Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A C-terminal truncated form of membrane-type 4 matrix metalloproteinase (MT4-MMP; MMP 17), lacking the hemopexin-like and transmembrane domain, was expressed in Escherichia coli. The catalytic domain was produced by tryptic activation of the recombinant proenzyme and proved to be catalytically active towards the fluorogenic substrate for matrix metalloproteinases (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu(3-(2,4-dinitrophenyl)-L-2,3-diaminopro-p ionyl)-Ala-Arg-NH2. In contrast to the other three MT-MMPs (MT1-, MT2-, and MT3-MMP), the catalytic domain of MT4-MMP does not activate progelatinase A, nor does it hydrolyze one of the offered extracellular matrix (ECM) proteins, such as collagen types I, II, III, IV, and V, gelatin, fibronectin, laminin or decorin. TIMP-1, a poor inhibitor of MT1-, MT2- and MT3-MMP, suppresses MT4-MMP activity effectively. The progelatinase A/TIMP-2 complex that usually reacts like TIMP-2 also inhibits MT4-MMP. TIMP-2, a strong inhibitor of other MT-MMPS, inhibits MT4-MMP at low concentrations. With increasing TIMP-2 concentration, however, activity passes through a minimum and then increases until at high TIMP-2 concentration the activity is the same as in the absence of TIMP-2. TIMP-1 or the progelatinase A/TIMP-2 complex do not prevent reactivation of MT4-MMP catalytic domain at high TIMP-2 concentrations.
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PMID:Biochemical characterization of the catalytic domain of membrane-type 4 matrix metalloproteinase. 1054 48

Membrane type 1 matrix metalloproteinase (MT1-MMP) with a transmembrane domain is a new member of the MMP gene family and is expressed on the cell surfaces of many carcinoma cells to activate the zymogen of MMP-2 (gelatinase A). We have previously reported that MT1-MMP is released into culture media in a complex form with tissue inhibitor of metalloproteinases 2 (TIMP-2) from a human breast carcinoma cell line, MDA-MB-231, treated with concanavalin A (Con A). In the present study, we further studied the release mechanism of MT1-MMP. Immunoblot analysis indicated that the amounts of MT1-MMP in culture media increase with the time of exposure and the concentration of Con A, and those in cell lysates conversely decrease in a similar way. Time- and dose-dependent release of MT1-MMP into the media was confirmed by a sandwich enzyme immunoassay specific to MT1-MMP. The molecular weight of the immunoreactive MTI-MMP in the media was Mr 56,000, which was 4,000-Mr smaller than that in the cell lysates. Northern blot analysis demonstrated that the mRNA expression level of MT1-MMP is about 3-fold enhanced after a 24 h-exposure to Con A and this is maintained up to 72-h exposure. The release of MT1-MMP from the Con A-treated cells was inhibited by metalloproteinase inhibitors such as EDTA and o-phenanthroline, but not by MMP inhibitors including TIMP-1, TIMP-2 and BB94 or other proteinase inhibitors of serine, cysteine and aspartic proteinases. During the Con A treatment of the cells, cell viability decreased time- and dose-dependently and dead cells reacted positively in the TdT-mediated dUTP Nick-End Labeling (TUNEL) method. Con A-treated MDA cells showed apoptotic morphology when stained with Hoechst dye and hematoxylin and eosin. DNA ladder formation was detected by electrophoresis of the DNA from Con A-treated MDA cells. These results suggest that MT1-MMP release from Con A-treated cells is due to shedding mediated by metalloproteinase(s) other than MMPs, and is associated with apoptosis.
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PMID:Shedding of membrane type 1 matrix metalloproteinase in a human breast carcinoma cell line. 1055 22

