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:3.4.21.68 (tissue plasminogen activator)
11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroid-induced glaucoma is believed to result from increased aqueous outflow resistance and evidence suggests that this is the result of an excess accumulation of extracellular matrix components. This accumulation could result from an imbalance in the natural turnover of these components. We have investigated the effect of corticosteroid treatment of trabecular meshwork (TM) organ and cell cultures on the extracellular activities of the matrix metalloproteinases and plasminogen activators. We find that corticosteroid treatment results in decreased extracellular activity of stromelysin and tissue plasminogen activator in trabecular meshwork cell culture, and decreased 92 kDa collagenase IV, stromelysin, and tissue plasminogen activator in trabecular meshwork organ culture. These data suggest that decreased levels of proteolytic activities could account, in part, for the accumulation of some extracellular matrix components and be a contributing mechanism in steroid-induced glaucoma.
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PMID:Corticosteroid treatment and trabecular meshwork proteases in cell and organ culture supernatants. 828 32

Constitutive overexpression of both urokinase and matrix metalloproteinase (MMP) activity is frequently observed in individual malignant tumors. In this study we describe the combined contribution of these distinct enzyme systems to the invasive phenotype of a highly metastatic human melanoma cell line (M24met). M24met cells were found to secrete a spectrum of MMPs, including interstitial collagenase, type IV collagenases (M(r) 92,000 and 72,000 progelatinases), and stromelysin. Urokinase, but not tissue-type plasminogen activator, was detected in M24met-conditioned media and on cell surfaces. The contribution of these enzymes to extracellular matrix dissolution was determined by exploiting specific inhibitors, namely tissue inhibitor of the metalloproteinases-2 and plasminogen activator inhibitor-2. Due to the coexpression of urokinase and MMP-dependent activity, M24met cells were observed to degrade multiple components of the extracellular matrix and to significantly degrade both interstitial and basement membrane matrices. Urokinase-dependent removal of matrix glycoprotein was observed to precede MMP-dependent collagenolysis as a prerequisite rate-limiting step. We present evidence which suggests that this temporal relationship is imposed by the structural architecture of the matrix such that matrix glycoprotein serves to protect associated collagen from MMP-dependent degradation. In addition to mediating significant collagenolysis, MMP activity was further implicated in the dissolution of matrix tropoelastin. Urokinase/plasmin activity was not found to be required for MMP-zymogen activation.
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PMID:Melanoma-mediated dissolution of extracellular matrix: contribution of urokinase-dependent and metalloproteinase-dependent proteolytic pathways. 842 5

Decidual and placental relaxins have been proposed as autocrine/ paracrine hormones in the remodeling of collagen in the amnion and chorion in the last weeks of pregnancy. The matrix metalloproteinase-1 (MMP-1) is a key enzyme in the degradation of the interstitial collagens which predominate in the fetal membranes. Distribution of the MMP-1 gene and of the MMP-1 protein was shown by in situ hybridization and immunolocalization, respectively, in amnion, chorion, and decidua collected from patients before the onset of spontaneous labor. The distribution of MMP-1 in the chorionic cytotrophoblast and decidua coincided with that of the human relaxin receptor, detected by tissue section autoradiography in tissues collected at the same stage of pregnancy. Fetal membrane explants were used to study the effect of exogenous human relaxin H2. These responded by a dose-dependent increase in expression of the MMP-1 gene, in its secreted protein, and in its enzyme activity in the medium. A similar dose-dependent increase in the tissue plasminogen activator (tPA) gene and protein upon exposure of the explants to relaxin H2 suggested a coordinated cascade system, resulting in increases in secreted activities of MMP-1, MMP-3 (stromelysin), and MMP-9 (gelatinase B). There was no effect on the genes or proteins for MMP-2 (gelatinase A) or tissue inhibitor of metalloproteinase-1 (TIMP-1), showing the specificity of the response. This coordinated regulation by relaxin H2 of tPA, MMP-1, MMP-3, and MMP-9 would result in more complete degradation of the fetal membrane extracellular matrix components.
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PMID:An autocrine/paracrine role of human decidual relaxin. I. Interstitial collagenase (matrix metalloproteinase-1) and tissue plasminogen activator. 909 59

