Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neutral zinc metalloendopeptidase (NEP, EC 3.4.24.11) is an integral membrane protein found in brain tissue, polymorphonuclear leukocytes, and many epithelia. We show here that NEP is expressed on rabbit synovial fibroblasts and on simian virus 40 (SV40) DNA- and H-ras-transformed rabbit mammary epithelial cells. Treatment of these cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 24 h decreased expression of NEP mRNA transcripts and decreased the biosynthetically labeled immunoprecipitable NEP antigen. In contrast to its effects on NEP, TPA treatment induced expression of the secreted metalloproteinase collagenase and the tissue inhibitor of metalloproteinases. TPA induced stromelysin, another secreted metalloproteinase, only in the fibroblasts. These data provide evidence that the expression of the membrane-bound NEP is regulated in several cell types.
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PMID:Phorbol diesters regulate expression of the membrane neutral metalloendopeptidase (EC 3.4.24.11) in rabbit synovial fibroblasts and mammary epithelial cells. 254 98

No measurable amounts of matrix metalloproteinases (MMPs) were produced by human breast adenocarcinoma cell lines MCF-7 and BT-20 in culture. When MCF-7 cells were co-cultured with human dermal fibroblasts enhanced production of precursors of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1) and tissue inhibitor of metalloproteinase type 1 (TIMP-1) was observed. Immunohistochemical studies indicated that these pro-MMPs originated primarily from the fibroblasts, suggesting that MCF-7 cells have a stimulatory effect on stromal cells to produce at least three pro-MMPs and TIMP-1. BT-20 cells also enhanced the production of pro-MMP-2 and TIMP-1 in the dermal fibroblasts, but not of pro-MMP-1 and pro-MMP-3. Normal mammary epithelial cells promoted only TIMP-1 production. To investigate further the stimulatory factors from MCF-7 cells, the conditioned medium and the cell membrane were prepared and examined. The cell membrane fraction enhanced the production of pro-MMP-1 and -3 and TIMP-1, but not of pro-MMP-2. The conditioned medium, on the other hand, augmented the production of all four proteins in the fibroblasts. These observations suggest that breast adenocarcinoma MCF-7 cells in culture produce both soluble and membrane-bound factor(s) which stimulate the production of pro-MMPs and TIMP-1 in neighbouring stromal cells, but the factor(s) released into the medium and that associated with cell membranes are probably different. Such communication between the normal and malignant cell types may, in part, assist the cancer cells to invade and metastasise.
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PMID:Co-culture of human breast adenocarcinoma MCF-7 cells and human dermal fibroblasts enhances the production of matrix metalloproteinases 1, 2 and 3 in fibroblasts. 773 96

The neuron-like differentiation of PC12 cells is induced by nerve growth factor (NGF) through stimulation of a membrane-bound protooncoprotein signaling pathway containing the NGF receptor Trk, the tyrosine kinase Src, and the GTP-binding protein Ras. The Raf-1 and B-raf protooncogenes encode cytoplasmic serine/threonine kinases that are stimulated by NGF in a Ras-dependent manner. To investigate the possible roles of cytoplasmic Raf kinases in eliciting neuronal differentiation, we have expressed the activated Raf-1 oncogene in PC12 cells. Expression of the raf oncogene results in the elaboration of a neuron-like phenotype, including neurite growth and the induction of the NGF-responsive genes NGFI-A and transin. The actions of activated Raf-1 and NGF are not additive. Furthermore, activated Raf-1 oncoprotein can prime cells for transcription-independent neurite growth by NGF and can elicit rapid neurite growth from NGF-primed cells. Our data indicate that the pathways utilized by NGF and activated raf to effect PC12 differentiation overlap and lead to the suggestion that cellular raf kinase activities play significant roles in transducing the differentiating signals of neuronal growth factors.
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PMID:The cytoplasmic raf oncogene induces a neuronal phenotype in PC12 cells: a potential role for cellular raf kinases in neuronal growth factor signal transduction. 838 63

