Abstract
MMP-9 (gelatinase B) is produced in a latent form (pro-MMP-9) that requires activation to achieve catalytic activity. Previously, we showed that MMP-2 (gelatinase A) is an activator of pro-MMP-9 in solution. However, in cultured cells pro-MMP-9 remains in a latent form even in the presence of MMP-2. Since pro-MMP-2 is activated on the cell surface by MT1-MMP in a process that requires TIMP-2, we investigated the role of the MT1-MMP/MMP-2 axis and TIMPs in mediating pro-MMP-9 activation. Full pro-MMP-9 activation was accomplished via a cascade of zymogen activation initiated by MT1-MMP and mediated by MMP-2 in a process that is tightly regulated by TIMPs. We show that TIMP-2 by regulating pro-MMP-2 activation can also act as a positive regulator of pro-MMP-9 activation. Also, activation of pro-MMP-9 by MMP-2 or MMP-3 was more efficient in the presence of purified plasma membrane fractions than activation in a soluble phase or in live cells, suggesting that concentration of pro-MMP-9 in the pericellular space may favor activation and catalytic competence.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Line
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Cell Membrane / metabolism
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Collagenases / chemistry
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Collagenases / genetics
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Collagenases / metabolism*
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Enzyme Activation
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Enzyme Precursors / chemistry
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Enzyme Precursors / genetics
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Enzyme Precursors / metabolism*
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HeLa Cells
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Hemopexin / chemistry
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Hemopexin / metabolism
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Humans
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In Vitro Techniques
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Matrix Metalloproteinase 2 / metabolism*
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Matrix Metalloproteinase 3 / metabolism*
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Matrix Metalloproteinase 9
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases / metabolism*
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Mutagenesis, Site-Directed
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Protein Structure, Tertiary
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Solutions
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Tissue Inhibitor of Metalloproteinase-2 / metabolism*
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Transfection
Substances
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Enzyme Precursors
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Recombinant Proteins
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Solutions
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Tissue Inhibitor of Metalloproteinase-2
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Hemopexin
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Collagenases
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases
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pro-matrix metalloproteinase 9
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Matrix Metalloproteinase 3
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9