A high quality solution structure of the matrix metalloproteinase inhibitory N-terminal domain of recombinant human tissue inhibitor of metalloproteinases-1 (N-TIMP-1) has been determined. For the rigidly packed residues, the average RMSD to the mean structure is 0. 57 A for the backbone atoms and 1.00 A for all heavy atoms. Comparison of the solution structure of free N-TIMP-1 with the crystal structure of TIMP-1 bound to the catalytic domain of MMP-3 ( Gomis-R]uth et al., 1997 ) shows that the structural core of the beta barrel flanked by helices is nearly unchanged by the association with MMP-3, evident from a backbone RMSD of 1.15 A. However, clear differences in the conformation of the MMP-binding ridge of free and MMP-bound TIMP-1 suggest induced fit throughout the ridge. The MMP-dependent conformational changes in the ridge include a dramatic bending of AB loop residues Glu28 through Leu34, moderate hinge bending of the CD-loop about residues Ala65 and Cys70, and modest bending of the Cys1 through Pro6 segment. A large number of interresidue Nuclear Overhauser enhancements (NOEs) augmented by stereospecific assignments, torsion restraints, and dipolar couplings (an average of 18 non-trivial restraints per residue) engender confidence in these structural inferences. A tight cluster of three lysine residues and one arginine residue atop beta-strands A and B, and identical among TIMP sequences, form the heart of a highly conserved electropositive patch that may interact with anionic components of the extracellular matrix.
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PMID:NMR structure of tissue inhibitor of metalloproteinases-1 implicates localized induced fit in recognition of matrix metalloproteinases. 1062 24

Matrix metalloproteinase-9 (MMP-9) is a member of the MMP family that has been associated with degradation of the extracellular matrix in normal and pathological conditions. A unique characteristic of MMP-9 is its ability to exist in a monomeric and a disulfide-bonded dimeric form. However, there exists a paucity of information on the properties of the latent (pro-MMP-9) and active MMP-9 dimer. Here we report the purification to homogeneity of the monomer and dimer forms of pro-MMP-9 and the characterization of their biochemical properties and interactions with tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Gel filtration and surface plasmon resonance analyses demonstrated that the pro-MMP-9 monomeric and dimeric forms bind TIMP-1 with similar affinities. In contrast, TIMP-2 binds only to the active forms. After activation, the two enzyme forms exhibited equal catalytic competence in the turnover of a synthetic peptide substrate with comparable kinetic parameters for the onset of inhibition with TIMPs and for dissociation of the inhibited complexes. Kinetic analyses of the activation of monomeric and dimeric pro-MMP-9 by stromelysin 1 revealed K(m) values in the nanomolar range and relative low k(cat) values (1.9 x 10(-3) and 4.1 x 10(-4) s(-1), for the monomer and dimer, respectively) consistent with a faster rate (1 order of magnitude) of activation of the monomeric form by stromelysin 1. This suggests that the rate-limiting event in the activation of pro-MMP-9 may be a requisite slow unfolding of pro-MMP-9 near the site of the hydrolytic cleavage by stromelysin 1.
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PMID:Characterization of the monomeric and dimeric forms of latent and active matrix metalloproteinase-9. Differential rates for activation by stromelysin 1. 1064 27

Several studies on polycystic kidney disease (PKD) have revealed a number of extracellular matrix (ECM) abnormalities, suggesting that an abnormal ECM plays a role in the development of tubular cysts. Cystic kidney tubules synthesize and secrete high levels of metalloproteinases (MMP), which may participate in the restructuring of the tubular basement membrane. The aim of the present study was to determine whether serum MMP-1, tissue inhibitor of metalloproteinase (TIMP)-1, and type IV collagen levels, and plasma MMP-9 levels were altered in patients with PKD. Sixteen patients with autosomal dominant polycystic kidney disease, and 20 healthy controls were included in this study. Specific enzyme immunoassays were used to measure MMP-1, MMP-9, TIMP-1, and type IV collagen levels. Serum MMP-1 (14.8 +/- 3.6 ng/ml), TIMP-1 (288.6 +/- 48.6 ng/ml), and type IV collagen (192.6 +/- 38.8 ng/ml) concentrations, and plasma MMP-9 (90.2 +/- 26.8 ng/ml) concentrations in patients with PKD were significantly higher than those in healthy controls (MMP-1; 6.6 +/- 0.9 ng/ml, p < 0.01, MMP-9; 36.4 +/- 12.2 ng/ml, p < 0.01, TIMP-1; 164.6 +/- 22.8 ng/ml, p < 0.01, and type IV collagen; 86.6 +/- 14.2 ng/ml, p < 0.001). The present results suggest that ECM abnormalities associated with cystic kidney may result from aberrant degradation as well as from abnormal synthesis of ECM components.
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PMID:Elevation of serum levels of metalloproteinase-1, tissue inhibitor of metalloproteinase-1 and type IV collagen, and plasma levels of metalloproteinase-9 in polycystic kidney disease. 1064 65