Collagens of most connective tissues are subject to continuous remodelling and turnover, a phenomenon which occurs under both physiological and pathological conditions. Degradation of these proteins involves participation of a variety of proteolytic enzymes including members of the following proteinase classes: matrix metalloproteinases (e.g. collagenase, gelatinase and stromelysin), cysteine proteinases (e.g. cathepsin B and L) and serine proteinases (e.g. plasmin and plasminogen activator). Convincing evidence is available indicating a pivotal role for matrix metalloproteinases, in particular collagenase, in the degradation of collagen under conditions of rapid remodelling, e.g. inflammation and involution of the uterus. Under steady state conditions, such as during turnover of soft connective tissues, involvement of collagenase has yet to be demonstrated. Under these circumstances collagen degradation is likely to take place particularly within the lysosomal apparatus after phagocytosis of the fibrils. We propose that this process involves the following steps: (i) recognition of the fibril by membrane-bound receptors (integrins?), (ii) segregation of the fibril, (iii) partial digestion of the fibril and/or its surrounding non-collagenous proteins by matrix metalloproteinases (possibly gelatinase), and finally (iv) lysosomal digestion by cysteine proteinases, such as cathepsin B and/or L. Modulation of this pathway is carried out under the influence of growth factors and cytokines, including transforming growth factor beta and interleukin 1 alpha.
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PMID:Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling. 876 55

The cell-surface activation of pro-matrix metalloproteinase 2 (pro-MMP-2) is considered to be critical for cell migration and invasion. Treatment of human uterine cervical fibroblasts with concanavalin A activates pro-MMP-2 on the cell surface by converting it to the 65-kDa form with a minor form of 45 kDa. However, the 65-kDa MMP-2 was inactivated by tissue inhibitor of metalloproteinases (TIMP)-2 that was bound to the plasma membrane upon concanavalin A treatment. TIMP-2 binds to the plasma membrane through its N-terminal domain by two different modes of interaction as follows: one is sensitive to a hydroxamate (HXM) inhibitor of MMPs and the other is HXM-insensitive. TIMP-2 bound to the membrane in a HXM-insensitive manner, comprising about 40-50% of TIMP-2 on the membrane, is the inhibitor of the cell surface-activated MMP-2. It, however, does not inhibit MMP-3, MMP-9, and the 45-kDa MMP-2 lacking the C-terminal domain. The inhibition of the 65-kDa MMP-2 by TIMP-2 is initiated by the interaction of their C-terminal domains. Subsequently, the MMP-2.TIMP-2 complex is released from the membrane, and the activity of MMP-2 is blocked by TIMP-2. In the presence of collagen types I, II, III, V, or gelatin, the rate of inhibition of the 65-kDa MMP-2 by the membrane-bound TIMP-2 decreased considerably. These results suggest that the pericellular activity of MMP-2 is tightly regulated by membrane-bound TIMP-2 and surrounding extracellular matrix components.
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PMID:Plasma membrane-bound tissue inhibitor of metalloproteinases (TIMP)-2 specifically inhibits matrix metalloproteinase 2 (gelatinase A) activated on the cell surface. 973 24

Both Fas ligand (FasL) and tumor necrosis factor-alpha (TNF-alpha) are type II integral membrane proteins. Recently, we have reported that FasL is processed to a soluble form by an unknown metalloproteinase at the cell surface and some hydroxamate matrix metalloproteinase (MMP) inhibitors inhibit the processing similar to the case observed with TNF-1alpha. We studied the inhibitory effects of various hydroxamate MMP inhibitors on FasL and TNF-alpha processing in order to characterize the processing enzymes using human FasL cDNA transfectants and LPS-stimulated THP-1 cells. It turned out that (1) the P1' group of hydroxamates was very important for the selective inhibitory activity toward TNF-alpha and FasL processing, (2) P1' 3-phenylpropyl group was favorable for the inhibition of FasL processing, and (3) P1' isobutyl and isopropyl groups were favorable for that of TNF-alpha processing. These differences in sensitivity to inhibitors imply that (1) membrane-bound FasL and TNF-alpha might be processed by distinct metalloproteinases, (2) the S1' site of FasL processing enzyme differs from that of MMP-1 and MMP-9, but appears to be similar to that of MMP-3, and (3) the S1' site of TNF-alpha processing enzyme is smaller than that of FasL processing enzyme. These results would be helpful in designing a more selective inhibitor.
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PMID:Structure-activity relationship of hydroxamate-based inhibitors on membrane-bound Fas ligand and TNF-alpha processing. 1053 8

