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)

Matrix metalloproteinase-2 (MMP-2, gelatinase A) and membrane type (MT)1-MMP (MMP-14) are cooperative dynamic components of a cell surface proteolytic axis involved in regulating the cellular signaling environment and pericellular collagen homeostasis. Although MT1-MMP exhibits type I collagenolytic but poor gelatinolytic activities, MMP-2 is a potent gelatinase with weak type I collagenolytic behavior. Recombinant linker/hemopexin C domain (LCD) of MT1-MMP binds native type I collagen, blocks MT1-MMP collagenolytic activity in trans, and by circular dichroism spectroscopy, induces localized structural perturbation in the collagen. These changes were reflected by enhanced cleavage of the MT1-LCD-bound collagen by the collagenases MMP-1 and MMP-8 but not by trypsin or MMP-7. Thus, the MT1-LCD alone can initiate triple helicase activity. In contrast, the native and denatured collagen binding properties of MMP-2 reside in the fibronectin type II modules, accordingly termed the collagen binding domain (CBD). Recombinant CBD (but not the MMP-2 LCD) also changed the circular dichroism spectra leading to increased MMP-1 and -8 cleavage of native collagen. However, recombinant CBD reduced gelatin and collagen cleavage by MMP-2 in trans as did CBD23, which comprises the second and third fibronectin type II modules, but not the CBD23 mutant W316A/W374A, which neither binds gelatin nor collagen. This indicates that MMP-2 and MT1-MMP bind collagen at a different site than MMP-1 and MMP-8. Thus, MMP-2 utilizes the CBD in cis for collagen binding and triple helicase activity, which compensates for the lack of collagen binding by the MMP-2 LCD. Hence, the MMP family has evolved two distinct mechanisms for collagen triple helicase activity using two structurally distinct domains, with triple helicase activity occurring independent of alpha-chain hydrolysis.
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PMID:Characterization of the distinct collagen binding, helicase and cleavage mechanisms of matrix metalloproteinase 2 and 14 (gelatinase A and MT1-MMP): the differential roles of the MMP hemopexin c domains and the MMP-2 fibronectin type II modules in collagen triple helicase activities. 1529 30

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a potent modulator of pericellular environment through its proteolytic activity and promotes migration, invasion, and proliferation of tumor cells. During cell migration, MT1-MMP binds to CD44H, a major hyaluronan receptor, through the hemopexin-like (HPX) domain and localizes at the migration front. MT1-MMP is also responsible for shedding CD44H, which supports CD44H-mediated cell migration. In this study, we asked whether the binding of MT1-MMP to CD44H is a prerequisite step for the successive shedding. Deletion of the HPX domain deprived MT1-MMP of its shedding activity. Furthermore, disruption of the CD44H/MT1-MMP complex by overexpressing the HPX fragments resulted in inhibition of the shedding. Thus, the CD44H in the complex appears to be the direct substrate of MT1-MMP for shedding. Interestingly, other members of the MT-MMP family showed varied extents of CD44H shedding. Domain swapping between MT1-MMP and other MT-MMPs revealed that the ability of the HPX domains to bind CD44H is conserved among them. However, the shedding activity was different depending on the catalytic domains. The conserved binding ability of the HPX domains suggests that CD44H may act as a core molecule assembling multiple MT-MMPs on the cell surface.
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PMID:CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase. 1555 18

Type I collagen (Col I)-stimulated matrix metalloproteinase-2 (MMP-2) activation via membrane type 1 MMP (MT1-MMP) involves both a transcriptional increase in MT1-MMP expression and a nontranscriptional response mediated by preexisting MT1-MMP. In order to identify which MT1-MMP domains were required for the nontranscriptional response, MCF-7 cells that lack endogenous MT1-MMP were transfected with either wild type or domain mutant MT1-MMP constructs. We observed that mutant constructs lacking the MT1-MMP cytoplasmic tail were able to activate MMP-2 in response to Col I but not a construct lacking the MT1-MMP hemopexin domain. Col I did not alter total MT1-MMP protein levels; nor did it appear to directly induce MT1-MMP oligomerization. Col I did, however, redistribute preexisting MT1-MMP to the cell periphery compared with unstimulated cells that displayed a more diffuse staining pattern. In addition, Col I blocked the internalization of MT1-MMP in a dynamin-dependent manner via clathrin-coated pit-mediated endocytosis. This mechanism of impaired internalization is different from that reported for concanavalin A, since it is not mediated by the cytoplasmic tail of MT1-MMP but rather by the hemopexin domain. In summary, upon Col I binding to its cell surface receptor, MT1-MMP internalization via clathrin-coated pit-mediated endocytosis is impaired through interactions with the hemopexin domain, thereby regulating its function and ability to activate MMP-2.
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PMID:Type I collagen abrogates the clathrin-mediated internalization of membrane type 1 matrix metalloproteinase (MT1-MMP) via the MT1-MMP hemopexin domain. 1640 77

