Membrane‐Type Matrix Metalloproteinases 1 and 2 Exhibit Broad‐Spectrum Proteolytic Capacities Comparable to Many Matrix Metalloproteinases

d’Ortho, Marie-Pia; Will, Horst; Atkinson, Susan J.; Butler, Georgina S.; Messent, Anthea J.; Gavrilović, Jelena; Smith, Bryan John; Timpl, Rupert; Zardi, Luciano; Murphy, Gillian

doi:10.1111/j.1432-1033.1997.00751.x

Cited by 407 publications

(296 citation statements)

References 41 publications

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“…The biological effects of MMP14 are multiple and complex. MMP14 is a fibrillar collagenase 23,24 and as such is able to degrade the type III collagen present in scar tissue. Our initial strategy involved removal of the scar tissue rich in type III collagene, by proteolysis via MMP14.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase 14 overexpression reduces corneal scarring

Fournié

Massoudi

et al. 2010

Gene Ther

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Once a corneal scar develops, surgical management remains the only option for visual rehabilitation. Corneal transplantation is the definitive treatment for a corneal scar. In addition to the challenges posed by graft rejections and other postoperative complications, the lack of high-quality donor corneas can limit the benefits possible with keratoplasty. The purpose of our study was to evaluate a new therapeutic strategy for treating corneal scarring by targeting collagen deposition. We overexpressed a fibril collagenase (matrix metalloproteinase 14 (MMP14)) to prevent collagen deposition in the scar tissue. We demonstrated that a single and simple direct injection of recombinant adeno-associated virus-based vector expressing murine MMP14 can modulate gene expression of murine stromal keratocytes. This tool opens new possibilities with regard to treatment. In a mouse model of corneal full-thickness incision, we observed that MMP14 overexpression reduced corneal opacity and expression of the major genes involved in corneal scarring, especially type III collagen and a-smooth muscle actin. These results represent proof of concept that gene transfer of MMP14 can reduce scar formation, which could have therapeutic applications after corneal trauma.

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Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase 14 overexpression reduces corneal scarring

Fournié

Massoudi

et al. 2010

Gene Ther

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“…MT1-MMP (MMP14) is the prototypic member of the MT-MMPs and its expression has been associated with a variety of cellular and developmental processes, as well as multiple pathophysiological conditions (Pepper, 2001;Yana and Seiki, 2002). MT1-MMP displays a broad spectrum of activity against ECM components such as type I and II collagen, fibronectin, vitronectin, laminin, fibrin and proteoglycan (d'Ortho et al, 1997;Koshikawa et al, 2000). However, it has substrates that extend beyond ECM components such as cell surface molecules including CD44 (Kajita et al, 2001), pro α V integrin (Deryugina et al, 2002b) and transglutaminase (Belkin et al, 2001).…”

Section: Membrane-associated Mmpsmentioning

confidence: 99%

“…The generation of a permissive substrate for cell migration via the degradation of various specific ECM components is considered as a key event facilitating cell migration. MT1-MMP may function at least as a fibrinolytic and gelatinolytic enzyme (Hotary et al, 2000;d'Ortho et al, 1997). Cleavage of laminin-5 by MMP2 and MT1-MMP reveals a cryptic site that trigger epithelial cell motility (Gilles et al, 2001;Koshikawa et al, 2000).…”