Isolated human granulocyte plasma membranes contain progelatinase B. The binding of progelatinase B to the membrane, however, is relatively weak, and a considerable part of progelatinase B can be removed by simply washing the membrane with buffer. This detachment does not depend on the ionic strength of the buffer, indicating that electrostatic forces do not play an important role in the binding of progelatinase B to the membrane. A complete removal of progelatinase B is achieved by chromatography of neutrophil membranes on gelatin-agarose. The plasma membrane of human granulocytes activates added progelatinase B. This activation is inhibited by soybean trypsin inhibitor and is thus performed by membrane bound serine proteinases. In contrast to other reports that claimed an important role of elastase in activating progelatinase B, we found that this activation is mostly inhibited by chymostatin and not by elastatinal and is thus primarily due to cathepsin G. Proteinase 3 was shown to activate progelatinase B as efficient as neutrophil elastase, i. e. much weaker than cathepsin G. Binding of cathepsin G and elastase to the neutrophil membrane does not change their ability to activate progelatinase B. However, cathepsin G, the most potent activator of the three neutrophil serine proteinases, is only a weak activator, when compared to stromelysin-1. This, as well as only a weak binding of progelatinase B, make it doubtful that activation of membrane-bound progelatinase B by membrane-bound serine proteinases is of significant physiological importance.
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PMID:Activation of progelatinase B by membranes of human polymorphonuclear granulocytes. 1072 50

The thinning of the cornea that occurs in keratoconus has been well described; however, the mechanism of tissue degradation remains unknown. Elevated proteinase activity is one possibility and approximately 20 publications over the last 20 years have addressed this hypothesis. Early studies reported increased collagenase and gelatinase activities in the medium of keratoconus corneal cultures. After the characterization of the matrix metalloproteinase (MMP) enzymes, studies focused on the expression of specific MMPs, in particular the gelatinases, MMP-2 and MMP-9. Matrix metalloproteinase-2 was found to be the major MMP of the cornea and was constitutively produced in normal tissue, whereas MMP-9 expression was induced by various stimuli, including phorbol esters and even tissue culturing. These studies suggested that there were no differences in the amounts or states of activation of MMP between normal and keratoconus corneas, although the amounts of some proteinase inhibitors, including tissue inhibitors of metalloproteinases, alpha-1-proteinase inhibitor and alpha-2-macroglobulin, were decreased in keratoconus. Most recently, the lysosomal proteinases, cathepsin B and cathepsin G were reported to be elevated in keratoconus corneas, and it is possible that it was cathepsin activity, not MMP activity, that was measured in some early studies. Nevertheless, there are now about 20 human MMPs identified and it is possible that some of these, other than the well known collagenase (MMP-1) and gelatinases (MMP-2 and MMP-9), could be implicated in the pathology of keratoconus. Studies have begun to address more recently described MMPs and it has been reported that the membrane-bound MT1-MMP (MMP-14), which activates latent MMP-2, was found to have increased expression in keratoconus corneas, whereas the stromelysins, MMP-3 and MMP-10, were not.
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PMID:Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? 1177

