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)

In developing rabbit brain we studied expression of metalloproteinases (MMP) 1 and 3 by in situ hybridization and MMP2 and tissue and urokinase-type plasminogen activators (tPA and uPA) by immunohistochemistry. All are detected in developing cell populations. Mature olfactory bulb neurons express MMP1 and MMP3. uPA is expressed by glial cells during myelination and by mature cortical neurons. MMP2 is expressed by mature subpial and perivascular astrocytes.
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PMID:Localization of proteinase expression in the developing rabbit brain. 765 27

Malignant human melanoma cells produce many matrix-degrading enzymes, including plasminogen activators and matrix metalloproteinases. These enzymes have substrate specificity for different components of ECM and most of them have been demonstrated to contribute to melanoma cell-mediated dissolution of matrices and to melanoma cell invasion. The degradation of complex matrices in vitro requires the cooperation of proteases with specificity for glycoproteins and collagens. The contribution of proteases to spontaneous melanoma metastasis was studied by overexpressing specific protease inhibitors in human melanoma cells. Overexpression of PAI-2 inhibited the spread of distant metastasis indicating a role for uPA/plasmin in melanoma invasion. Overexpression of TIMP-2, in contrast, reduced the growth rate of subcutaneous tumors, but did not inhibit metastasis, indicating that MMP activities promote melanoma growth in the skin and may not be required for metastatic dissemination. Thus, uPA and MMP activities are involved in different processes, but they both contribute to melanoma malignancy.
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PMID:Different roles for plasminogen activators and metalloproteinases in melanoma metastasis. 881 95

The studies described here examine the involvement of the fibrinolytic cascade and its endogenous inhibitors in the regulation of activity of matrix metalloproteinases and cartilage degradation related to non-inflammatory joint disease, like osteoarthritis. An interleukin-1-induced model of degradation using [35S]-labeled bovine and human articular cartilage explants was utilized. One goal of these studies was to compare the responses of bovine and human articular cartilage. Degradation was not inhibited by alpha 1-PI, PAI-1, alpha 2-macroglobulin, alpha 2-antiplasmin or TIMP-2, when IL-1 alone was added. Addition of human plasminogen to bovine explants, at concentrations found in human synovial fluid, increased degradation by three to four-fold. Under these conditions, the degradation was inhibited effectively by all of the endogenous inhibitors tested, indicating the presence of a cascade where activated chondrocytes are a source of u-PA. Plasminogen activated by u-PA gives plasmin, which is known to further activate pro-stromelysin. Stromelysin is essential for activation of collegenase. Not only TIMP, but also inhibitors at earlier steps of activation like PAI-1, alpha 2-antiplasmin, alpha 1-PI and alpha 2-macroglobulin inhibited degradation, and could provide cartilage protection in vivo. An experiment with human articular cartilage explants showed that very little or no degradation occurred when human articular cartilage explants were stimulated with interleukin-1 alone. Addition of human plasminogen (at physiologically relevant concentrations) resulted in significant degradation, which was inhibited in the same manner as in bovine explants, by inhibitors of the fibrinolytic cascade and TIMP. TIMP is much more efficient in human explants, indicating the limited participation of human plasmin in the degradation of human cartilage. Although speculative, it is possible that in vivo, cartilage degradation could be promoted not only by TIMP/MMP imbalance, but also accelerated by decreased levels of certain serpins in synovial fluid (e.g. PAIs, alpha 2-antiplasmin and alpha 1-PI).
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PMID:Plasminogen modulation of IL-1-stimulated degradation in bovine and human articular cartilage explants. The role of the endogenous inhibitors: PAI-1, alpha 2-antiplasmin, alpha 1-PI, alpha 2-macroglobulin and TIMP. 889 58

