Cell Surface Collagenolysis Requires Homodimerization of the Membrane-bound Collagenase MT1-MMP

Itoh, Yoshifumi; Ito, Noriko; Nagase, Hideaki; Evans, Richard D.; Bird, Sarah; Seiki, Motoharu

doi:10.1091/mbc.e06-08-0740

Cited by 97 publications

(121 citation statements)

References 48 publications

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“…Contrary to our findings, previous studies showed that expression of a recombinant 44-kDa form inhibited MT1-MMP activity (57,59,60). This inhibitory function was ascribed to a competitive interference of the hemopexin and cytosolic domains of the 44-kDa form with the tendency of MT1-MMP to undergo homophilic interactions (1,57,59,62) and to cleave collagen I (60,76). According to these studies, the 44-kDa species acts in a manner consistent with being a dominant negative regulator of MT1-MMP activity.…”

Section: Discussioncontrasting

confidence: 99%

“…Previous studies demonstrated that expression of an N-terminally tagged 44-kDa form inhibits MT1-MMP-mediated pro-MMP-2 activation (57,59,76). These species, as opposed to 44-MT1, lack significant parts of the hinge region, which may affect the experimental outcome (see "Discussion").…”

Section: Resultsmentioning

confidence: 98%

“…The majority of the studies reporting a dominant negative effect of the 44-kDa form used recombinant 44-kDa-like proteins lacking most of the hinge region. In addition, these forms included either a FLAG or a 25-kDa glutathione S-transferase tag at the N terminus (57)(58)(59)76). The FLAG-tagged, hinge-deleted 44-kDa species was found to be processed to a smaller form (57), possibly because of the lack of O-glycosylation, as discussed below (25,36).…”

Section: Discussionmentioning

confidence: 99%

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The Inactive 44-kDa Processed Form of Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Enhances Proteolytic Activity via Regulation of Endocytosis of Active MT1-MMP

Cho

Osenkowski

Zhao

et al. 2008

Journal of Biological Chemistry

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Membrane type 1 (MT1) matrix metalloproteinase (MMP-14)is a membrane-tethered MMP considered to be a major mediator of pericellular proteolysis. MT1-MMP is regulated by a complex array of mechanisms, including processing and endocytosis that determine the pool of active proteases on the plasma membrane. Autocatalytic processing of active MT1-MMP generates an inactive membrane-tethered 44-kDa product (44-MT1) lacking the catalytic domain. This form preserves all other enzyme domains and is retained at the cell surface. Paradoxically, accumulation of the 44-kDa form has been associated with increased enzymatic activity. Here we report that expression of a recom- Membrane type 1 matrix metalloproteinase (MT1-MMP, 2 MMP-14) is a type I-transmembrane protease and a major mediator of pericellular proteolysis. MT1-MMP is responsible for the proteolytic cleavage of multiple pericellular and membrane-associated substrates, including collagens and other extracellular matrix proteins, growth factors, growth factor receptors, cell adhesion proteins and their receptors, cytokines, protease inhibitors, and proteases, just to mention a few (1-5). MT1-MMP is also the major physiological activator of pro-MMP-2 (pro-gelatinase A) on the cell surface (6, 7), a process that further contributes to pericellular proteolysis. As a multifunctional protease, MT1-MMP elicits profound effects on cell behavior and has been implicated in the pathogenesis of various human diseases, including cancer (8 -10), diabetes (11, 12), vascular (13, 14), and connective tissue diseases (2).The importance of MT1-MMP for pericellular proteolysis demands a tight control of its catalytic activity at the cell surface. This is partly achieved by the action of endogenous protease inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), which bind to the active site inhibiting catalysis (15). In addition, by virtue of being a membrane-anchored protease, MT1-MMP developed a unique set of regulatory mechanisms that control enzymatic activity independently of TIMPs. These processes include the targeting of active enzyme to specific plasma membrane locations, endocytosis, and autocatalytic processing (1, 16 -19). Together, these distinct processes determine the level of active enzyme on the cell surface. However, how these processes are integrated to control the pool of active MT1-MMP is not understood.The processing of MT1-MMP is a cell surface event in which the active enzyme is usually autocatalytically cleaved in trans to generate a major membrane-anchored product of ϳ44 kDa (also referred to as the 43-or 45-kDa species in some studies) and a soluble ϳ18-kDa inactive fragment of the catalytic domain (6, 20 -25). The 44-kDa product of MT1-MMP is detected in cultured cells expressing natural MT1-MMP (20, 26 -32) and has been found in platelets (33), human tumors extracts (34 -36), and extracts of arthritic synovial tissues (37). MT1-MMP processing is stimulated by a variety of factors known to stimulate MT1-MMP expression, trafficking, and/or endocytosi...

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Section: Discussioncontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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The Inactive 44-kDa Processed Form of Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Enhances Proteolytic Activity via Regulation of Endocytosis of Active MT1-MMP

Cho

Osenkowski

Zhao

et al. 2008

Journal of Biological Chemistry

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“…Upon trafficking of MMP-14 to the plasma membrane and subsequent docking, Itoh et al (32) reported that homodimer formation of MMP-14 through the PEX domain facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion. It has also been established that cross-talk between MMP-14 and CD44 exists whereby heterodimerization of the surface proteins regulates the invasive front of the cell (33).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Matrix Metalloproteinase 14 (MMP-14)-mediated Cancer Cell Migration

Zarrabi

Dufour

et al. 2011

Journal of Biological Chemistry

175

189

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Matrix metalloproteinases (MMPs) have been shown to be key players in both extracellular matrix remodeling and cell migration during cancer metastasis. MMP-14, a membraneanchored MMP, in particular, is closely associated with these processes. The hemopexin (PEX) domain of MMP-14 has been proposed as the modulating region involved in the molecular cross-talk that initiates cell migration through homodimerization of MMP-14 as well as heterodimerization with the cell surface adhesion molecule CD44. In this study, minimal regions required for function within the PEX domain were investigated through a series of substitution mutations. Blades I and IV were found to be involved in cell migration. We found that blade IV is necessary for MMP-14 homodimerization and that blade I is required for CD44 MMP-14 heterodimerization. Cross-talk between MMP-14 and CD44 results in phosphorylation of EGF receptor and downstream activation of the MAPK and PI3K signaling pathways involved in cell migration. Based on these mutagenesis analyses, peptides mimicking the essential outermost strand motifs within the PEX domain of MMP-14 were designed. These synthetic peptides inhibit MMP-14-enhanced cell migration in a dose-dependent manner but have no effect on the function of other MMPs. Furthermore, these peptides interfere with cancer metastasis without affecting primary tumor growth. Thus, targeting the MMP-14 hemopexin domain represents a novel approach to inhibit MMP-14-mediated cancer dissemination.

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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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Cell Surface Collagenolysis Requires Homodimerization of the Membrane-bound Collagenase MT1-MMP

Cited by 97 publications

References 48 publications

The Inactive 44-kDa Processed Form of Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Enhances Proteolytic Activity via Regulation of Endocytosis of Active MT1-MMP

The Inactive 44-kDa Processed Form of Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Enhances Proteolytic Activity via Regulation of Endocytosis of Active MT1-MMP

Inhibition of Matrix Metalloproteinase 14 (MMP-14)-mediated Cancer Cell Migration

Matrix metalloproteinase 14 overexpression reduces corneal scarring

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