Gelatinase B/matrix metalloproteinase-9 (MMP-9) is a multidomain enzyme functioning in acute and chronic inflammatory and neoplastic diseases. It belongs to a family of more than 20 related zinc proteinases. Therefore, the discovery and the definition of the action mechanism of selective MMP inhibitors form the basis for future therapeutics. The monoclonal antibody REGA-3G12 is a most selective inhibitor of human gelatinase B. REGA-3G12 was found to recognize the aminoterminal part and not the carboxyterminal O-glycosylated and hemopexin protein domains. A variant of gelatinase B, lacking the two carboxyterminal domains, was expressed in insect cells and fragmented with purified proteinases. The fragments were probed by one- and two-dimensional Western blot and immunoprecipitation experiments with REGA-3G12 to map the interactions between the antibody and the enzyme. The interaction unit was identified by Edman degradation analysis as the glycosylated segment from Trp(116) to Lys(214) of gelatinase B. The sequence of this segment was analysed by hydrophobicity/hydrophilicity, accessibility and flexibility profiling. Four hydrophilic peptides were chemically synthesized and used in binding and competition assays. The peptide Gly(171)-Leu(187) in molar excess inhibited partially the binding of MMP-9 to REGA-3G12 and thus refines the structure of the conformational binding site. These results define part of the catalytic domain of gelatinase B/MMP-9, and not the zinc-binding or fibronectin domains, as target for the development of selective inhibitors.
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PMID:A monoclonal antibody inhibits gelatinase B/MMP-9 by selective binding to part of the catalytic domain and not to the fibronectin or zinc binding domains. 1713 15

By mining DNA microarray data bases at GenBank, we identified up-regulation of membrane type 1 matrix metalloproteinase (MT1-MMP) in human primary and metastatic prostate cancer specimens as compared with nonmalignant prostate tissues. To explore the role of up-regulated MT1-MMP in early stage cancer progression, we have employed a three-dimensional cell culture model. Minimally invasive human prostate cancer cells (LNCaP) were transfected with MT1-green fluorescent protein (GFP) chimeric cDNA as compared with GFP cDNA, and morphologic and phenotypic changes were characterized. GFP-expressing LNCaP cells formed multicellular spheroids with cuboidal-like epithelial morphology, whereas MT1-GFP-expressing cells displayed a fibroblast-like morphology and a scattered growth pattern in type I collagen gels. Cell morphologic changes were accompanied by decreased epithelial markers and enhanced mesenchymal markers, consistent with epithelial-to-mesenchymal transition. MT1-MMP-induced morphologic change and cell scattering were abrogated by target inhibition of either the catalytic domain or the hemopexin domain. We further demonstrated that MT1-MMP-induced phenotypic changes were dependent upon up-regulation of Wnt5a, which has been implicated in epithelial-to-mesenchymal transition. We conclude that MT1-MMP plays an important role in early cancer dissemination by converting epithelial cells to migratory mesenchymal-like cells.
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PMID:Membrane type 1 matrix metalloproteinase induces epithelial-to-mesenchymal transition in prostate cancer. 1817 74

The extracellular domain of beta-amyloid precursor protein (APP) contains an inhibitor against matrix metalloproteinase-2 (MMP-2, gelatinase A). Our previous study ( Higashi, S. and Miyazaki, K. (2003) J Biol Chem 278, 14020-14028 ) demonstrated that the inhibitor is localized within the ISYGN-DALMP sequence of APP, and a synthetic decapeptide containing this sequence (named APP-derived inhibitory peptide, APP-IP) selectively inhibits the activity of MMP-2. To determine the region of interaction that correlates with the selective inhibition, we constructed various MMP-2 mutants. An MMP-2 mutant, which had the hemopexin-like domain and three fibronectin-like type II domains of MMP-2 deleted, and native MMP-2 showed similar affinities for APP-IP, suggesting that only the catalytic domain of MMP-2 is essential for the interaction. Studies of chimeric proteases, consisting of various parts of the MMP-2 catalytic domain and those of MMP-7 (matrilysin) or MMP-9 (gelatinase B), further revealed that Ala(88) and Gly(94) in the non-prime side and Tyr(145) and Thr(146) in the prime side of the substrate-binding cleft of MMP-2 contribute separately to the selective inhibition. Replacement of the amino acid residue at position 94 of a chimeric MMP mutant affected its interaction with the C-terminal Pro(10) of APP-IP, whereas that of residues 145-148 affected the interaction with Tyr(3) of the inhibitor, suggesting that the N to C direction of APP-IP relative to the substrate-binding cleft of MMP is analogous to that of propeptide in proMMP, and opposite to that of substrate. When the APP-IP sequence was added to the N terminus of the catalytic domain of MMP-2, the activity of the protease was intramolecularly inhibited. We speculate that the direction of interaction makes the active site-bound APP-IP resistant to cleavage, thereby supporting the inhibitory action of the peptide inhibitor.
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PMID:Identification of amino acid residues of the matrix metalloproteinase-2 essential for its selective inhibition by beta-amyloid precursor protein-derived inhibitor. 1823 79