Extracellular matrix (ECM) adhesion and proteolysis play important roles in embryonic development. In previous work (Behrendtsen et al. [1992] Development 114:447-456) we showed that gelatinase B activity is rate-limiting for trophoblast-mediated invasion and degradation of ECM in culture. In the present study, we show that metalloproteinases (MMPs) have distinct roles in migration along ECM as opposed to invasion through ECM. We investigated the role of ECM proteolysis in the differentiation and migration of parietal endoderm (PE), the first embryonic migratory cell type, adhering to ECM surfaces. Gelatinase B was the major MMP of PE; mRNA and protein were detected in PE of 7.5- and 8.5-day embryos. Using cultures of inner cell masses (ICMs) isolated from mouse blastocysts, we found that inhibitors of metalloproteinases, specifically, tissue inhibitor of metalloproteinases (TIMP)-1 and a peptide hydroxamic acid stimulated outgrowth and differentiation of PE from ICMs cultured on fibronectin, but inhibitors of plasminogen activators did not. TIMP-1 increased the number of PE cells and mean distance migrated and increased expression of the PE differentiation marker vimentin; the increase in cell number was not at the expense of other cell types. The stimulatory effect of TIMP-1 was most marked on low concentrations of substrate fibronectin, decreasing as concentrations of fibronectin increased. TIMP-1 also stimulated the outgrowth of PE in blastocyst cultures and in ICM/trophectoderm co-cultures; in ICM/trophectoderm co-cultures TIMP-1 stimulated PE differentiation on higher concentrations of fibronectin than was permissive for ICMs cultured alone. These data indicate that metalloproteinase inhibitors preserved the migration-inducing status of the ECM. We conclude that metalloproteinases have distinct roles in invasive activity through ECM barriers and migratory activity along ECM surfaces.
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PMID:Metalloproteinases regulate parietal endoderm differentiating and migrating in cultured mouse embryos. 902 62

Angiostatin is one of the most potent inhibitors of angiogenesis. Reports have shown that metalloelastase, pancreas elastase, plasmin reductase, and plasmin convert plasminogen to angiostatin. However, the cleavage sites of plasminogen by those enzymes have not been determined. Here we demonstrate that two members of the human matrix metalloproteinase (MMP) family, matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9), hydrolyze human plasminogen to generate angiostatin fragments. The cleavage sites have been determined. The 58-kDa bands derived from plasminogen by MMP-7 and MMP-9 both have the N-terminal sequence KVYLSEXKTG, which corresponds to that of angiostatin. This N terminus is identical to that of the starting plasminogen itself and corresponds to residues 97-106 of prepro-plasminogen. The 42- and 38-kDa bands generated by MMP-7 both have the N-terminal sequence VVLLPNVETP, which corresponds to the amino acid sequence 467-476 of prepro-plasminogen, between kringle domain 4 and 5. MMP-9 cleaves plasminogen to generate a 42-kDa fragment with the N-terminal sequence PVVLLPNVE, 1 residue upstream of the MMP-7 cleavage site. These results indicate that MMP-7 and MMP-9 may regulate new blood vessel formation by cleaving plasminogen and generating angiostatin molecules.
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PMID:Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). 936 Sep 44

Matrix metalloproteinase-3 (MP-3 or stromelysin-1) specifically hydrolyzes the Glu59-Asn60, Pro447-Val448, and Pro544-Ser545 peptide bonds in plasminogen, yielding a 55 kDa NH2-terminal angiostatin-like domain (comprising kringles 1-4), a 14 kDa domain comprising kringle 5, and a 30 kDa domain comprising the serine proteinases domain. The conversion is completely abolished in the presence of the MMP inhibitors EDTA or 1,10-phenanthroline. Biospecific interactions analysis indicates that binding of proMMP-3 and MMP-3 to plasminogen occurs with comparable affinity (KA of 4.7 x 10(6) and 4.1 x 10(6) M-1, respectively) and is mediated via the miniplasminogen moiety (kringle 5 plus the proteinase domain) and via the catalytic domain of MMP-3. Thus, proteolytic cleavage of plasminogen by MMP-3 generates angiostatin-like fragments.
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PMID:Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP-3). 954 33