Rheumatoid arthritis is a chronic inflammatory disease characterized by destruction of cartilage and bone that is mediated by synovial fibroblasts. To determine the mechanisms by which these cells are activated to produce matrix metalloproteinases (MMPs), the effects of microparticles were investigated. Microparticles are small membrane-bound vesicles whose release from immune cells is increased during activation and apoptosis. Because microparticles occur abundantly in the synovial fluid in rheumatoid arthritis, they could represent novel stimulatory agents. Microparticles derived from T cells and monocytes strongly induced the synthesis of MMP-1, MMP-3, MMP-9, and MMP-13 in fibroblasts. The induction was time-dependent, with effects primarily observed after 36 h; under these conditions, MMP-2, MMP-14, and tissue inhibitor of MMP-1 (TIMP-1), TIMP-2, and TIMP-3 were not induced. Microparticles also increased the synthesis of inflammatory mediators including IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), and MCP-2. In Ikappa-B-transfected synovial fibroblasts, MMPs were less inducible by microparticles compared with wild-type fibroblasts. Blocking of TNFalpha and IL-1beta with antibodies against TNFalpha and with IL-1 receptor antagonist did not abrogate stimulation by microparticles. These data provide evidence for a novel mechanism by which vesicles derived from activated or apoptotic immune cells can promote the destructive activity of synovial fibroblasts in rheumatoid arthritis.
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PMID:The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. 1570 93

Research on matrix metalloproteinases (MMPs) and in particular on gelatinase B, alias MMP-9, has grown exponentially in the decade 2003-2012. Structural details about flexibility of MMP-9 monomers, together with glycosylation, oligomerization, heterogeneity and instability of the wildtype enzyme explain why crystallography experiments have not yet been successful for the intact enzyme. MMP-9 may be viewed as a multidomain enzyme in which the hemopexin, the O-glycosylated and the catalytic domains yield support for attachment, articulation and catalysis, respectively. The stepwise proteolytic activation of the inactive zymogen into a catalytically active form becomes gradually better understood. Priming of activation by MMP-3 may be executed by meprins that destabilize the interaction of the aminoterminus with the third fibronectin repeat. Alternatively, autocatalytic activation may occur in the presence of molecules that tightly bind to the catalytic site and that push the cystein residue in the prodomain away from the catalytic zinc ion. Thanks to the development of degradomics technologies, substrate repertoires of MMP-9 have been defined, but it remains a challenge to determine and prove which substrates are biologically relevant. The substrate repertoire has been enlarged from extracellular to membrane-bound and efficient intracellular substrates, such as crystallins, tubulins and actins. Biological studies of MMP-9 have tuned the field from being primarily cancer-oriented towards vascular and inflammatory research. In tumor biology, it has been increasingly appreciated that MMP-9 from inflammatory cells, particularly neutrophils, co-determines prognosis and outcome. Aside from the catalytic functions executed by aminoterminal domains of MMP-9, the carboxyterminal hemopexin (PEX) domain of gelatinase B exerts non-catalytic anti-apoptotic signaling effects. The recognition that gelatinase B is induced by many pro-inflammatory cytokines, whereas its inhibitors are increased by anti-inflammatory cytokines, has generated interest to target MMP-9 in acute lethal conditions, such as bacterial meningitis, sepsis and endotoxin shock, and in acute exacerbations of chronic diseases. Previously described transcriptional regulation of MMP-9 is complemented by epigenetic checkpoints, including histone modifications and microRNAs. Because activation of proMMP-9 may be executed by other MMPs, the therapeutic dogma that MMP inhibitors need to be highly selective may be keyed down for the treatment of life-threatening conditions. When inflammation and MMP-9 fulfill beneficial functions to clear damaging protein complexes, such as in systemic autoimmune diseases, therapeutic MMP inhibition has to be avoided. In Mmp9 gene knockout mice, specific spontaneous phenotypes emerged with effects on the skeletal, reproductive and nervous systems. These findings not only have clinical correlates in bone growth and fertility, but also stimulate research on the roles of MMPs and MMP-9 in endocrinology, immunology and the neurosciences. Mmp9-deficient mice are valuable tools to define MMP-9 substrates in vivo and to study the role of this enzyme in animal models of inflammatory, vascular, neoplastic and degenerative diseases. Future challenges include solving the crystal structure, definition of the functions of covalent oligomers and heteromers in biology and pathology, life-imaging of MMP-9 activity, substrate determination in situ and the study of inhibitor effects on fertility, cancer and inflammation and in neurobiology and regenerative medicine. Such studies will better define conditions in which inhibition of MMP-9 is beneficial or has to be avoided.
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PMID:Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. 2354 85


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