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

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

Membrane binding of urokinase type plasminogen activator (u-PA) is thought to play a pivotal role in connective tissue remodeling and invasive processes. We compare the ability of different matrix-metalloproteinases involved in connective tissue turnover to cleave pro-urokinase type plasminogen activator between the catalytic domain and the receptor binding part to investigate a potential role for matrix-metalloproteinases in the regulation of membrane-associated proteolytic activity. We employed several forms of human stromelysin-1 (full length, C-truncated, and recombinant catalytic domain), rabbit C-truncated stromelysin-1, the human gelatinases A and B and the human catalytic domain of neutrophil collagenase. The gelatinases and the collagenase did not separate the receptor binding domain of pro-urokinase type plasminogen activator from the catalytic domain, whereas all stromelysin-1 forms cleaved the glutamic acid 143-leucine 144 bond of pro-urokinase type plasminogen activator. This reaction could be inhibited by specific inhibitors of matrix metalloproteinases and was not affected by inhibitors of serine proteinases. The M(r) 31000 cleavage product with leucine 144 as N-terminus displayed no proteolytic activity towards the pro-urokinase type plasminogen activator substrate pyroGlu-Gly-Arg-pNA-HCI (S2444), but it could be activated by an additional treatment with plasmin. Comparison between full length stromelysin-1 and its C-truncated forms, showed that both exhibited the same cleavage properties towards pro-urokinase type plasminogen activator. Thus, the cleavage of pro-urokinase type plasminogen activator by stromelysin-1 is not influenced by the presence or absence of the C-terminal domain. The recombinant catalytic domain of MMP-3 generated pro-urokinase type plasminogen activator, whereas incubation of pro-urokinase type plasminogen activator with the native forms of human or rabbit stromelysin-1 led to a moderate activation of pro-uPA due to an additional cleavage that is catalyzed by a serine proteinase.
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PMID:The cleavage of pro-urokinase type plasminogen activator by stromelysin-1. 980 93

Normal as well as neoplastic cells traverse extracellular matrix barriers by mobilizing proteolytic enzymes in response to epidermal growth factor (EGF)-EGF receptor (EGFR) or hepatocyte growth factor/scatter factor (SF)-c-Met interactions. The plasminogen activator-plasminogen axis has been proposed to play a key role during cell invasion, but the normal development of plasminogen activator- as well as that of plasminogen-deficient mice supports the existence of alternate proteolytic systems that permit cells to traverse extracellular matrix barriers. To characterize the role that matrix-degrading proteinases play in EGF- or SF-stimulated invasion, a human squamous carcinoma cell line (UM-SCC-1) was triggered atop the matrices of type I collagen or human dermal explants in a three-dimensional culture system. During EGF- or SF-induced invasion, UM-SCC-1 cells expressed urokinase-type plasminogen activator (uPA) and uPA receptor as well as the matrix metalloproteinases (MMPs), membrane-type MMP-1, collagenase 1, stromelysin 1, and gelatinase B. Despite the presence of a positive correlation between uPA receptor-uPA expression and growth factor-stimulated invasion, UM-SCC-1 invasion was not affected by inhibitors directed against the plasminogen activator-plasminogen axis. In contrast, both recombinant and synthetic MMP inhibitors completely suppressed invasion by either EGF- or SF-stimulated cells without affecting either proteinase expression or cell motility across collagen-coated surfaces. These data demonstrate that MMPs, but not the plasminogen activator-plasmin system, can directly regulate the ability of either EGF- or SF-stimulated tumor cells to invade interstitial matrix barriers.
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PMID:Role of the plasminogen activator and matrix metalloproteinase systems in epidermal growth factor- and scatter factor-stimulated invasion of carcinoma cells. 982 36

Clinical trials with monoclonal antibodies directed against TNF alpha (anti-TNF mAbs) and soluble TNF receptor fusion proteins (sTNFR-IgGs) have demonstrated that systemic and synovial trapping of TNF alpha results in long lasting anti-inflammatory and anti-nociceptive effects in patients with rheumatoid arthritis. Clinical indices of inflammatory synovitis and laboratory parameters (CRP and ESR) respond to single and repeated administrations of anit-TNF alpha therapies in a dose-dependent fashion. Studies on the immuno-pharmacological profile in patients suggest evidence that TNF alpha trapping down-regulates the effector mechanisms involved in the immuno-inflammatory response in rheumatoid arthritis. Inhibition of PLA 2- and COX-2-derived pathways of mediators of inflammation (prostanoids and leukotrienes) decreases signs and symptoms of inflammatory synovitis such as joint swelling, tenderness and pain. Down-regulating of the cytokine-inducible adhesion molecules ICAM-1, VCAM-1 and ELAM-1 in endothelial cells and synoviocytes results in a marked inhibition of transendothelial migration of inflammatory and immune cells. A decrease of cytokine-regulated metalloproteinase expression results in normalization of circulating MMP-1 and MMP-3 levels. The effect of TNF alpha neutralization on mechanisms of rheumatoid joint destruction has the long-term potential for preventing or decreasing the rate of erosive changes of cartilage and bone.
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PMID:[Immunopharmacologic profile and therapeutic prospects of anti-TNF-alpha therapy]. 986 33

