Pro-MMP-9 activation by the MT1-MMP/MMP-2 axis and MMP-3: role of TIMP-2 and plasma membranes

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....

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2003-08, Vol.308 (2), p.386-395
Main Authors: Toth, Marta, Chvyrkova, Irina, Bernardo, M.Margarida, Hernandez-Barrantes, Sonia, Fridman, Rafael
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cell Membrane - metabolism
Collagenases - chemistry
Collagenases - genetics
Collagenases - metabolism
Enzyme Activation
Enzyme Precursors - chemistry
Enzyme Precursors - genetics
Enzyme Precursors - metabolism
HeLa Cells
Hemopexin - chemistry
Hemopexin - metabolism
Humans
In Vitro Techniques
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 3 - metabolism
Matrix Metalloproteinase 9
Matrix metalloproteinases
Matrix Metalloproteinases, Membrane-Associated
Metalloendopeptidases - metabolism
Mutagenesis, Site-Directed
Plasma membrane
Protease
Protease inhibitor
Protein Structure, Tertiary
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Solutions
Tissue Inhibitor of Metalloproteinase-2 - metabolism
Transfection
Zymogen
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Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/S0006-291X(03)01405-0