Pro-MMP-9 Activation by the MT1-MMP/MMP-2 Axis and MMP-3: Role of TIMP-2 and Plasma Membranes

Biochem Biophys Res Commun. 2003 Aug 22;308(2):386-95. doi: 10.1016/s0006-291x(03)01405-0.

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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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, Membrane-Associated
  • Metalloendopeptidases / metabolism*
  • Mutagenesis, Site-Directed
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Solutions
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism*
  • Transfection

Substances

  • Enzyme Precursors
  • Recombinant Proteins
  • Solutions
  • Tissue Inhibitor of Metalloproteinase-2
  • Hemopexin
  • Collagenases
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • pro-matrix metalloproteinase 9
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9