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. 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.
Toth
Marta
M
Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Chvyrkova
Irina
I
Bernardo
M Margarida
MM
Hernandez-Barrantes
Sonia
S
Fridman
Rafael
R
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D017364:Collagenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006466:Hemopexin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012996:Solutions; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D014162:Transfection
D004792:Enzyme Precursors; D011994:Recombinant Proteins; D012996:Solutions; D019716:Tissue Inhibitor of Metalloproteinase-2; D006466:Hemopexin; D017364:Collagenases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C120487:pro-matrix metalloproteinase 9; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9