In a comprehensive immunohistochemical study of the expression of ten metalloproteinases (MMPs) and their four inhibitors (TIMPs) in 115 non-small cell lung carcinomas (NSCLCs), the findings have been correlated with the histological and clinical features of the tumours. All MMPs and TIMPs were expressed in tumours, with frequencies ranging from 41% for MMP-2 to 68% for MMP-13. Stromal immunoreactivity ranged from 6% for TIMP-4 to 87% for MMP-13. In some tumours, an overexpression of these proteins, as revealed by stronger staining in cancer cells than in adjacent normal bronchial epithelium, was also observed. The frequency ranged from 1% for MMP-3 to 28% for MMP-13. Compared with squamous cell carcinoma (SqCC), adenocarcinoma (AdC) more frequently overexpressed MMP-1, -11, -13, -14, and TIMP-2, and TIMP-1 and/or TIMP-2 overexpression positively correlated with more advanced stage disease. None of the MMP or TIMP expression correlated with the ras genotype of the tumours. The higher frequency of MMP overexpression in AdC than in SqCC may relate to the greater tendency of the former for systemic metastasis. The association of TIMP-1 overexpression with more advanced disease may suggest a role in prognosis.
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PMID:Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer. 1065 12

Activation of T lymphocytes by human pathogens is a key step in the development of immune-mediated neurologic diseases. Because of their ability to invade the CNS and their increased secretion of proinflammatory cytokines, activated CD4+ T cells are thought to play a crucial role in pathogenesis. In the present study, we examined the expression of inflammatory mediators the cytokine-induced metalloproteinases (MMP-2, -3, and -9) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMP-1, -2, and -3), in human astrocytes in response to activated T cells. We used a model system of CD4+ T lymphocytes activated by persistent viral infection (human T lymphotropic virus, HTLV-I) in transient contact with human astrocytes. Interaction with T cells resulted in increased production of MMP-3 and active MMP-9 in astrocytes despite increased expression of endogenous inhibitors, TIMP-1 and TIMP-3. These data suggest perturbation of the MMP/TIMP balance. These changes in MMP and TIMP expression were mediated, in part, by soluble factors (presumably cytokines) secreted by activated T cells. Integrin-mediated cell adhesion is also involved in the change in MMP level, since blockade of integrin subunits (alpha1, alpha3, alpha5, and beta1) on T cells resulted in less astrocytic MMP-9-induced expression. Interestingly, in CNS tissues from neurological HTLV-I-infected patients, MMP-9 was detected in neural cells within the perivascular space, which is infiltrated by mononuclear cells. Altogether, these data emphasize the importance of the MMP-TIMP axis in the complex interaction between the CNS and invading immune cells in the context of virally mediated T cell activation.
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PMID:T lymphocytes activated by persistent viral infection differentially modify the expression of metalloproteinases and their endogenous inhibitors, TIMPs, in human astrocytes: relevance to HTLV-I-induced neurological disease. 1067 13