Section: Mt1-mmp and Cancermentioning

confidence: 99%

Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis

et al. 2003

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The matrix metalloproteinases (MMPs) constitute a multigene family of over 23 secreted and cell-surface associated enzymes that cleave or degrade various pericellular substrates. In addition to virtually all extracellular matrix (ECM) compounds, their targets include other proteinases, chemotactic molecules, latent growth factors, growth factor-binding proteins and cell surface molecules. The MMP activity is controlled by the physiological tissue inhibitors of MMPs (TIMPs). There is much evidence that MMPs and their inhibitors play a key role during extracellular remodeling in physiological situations and in cancer progression. They have other functions that promoting tumor invasion. Indeed, they regulate early stages of tumor progression such as tumor growth and angiogenesis. Membrane type MMPs (MT-MMPs) constitute a new subset of cell surface-associated MMPs. The present review will focus on MT1-MMP which plays a major role at least, in the ECM remodeling, directly by degrading several of its components, and indirectly by activating pro-MMP2. As our knowledge on the field of MT1-MMP biology has grown, the unforeseen complexities of this enzyme and its interaction with its inhibitor TIMP-2 have emerged, often revealing unexpected mechanisms of action.Keywords: MT1-MMP ; tumoral angiogenesis ; vascular endothelial growth factor ; protease inhibitors ; estradiol MMP structure and functionsMatrix metalloproteinases (MMPs) are a broad family of zinc-binding endopeptidases that play a key role in the extracellular matrix (ECM) degradation associated with cancer cell invasion, metastasis and angiogenesis (Egeblad and Werb, 2002;McCawley and Matrisian, 2000). At present, more than 21 human MMPs and the homologues from other species have been identified (Egeblad and Werb, 2002). The MMP family can be segregated into two groups, the soluble type and the membrane-type MMPs (MT-MMPs and MMP23). Although initially classified according to their substrate specificity (McCawley and Matrisian, 2000), the MMP classification is now based on their structure (Egeblad and Werb, 2002). The 'minimal-domain MMPs' (MMP7 and MMP26) contains (i) a signal peptide that directs them to the endoplasmic reticulum, (ii) a propeptide, with a zinc-interacting thiol (SH) group that maintains the proMMP in a latent form (zymogen), and (iii) a catalytic domain containing the highly conserved Zn 2+ binding site (HEXGHXXGXXHS/T) (Fig. 1). With the exception of MMP23, all other MMPs display a prolinerich hinge region that links the catalytic domain to the hemopexin/vitronectin-like domain. This C-terminal domain influences substrate specificity and the binding to tissue inhibitors of MMPs (TIMPs) and cell surface molecules. The hemopexin-containing MMPs are further distinguished by the presence of specific insert(s). The gelatin-binding MMPs (MMP2 and MMP9 or gelatinases) contain inserts that resemble the collagen-binding type II repeats of fibronectin. The membrane type (MT)-MMPs have a single pass transmembrane domain and a short cytoplasmic...

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“…Membrane type-1 (MT1)-MMP (MMP-14) was first identified as a protease that converts pro-MMP-2, a type IV collagenase/gelatinase A, to its mature form. It also cleaves a number of ECM substrates including collagens I, II and III, fibronectin and laminins (Kinoshita et al, 1996;d'Ortho et al, 1997;Lehti et al, 1998;Udayakumar et al, 2003). The activation of MMP-2 occurs in a cell surface activation complex consisting of MT1-MMP, TIMP-2 and pro-MMP-2 (Lehti et al, 1998;Zucker et al, 1998;Itoh et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

et al. 2005

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The process of cancer cell invasion involves degradation of the extracellular matrix (ECM) by proteases, integrin adhesion and cell motility. The role of ECM degrading proteases on the hypoxia-induced invasion of breast carcinoma cells was investigated. Hypoxia markedly increased the invasion capacity of MDA-MB-231 and MDA-MB-435 breast carcinoma cell lines. Matrix metalloproteinase (MMP) inhibitors blocked the hypoxia-induced invasion, whereas other protease inhibitors had no effect. Antibodies or siRNAs blocking either membrane type-1 MMP (MT1-MMP) or MMP-2 were effective in reducing the hypoxia-induced invasion. Serumfree reconstitution experiments confirmed the involvement of the MT1-MMP/MMP-2/tissue inhibitor of metalloproteinase-2 complex in this hypoxia-induced response. Overexpression of MT1-MMP in a poorly invasive breast cancer cell line, T47-D, promoted hypoxia-induced invasion and MMP-2 activation. Cell surface accumulation and activation of MT1-MMP without apparent regulation at the mRNA or protein levels indicated a post-translational adaptive response to hypoxia. Inhibition of the small GTPase RhoA eliminated the hypoxiainduced invasion and blocked the localization of MT1-MMP to the plasma membrane. Zymographic and molecular analysis of human breast tumors showed a strong correlation between hypoxic microenvironments and MMP-2 activation without changes in MT1-MMP expression. Our studies suggest that hypoxic tumor microenvironments promote breast cancer invasion through an MT1-MMP-dependent mechanism.

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Membrane‐Type Matrix Metalloproteinases 1 and 2 Exhibit Broad‐Spectrum Proteolytic Capacities Comparable to Many Matrix Metalloproteinases

Cited by 407 publications

References 41 publications

Matrix metalloproteinase 14 overexpression reduces corneal scarring

Matrix metalloproteinase 14 overexpression reduces corneal scarring

Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

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