Cultured fibroblasts from patients with systemic sclerosis (SSc) and normal individuals were examined for gene expression of types I and III collagen, decorin, matrix metalloproteinases (MMP) MMP-1, MMP-2, and MMP-3, tissue inhibitors of metalloproteinases (TIMP) TIMP-1 and TIMP-2, urokinase- and tissue-type plasminogen activators (u-PA and t-PA). Fibroblasts from patients with early stage SSC (less than 1 year duration of disease) exhibited higher levels of types I and III procollagen, decorin, MMP-1, MMP-3, TIMP-1, and PAs than those from normal individuals. The gene expression of procollagen alpha 1(I) and TIMP-1 mRNAs were increased, but those of decorin, MMP-1, MMP-2, and MMP-3 were decreased, in fibroblasts from SSc patients with mid-stage SSc (2 to 4 years duration) as compared with those from normal individuals. In contrast, no significant difference in gene expression was found between fibroblasts from normal individuals and from patients with late-stage SSc (more than 6 years duration). These results suggest that gene expression of collagen, decorin, and degrading factors is dynamically modulated during fibrillogenesis. The responses of procollagen alpha 1(I) mRNA to IL-1 and TGF-beta were lower in fibroblasts from SSc patients with early and mid-stage disease, but not in those from patients with-late stage disease, than in control fibroblasts, which indicates that these cytokines may be involved in the earlier phases of fibrosis in SSc.
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PMID:Gene expression of types I and III collagen, decorin, matrix metalloproteinases and tissue inhibitors of metalloproteinases in skin fibroblasts from patients with systemic sclerosis. 937 15

Al-trans retinoic acid (RA) enhanced human, S-type, SK-N-SH neuroblastoma cell invasion of reconstituted basement membrane in vitro but did not induce terminal differentiation of this cell line. In contrast to basal invasion, which was urokinase (uPA)- and plasmin-dependent, RA-enhanced invasion was dependent on tissue-type plasminogen activator (t-PA) and plasmin activity. Neither basal nor RA-enhanced invasion involved TIMP-2 inhibitable metalloproteinases. Enhanced invasion was associated with the induction of t-PA expression, increased expression of the putative t-PA receptor amphoterin, increased association of t-PA with cell membranes and increased net membrane-associated PA activity. Enhanced invasion was not associated with significant changes in the expression of uPA or its membrane receptor UPAR; plasminogen activator inhibitors PAI-1 and PAI-2; metalloproteinases MMP-1, MMP-2, MMP-3, MMP-9 and membrane type MMP1; or tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2. RA stimulated the association of t-PA with the external cell membrane surface, which could be inhibited by heparin sulphate but not by mannose sugars or chelators of divalent cations, consistent with a role for amphoterin. Our data indicate that RA can promote the malignant behavior of S-type neuroblastoma cells refractory to RA-mediated terminal differentiation by enhancing their basement membrane invasive capacity. We suggest that this results from the action of a novel, RA-regulated mechanism involving stimulation of t-PA expression and its association with the cell membrane leading to increased PA-dependent matrix degradation.
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PMID:Retinoic acid-enhanced invasion through reconstituted basement membrane by human SK-N-SH neuroblastoma cells involves membrane-associated tissue-type plasminogen activator. 939 56

Transforming growth factor-beta (TGFbeta1) enhances human MDA-MB-231 breast tumour cell invasion of reconstituted basement membrane in vitro but does not inhibit proliferation of this cell line. In contrast to basal invasion, which is plasmin-, urokinase (uPA)-, tissue-type plasminogen activator (t-PA)-, matrix metalloproteinase (MMP)-9- and TIMP-1-inhibitable MMP-dependent, TGFbeta1 enhanced-invasion is dependent upon plasmin and uPA activity but does not appear to involve t-PA-, MMP9- or TIMP-1-inhibitable MMPs, as judged by inhibitor studies. Enhanced invasion is associated with increased u-PA, UPAR, PAI-1, MT-MMP-1, MMP-9 and TIMP-1 expression; with reduced t-PA, MMP-1 and MMP-3 expression; and with the induction of membrane MMP-9 association. The net result of these changes includes increased secreted, but not membrane-associated, uPA levels and activity and reduced secreted levels of plasmin and APMA-activatable gelatinolytic, collagenolytic and caseinolytic MMP activity but no change in membrane-associated gelatinolytic activity, despite increased MT-MMP-1 expression and MMP-9 membrane association. TGFbeta1 does not induce MMP-2 expression. Our data indicate that TGFbeta1 can promote the malignant behaviour of MDA-MB-231 cells refractory to TGFbeta1-mediated proliferation control by enhancing their invasive capacity. We suggest that this results from the action of a uPA/plasmin-dependent mechanism resulting from stimulation of uPA expression, secretion and subsequent activity, despite elevated PAI-1 inhibitor levels.
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PMID:Transforming growth factor-beta1 enhances the invasiveness of human MDA-MB-231 breast cancer cells by up-regulating urokinase activity. 949 40