In most organs, remodelling of tissues after morphogenesis is minimal; however, normal ovarian function depends upon cyclical remodelling of the extracellular matrix (ECM). The ECM has a profound effect on cellular functions and probably plays an important role in the processes of follicular development and atresia, ovulation, and development, maintenance and regression of corpora lutea. Matrix metalloproteinases (MMPs; collagenases, gelatinases, stromelysins and membrane-type MMPs) cleave specific components of the ECM and are inhibited by tissue inhibitors of metalloproteinases (TIMPs). MMPs have been detected at all stages of follicular development and probably modulate follicular expansion or atresia within the ovarian stroma. In addition, increased MMP activity appears to be required for ovulation since follicular rupture occurred in the absence of plasminogen activator activity and inhibitors of MMPs blocked follicular rupture. Development and luteolysis of the corpus luteum are accompanied by extensive remodelling of the ECM. Differentiation and regression of luteal cells are associated with construction and degradation of ECM, respectively. There is increasing evidence that ECM components enhance luteinization; whereas loss of ECM results in luteal cell death. Ovine large luteal cells may be the primary type of cell responsible for controlling the extent of remodelling of luteal ECM since they produce TIMP-1, TIMP-2 and plasminogen activator inhibitor 1. The ratio of active MMPs to TIMPs may be important in maintaining an ECM microenvironment conducive to the differentiation of follicular-derived cells into luteal cells, and maintenance of the phenotype of luteal cells.
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PMID:Regulation of ovarian extracellular matrix remodelling by metalloproteinases and their tissue inhibitors: effects on follicular development, ovulation and luteal function. 1069 69

Numerous reports have shown an association between overexpression of the epidermal growth factor receptor (EGFR), and poor prognosis in head and neck squamous cell carcinomas (HNSCC), however, the underlying mechanisms are still unclear. In the present study, we set out to determine whether EGFR expression was associated with in vitro invasive capacity in a panel of four established and ten newly derived HNSCC lines. Ten of the cell lines expressed high levels of EGFR as determined by a ligand-binding assay and dot blot analysis, whereas the remaining four showed weak overexpression or normal levels of EGFR. The ability of cells to invade through Matrigel was found to be higher in the EGFR overexpressing cell lines (p < 0. 0001). Expression levels of matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, MT1-MMP) and tissue inhibitors of MMP (TIMP-1, TIMP-2) were evaluated by semiquantitative RT-PCR, substrate zymography and western blot. We found a strong positive correlation between EGFR levels and the expression of MMP-9 mRNA (r(2) = 0.95; p < 0.0001), MMP-9 enzyme activity (r(2) = 0.8099; p < 0.0001) and an inverse correlation with TIMP-1 (r(2) = 0.48; p = 0.0059). In six selected HNSCC lines, in vitro invasion was assayed in the presence of an anti-EGFR monoclonal antibody, ICR62. A significant reduction of invasion in four selected EGFR-overexpressing cell lines was found with 30 nM ICR62 (from 50% to 70%; p < 0.001) but there was no effect in two cell lines with normal EGFR levels. Our results show that the in vitro invasive phenotype of HNSCC lines correlates with high EGFR and MMP-9 expression, and it is therefore suggested that the EGFR signaling pathway might play an important role in the invasive behavior of HNSCC via specific upregulation of MMP-9 and downregulation of TIMP-1.
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PMID:Overexpression of epidermal growth factor receptor in human head and neck squamous carcinoma cell lines correlates with matrix metalloproteinase-9 expression and in vitro invasion. 1076 Aug 16

During angiogenesis, proteases and their inhibitors interact in the remodelling of the basement membrane. It has been demonstrated that nafoxidine has antiangiogenic activity in the chick egg chorioallantoic membrane assay, but the precise mechanism of action is unknown. We have analyzed the effect of the partial estrogen antagonist nafoxidine on human umbilical vein endothelial cells (HUVEC). Our data indicated that in nafoxidine-treated endothelial cells MMP-2 was activated. Nafoxidine upregulated, in a dose-dependent manner, the secretion of a 66 kDa TIMP-1 dimer, that lacks anti-MMP activity and inhibited angiogenesis in the endothelial cord formation assay. We can postulate that nafoxidine induces an increase in TIMP-1, which has antiangiogenic activity in the late stages of tube formation, independent of its capacity to inhibit MMPs.
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PMID:Nafoxidine modulates the expression of matrix-metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in endothelial cells. 1076 86


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