6

In this study we examined the effects of exogenous nitric oxide (sodium nitroprusside, SNP) and hydrogen peroxide (H2O2) on the expression level of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), urokinase-type plasminogen activator receptor (u-PAR), and plasminogen activator inhibitor type 1 (PAI-1) in human umbilical vein endothelial cells (HUVEC). The expression of selected genes involved in fibrynolysis under the influence of oxidative stress was analyzed at the levels of mRNA, protein, and promoter activity. The results of the conducted studies revealed that oxidative stress in endothelial cells causes a significant increase in PAI-1 and u-PAR expression and a moderate increase in t-PA and u-PA expression at all of the investigated levels. We attempted to elucidate the molecular signaling mechanisms by which SNP and H2O2 regulate expression of the respective fibrinolytic factors. Therefore, we tested the protein levels of AP-1, NF-kappaB, and HIF-1 and their DNA-binding activity in endothelial cells subjected to oxidative stress. We found strong correlation between AP-1, NF-kappaB, and HIF-1 in the contribution of regulation of selected genes. In addition, we also found that the inhibition of PAI-1 synthesis by antisense oligonucleotide to PAI-1 mRNA results in markedly increased u-PAR expression and that NF-kappaB and AP-1 are involved in this regulation.
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PMID:Effect of oxidative stress on the expression of t-PA, u-PA, u-PAR, and PAI-1 in endothelial cells. 1908 96


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