To examine MMP-9 activation in a cellular setting we employed cultures of human tumor cells that were induced to produce MMP-9 over a 200-fold concentration range (0.03 to 8.1 nM). The secreted levels of TIMPs in all the induced cultures remain relatively constant at 1-4 nM. Quantitation of the zymogen/active enzyme status of MMP-9 in the cultures indicates that even in the presence of potential activators, the molar ratio of endogenous MMP-9 to TIMP dictates whether proMMP-9 activation can progress. When the MMP-9/TIMP ratio exceeds 1.0, MMP-9 activation progresses, but only via an interacting protease cascade involving plasmin and stromelysin 1 (MMP-3). Plasmin, generated by the endogenous plasminogen activator (uPA), is not an efficient activator of proMMP-9. Plasmin, however, is very efficient at generating active MMP-3 from exogenously added proMMP-3. The activated MMP-3, when its concentration exceeds that to TIMP, becomes a potent activator of proMMP-9. Addition to the cultures of already-activated MMP-3 relinquishes the requirement for plasminogen and proMMP-3 additions and results in direct activation of the endogenous proMMP-9. The activated MMP-9 enhances the invasive phenotype of the cultured cells as their ability to transverse basement membrane is significantly increased following zymogen activation. That this enhanced tissue remodeling capability is due to the activation of MMP-9 is demonstrated through the use of a specific anti-MMP-9-blocking monoclonal antibody.
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PMID:Activation of proMMP-9 by a plasmin/MMP-3 cascade in a tumor cell model. Regulation by tissue inhibitors of metalloproteinases. 1041 42

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

Previous studies have shown that matrix vesicles isolated from cultures of costochondral growth zone chondrocytes and treated with 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] can activate recombinant human latent transforming growth factor beta1 (rhTGF-beta1). It is unknown what enzyme or other factor in the extracellular organelles is responsible for the activation. This study tested the hypothesis that enzymes present in matrix vesicles can activate latent TGF-beta1 and that this is regulated by 1alpha,25(OH)2D3. To do this, we examined the ability of matrix vesicle extracts to activate small latent rhTGF-beta1. In addition, enzymes previously determined to be present in matrix vesicles were screened for their ability to activate small latent rhTGF-beta1. Recombinant human matrix metalloproteinase 2 (rhMMP-2; 72 kDa gelatinase), rhMMP-3 (stromelysin 1), purified human plasminogen, and purified urokinase (plasminogen activator) were each tested at varying concentrations. To assess the role of cell maturation, we used a cell culture model in which chondrocytes are derived from two distinct zones of rat costochondral cartilage, the resting zone and the growth zone. Matrix vesicles were isolated from these cultures and then tested. The results showed that extracts of matrix vesicles produced by both growth zone and resting zone chondrocytes were able to activate small latent rhTGF-beta1. The effects were dose and time dependent, with greater activity being found in extracts of matrix vesicles from the growth zone chondrocyte cultures. Only rhMMP-3 was able to activate small latent rhTGF-beta1, indicating that stromelysin-1, but not MMP-2, plasminogen, or urokinase, was involved. As observed in the extracts, the effect of rhMMP-3 was time and dose dependent. When anti-MMP-3 antibody was added to matrix vesicle extracts from both cell types, activation of small latent rhTGF-beta1 was dose-dependently blocked. Neither 1alpha,25(OH)2D3 nor 24R,25(OH)2D3 had a direct effect on activation of small latent rhTGF-beta1 by the extracts. However, when intact matrix vesicles were treated with 1alpha,25(OH)2D3, their ability to activate small latent rhTGF-beta1 was increased. Inhibition of phospholipase A2 with quinacrine blocked the 1alpha,25(OH)2D3-dependent effect. These results suggest that the ability of 1alpha,25(OH)2D3-treated matrix vesicles to activate small latent TGF-beta1 is via action of the secosteroid on the matrix vesicle membrane, not on the enzymes responsible for activating latent TGF-beta1. Because matrix vesicles isolated from growth zone chondrocytes have been shown to contain increased phospholipase A2 activity after treatment with 1alpha,25(OH)2D3, it is likely that this secosteroid promotes loss of membrane integrity through phospholipase A2-dependent formation of lysophospholipids, resulting in the release of MMP-3 into the matrix, where latent TGF-beta1 is stored. Taken together, the results of the current study show that matrix vesicles produced by growth plate chondrocytes contain MMP-3, that this enzyme is at least partially responsible for activation of small latent TGF-beta1 in the matrix, and that 1alpha,25(OH)2D3 regulates MMP release from matrix vesicles.
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PMID:Activation of latent transforming growth factor beta1 by stromelysin 1 in extracts of growth plate chondrocyte-derived matrix vesicles. 1145 Jul 4


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