Matrix metalloproteinase-3 (MMP-3, or stromelysin-1) specifically hydrolyzes the Glu143-Leu144 peptide bond in 45-kDa single-chain urokinase-type plasminogen activator (scu-PA) and in its two-chain (tcu-PA) derivative, yielding a 17-kDa NH2-terminal domain comprising the u-PA receptor (u-PAR) binding site and a 32-kDa COOH-terminal moiety containing the serine proteinase domain of u-PA. The conversion is completely abolished in the presence of the MMP inhibitors EDTA or 1,10-phenanthroline. Biospecific interaction analysis indicates that binding of MMP-3 occurs through the 32-kDa fragment. The 32-kDa fragment derived from scu-PA (scu-PA-32k) has a specific activity of </=500 IU/mg, but it can be activated with plasmin to a two-chain derivative (tcu-PA-32k) with a specific activity of 79 000 IU/mg. tcu-PA and tcu-PA-32k moieties derived from scu-PA-32k by plasmin or from tcu-PA by MMP-3 have comparable amidolytic activities toward the chromogenic substrate S-2444 (kcat/Km of 110 and 160 mM-1 s-1, respectively) and similar plasminogen activating activities in a coupled chromogenic substrate assay. Specific binding of the 17-kDa NH2-terminal domain to THP-1 monocytoid cells is completely abolished by competition with scu-PA but is not affected by scu-PA-32k (residual binding of 88 +/- 9% (mean +/- SEM; n = 3) with 25-fold molar excess). Thus, MMP-3 removes a functional NH2-terminal u-PAR-binding domain from u-PA without affecting its enzymatic properties.
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PMID:Proteolytic cleavage of urokinase-type plasminogen activator by stromelysin-1 (MMP-3). 958 35

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a significant role in regulating angiogenesis, the process of new blood vessel formation. Interstitial collagenase (MMP-1), 72 kDa gelatinase A/type IV collagenase (MMP-2), and 92 kDa gelatinase B/type IV collagenase (MMP-9) dissolve extracellular matrix (ECM) and may initiate and promote angiogenesis. TIMP-1, TIMP-2, TIMP-3, and possibly, TIMP-4 inhibit neovascularization. A new paradigm is emerging that matrilysin (MMP-7), MMP-9, and metalloelastase (MMP-12) may block angiogenesis by converting plasminogen to angiostatin, which is one of the most potent angiogenesis antagonists. MMPs and TIMPs play a complex role in regulating angiogenesis. An understanding of the biochemical and cellular pathways and mechanisms of angiogenesis will provide important information to allow the control of angiogenesis, e.g. the stimulation of angiogenesis for coronary collateral circulation formation; while the inhibition for treating arthritis and cancer.
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PMID:Complex role of matrix metalloproteinases in angiogenesis. 979 30

Angioplasty is a principal treatment for occlusive vascular disease but 30-50% of patients show a restenosis of the vessel. There is no clinical effective therapy for this disease. It has been demonstrated, in animal models, that various drugs such as NO-donor, plasminogen inhibitor tranexamic acid and MMP (matrix metalloproteinases) reduce the rate of restenosis. Other therapeutic approaches are cytotoxic therapy, and strategies to inhibit cell cycle progression. Systemic administration of conventional pharmacologic agents inhibit cell cycle kinases and vascular lesion formation in animal models. As cell cycle progression is accompanied by fluctuations in the concentration of adenosine 3',5-monophospate (cAMP) and in the activity of the cAMP dependent protein kinase (PKA), local administration of cAMP and phospodiesterase-inhibitor drugs (aminophylline or amrinone) markedly inhibit neointima formation. The successful use of local radiation therapy to inhibit neointima formation after vascular injury may reflect a similar combination of cell-cycle arrest and vascular cell apoptosis. The most effective therapy for occlusive vascular disease will likely combine intravascular stenting with an antiproliferative therapy.
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PMID:Mechanisms of restenosis after angioplasty and approach to therapy (Review). 985 80

Angiostatin, a cleavage product of plasminogen, has been shown to inhibit endothelial cell proliferation and metastatic tumor cell growth. Recently, the production of angiostatin has been correlated with tumor-associated macrophage production of elastolytic metalloproteinases in a murine model of Lewis lung cell carcinoma. In this report we demonstrate that purified murine and human matrix metalloproteinases generate biologically functional angiostatin from plasminogen. Macrophage elastase (MMP-12 or MME) proved to be the most efficient angiostatin-producing MMP. MME was followed by gelatinases and then the stomelysins in catalytic efficiency; interstitial collagenases had little capacity to generate angiostatin. Both recombinant angiostatin and angiostatin generated from recombinant MME-treated plasminogen inhibited human microvascular endothelial cell proliferation and differentiation in vitro. Finally, employing macrophages isolated from MME-deficient mice and their wild-type littermates, we demonstrate that MME is required for the generation of angiostatin that inhibits the proliferation of human microvascular endothelial cells.
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PMID:Matrix metalloproteinases generate angiostatin: effects on neovascularization. 986 16


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