Substrate choice of membrane-type 1 matrix metalloproteinase is dictated by tissue inhibitor of metalloproteinase-2 levels

Cancer Sci. 2007 Apr;98(4):563-8. doi: 10.1111/j.1349-7006.2007.00426.x.


Although tissue inhibitor of metalloproteinase-2 (TIMP-2) is known to be not only an inhibitor of matrix metalloproteinases (MMP) but also a cofactor for membrane-type 1 MMP (MT1-MMP)-mediated MMP-2 activation, it is still unclear how TIMP-2 regulates MMP-2 activation and cleavage of substrates by MT1-MMP. In the present study we examined the levels of cell-surface MT1-MMP, MMP-2 activation and cleavage of MT1-MMP substrates in 293T cells transfected with the MT1-MMP and TIMP-2 genes. Co-expression of TIMP-2 at an appropriate level increased the level of cell-surface MT1-MMP, both the TIMP-2-bound and free forms, and generated processed MMP-2 with gelatin-degrading activity. In contrast, MT1-MMP substrates testican-1 and syndecan-1 were cleaved by the cells expressing MT1-MMP, which was inhibited by TIMP-2 even at levels that stimulate MMP-2 activation. These results suggest that TIMP-2 environment determines MT1-MMP substrate choice between direct cleavage of its own substrates and MMP-2 activation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Enzyme Activation
  • Humans
  • Matrix Metalloproteinase 14 / biosynthesis*
  • Matrix Metalloproteinase 14 / genetics
  • Proteoglycans / metabolism
  • Recombinant Proteins / metabolism*
  • Syndecan-1 / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism*
  • Transfection


  • Proteoglycans
  • Recombinant Proteins
  • SDC1 protein, human
  • SPOCK1 protein, human
  • Syndecan-1
  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinase 14