Activation of proMMP-2 and cell surface collagenolysis are important activities of membrane-type 1 matrix metalloproteinase (MT1-MMP) to promote cell migration in tissue, and these activities are regulated by homodimerization of MT1-MMP on the cell surface. In this study, we have identified the transmembrane domain as a second dimer interface of MT1-MMP in addition to the previously identified hemopexin domain. Our analyses indicate that these two modes of dimerization have different roles; transmembrane-dependent dimerization is critical for proMMP-2 activation, whereas hemopexin-dependent dimerization is important for degradation of collagen on the cell surface. Our finding provides new insight into the potential molecular arrangement of MT1-MMP contributing to its function on the cell surface.
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PMID:The second dimer interface of MT1-MMP, the transmembrane domain, is essential for ProMMP-2 activation on the cell surface. 1833 48

Membrane type-1 matrix metalloproteinase (MT1-MMP) drives cell invasion through three-dimensional (3-D) extracellular matrix (ECM) barriers dominated by type I collagen or fibrin. Based largely on analyses of its impact on cell function under two-dimensional culture conditions, MT1-MMP is categorized as a multifunctional molecule with 1) a structurally distinct, N-terminal catalytic domain; 2) a C-terminal hemopexin domain that regulates substrate recognition as well as conformation; and 3) a type I transmembrane domain whose cytosolic tail controls protease trafficking and signaling cascades. The MT1-MMP domains that subserve cell trafficking through 3-D ECM barriers in vitro or in vivo, however, remain largely undefined. Herein, we demonstrate that collagen-invasive activity is not confined strictly to the catalytic, hemopexin, transmembrane, or cytosolic domain sequences of MT1-MMP. Indeed, even a secreted collagenase supports invasion when tethered to the cell surface in the absence of the MT1-MMP hemopexin, transmembrane, and cytosolic tail domains. By contrast, the ability of MT1-MMP to support fibrin-invasive activity diverges from collagenolytic potential, and alternatively, it requires the specific participation of MT-MMP catalytic and hemopexin domains. Hence, the tissue-invasive properties of MT1-MMP are unexpectedly embedded within distinct, but parsimonious, sequences that serve to tether the requisite matrix-degradative activity to the surface of migrating cells.
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PMID:Molecular dissection of the structural machinery underlying the tissue-invasive activity of membrane type-1 matrix metalloproteinase. 1849 69

Current understanding on the collagenolytic activity performed by the MMPs assumes some degree of relative motion between the catalytic and the hemopexin-like domains of the enzyme. However, all the crystal structures available for the full-length enzymes display a compact arrangement of the protein domains. Herein, we employ Molecular Dynamics simulations to investigate the structure of the full-length MMP-2 enzyme in aqueous solution. This simulation, together with previous experimental results that have been obtained very recently for the MMP-9 and MMP-12 enzymes, gives strong support to the hypothesis that the interdomain dynamics of the MMP enzymes in solution can result in a manifold of conformations including some structures with a large interdomain separation. The simulation of MMP-2 provides also a detailed molecular picture of the structures involved in the transition from the compact X-ray arrangement to the extended form in solution. Such information could be helpful in future studies of the regulation and/or the collagenolytic activity of these important enzymes.
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PMID:From the X-ray compact structure to the elongated form of the full-length MMP-2 enzyme in solution: a molecular dynamics study. 1883 22

Membrane type-1 matrix metalloproteinase (MT1-MMP) is a proinvasive protease that regulates various cellular functions as evidenced by myriad defects in different types of cells and tissues in MT1-MMP-deficient (MT1(-/-)) mice. Here we demonstrate that MT1(-/-) mice exhibit fewer infiltrating macrophages into sites of inflammation. MT1(-/-)macrophages exhibited a reduced ability to invade reconstituted basement membrane (Matrigel) and invasion by wild type (WT) macrophages was inhibited by a synthetic MMP inhibitor (BB94) to a level similar to that of MT1(-/-) cells. The rate of migration of MT1(-/-) macrophages was also low compared to that of the WT cells and re-expression of MT1-MMP in MT1(-/-) macrophages reconstituted their migratory activity. Unexpectedly, however, BB94 did not inhibit the migration of WT macrophages. The migration-boosting activity of MT1-MMP is retained in a mutant that lacks most of the extracellular portion including the catalytic and hemopexin-like domains. In contrast, deletion of the cytoplasmic (CP) tail abolished the activity completely. Thus, we have demonstrated that MT1-MMP regulates macrophages via its invasion-promoting protease activity as well as its CP-dependent non-proteolytic activity to boost cell migration.
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PMID:Cytoplasmic tail of MT1-MMP regulates macrophage motility independently from its protease activity. 1937 80


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