Proteolytic enzymes, postulated to create an avenue for cell migration by digestion of host extracellular matrix molecules, have been implicated in neoplastic glial cell migration. A similar process is likely to occur in the developing brain. Fetal rabbit brain fragments transplanted into the striatum of the neonatal Shiverer mouse give rise to cells which migrate from the graft site and differentiate into astrocytes and oligodendrocytes. Proteinase expression by transplanted brain cells was studied using immunohistochemistry and in situ hybridization. Immature donor cells expressed the mRNAs for matrix metalloproteinases (MMP) 1 (collagenase) and 3 (stromelysin). Northern blot analysis of rabbit brain showed that MMP-1 in particular is expressed in the immature rabbit cerebrum and down-regulated during maturation. Immature donor cells exhibited immunoreactivity for urokinase plasminogen activator. However, immunoreactivity was also present in maturing neurons. Donor and host astroglia in the vicinity of grafts were immunoreactive for MMP-2 and tissue-type plasminogen activator. This expression may represent a reactive phenomenon, not specifically related to cell migration, by mature astrocytes. Based upon our findings, MMP-1 appears to be a candidate for involvement in migration of immature brain cells in the cerebrum.
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PMID:Expression of extracellular matrix degrading enzymes during migration of xenografted brain cells. 1019 76

Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.
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PMID:Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. 1050 7

Matrix metalloproteinase-3 (MMP-3 or stromelysin-1) specifically hydrolyzes the Ser(337)-Ser(338) (P10-P9) and Val(341)-Ile(342) (P6-P5) peptide bonds in human plasminogen activator inhibitor-1 (PAI-1). Cleavage is completely abolished in the presence of the metal chelators EDTA or 1,10-phenanthroline. A stabilized active PAI-1 variant was also cleaved by MMP-3. At an enzyme/substrate ratio of 1/10 at 37 degrees C, PAI-1 protein cleavage occurred with half-lives of 27 or 14 min for active or stable PAI-1 and was associated with rapid loss of inhibitory activity toward tissue-type plasminogen activator with half-lives of 15 or 13 min, respectively. A substrate-like variant of PAI-1, lacking inhibitory activity but with exposed reactive site loop, was cleaved with a half-life of 23 min, whereas latent PAI-1 in which a major part of the reactive site loop is inserted into the molecule, was resistant to cleavage. Biospecific interaction analysis indicated comparable binding of active, stable, and substrate PAI-1 to both proMMP-3 and MMP-3 (K(A) of 12-22 x 10(6) m(-1)), whereas binding of latent PAI-1 occurred with lower affinity (1.7-2.3 x 10(6) m(-1)). Stable PAI-1 bound to vitronectin was cleaved and inactivated by MMP-3 in a manner comparable with that of free PAI-1; however, the cleaved protein did not bind to vitronectin. Cleavage and inactivation of PAI-1 by MMP-3 may thus constitute a mechanism decreasing the antiproteolytic activity of PAI-1 and impairing the potential inhibitory effect of vitronectin-bound PAI-1 on cell adhesion and/or migration.
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PMID:Inactivation of plasminogen activator inhibitor-1 by specific proteolysis with stromelysin-1 (MMP-3). 1096 18

Matrix metalloproteinase-3 (MMP-3 or stromelysin-1) specifically binds to tissue-type plasminogen activator (t-PA), without however, hydrolyzing the protein. Binding affinity to proMMP-3 is similar to single chain t-PA, two chain t-PA and active site mutagenized t-PA (Ka of 6.3 x 106 to 8.0 x 106 M-1), but is reduced for t-PA lacking the finger and growth factor domains (Ka of 2.0 x 106 M-1). Activation of native Glu-plasminogen by t-PA in the presence of proMMP-3 obeys Michaelis-Menten kinetics; at saturating concentrations of proMMP-3, the catalytic efficiency of two chain t-PA is enhanced 20-fold (kcat/Km of 7.9 x 10-3 vs. 4.1 x 10-4 microM-1.s-1). This is mainly the result of an enhanced affinity of t-PA for its substrate (Km of 1.6 microM vs. 89 microM in the absence of proMMP-3), whereas the kcat is less affected (kcat of 1.3 x 10-2 vs. 3.6 x 10-2 s-1). Activation of Lys-plasminogen by two chain t-PA is stimulated about 13-fold at a saturating concentration of proMMP-3, whereas that of miniplasminogen is virtually unaffected (1.4-fold). Plasminogen activation by single chain t-PA is stimulated about ninefold by proMMP-3, whereas that by the mutant lacking finger and growth factor domains is stimulated only threefold. Biospecific interaction analysis revealed binding of Lys-plasminogen to proMMP-3 with 18-fold higher affinity (Ka of 22 x 106 M-1) and of miniplasminogen with fivefold lower affinity (Ka of 0.26 x 106 M-1) as compared to Glu-plasminogen (Ka of 1.2 x 106 M-1). Plasminogen and t-PA appear to bind to different sites on proMMP-3. These data are compatible with a model in which both plasminogen and t-PA bind to proMMP-3, resulting in a cyclic ternary complex in which t-PA has an enhanced affinity for plasminogen, which may be in a Lys-plasminogen-like conformation. Maximal binding and stimulation require the N-terminal finger and growth factor domains of t-PA and the N-terminal kringle domains of plasminogen.
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PMID:Prostromelysin-1 (proMMP-3) stimulates plasminogen activation by tissue-type plasminogen activator. 1102 80


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