Dimerization of endogenous MT1-MMP is a regulatory step in the activation of the 72-kDa gelatinase MMP-2 on fibroblasts and fibrosarcoma cells

Biol Chem. 2008 Jul;389(7):943-53. doi: 10.1515/BC.2008.097.


The secreted gelatinase matrix metalloprotease-2 (MMP-2) and the membrane-anchored matrix metalloprotease MT1-MMP (MMP-14), are central players in pericellular proteolysis in extracellular matrix degradation. In addition to possessing a direct collagenolytic and gelatinolytic activity, these enzymes take part in a cascade pathway in which MT1-MMP activates the MMP-2 proenzyme. This reaction occurs in an interplay with the matrix metalloprotease inhibitor, TIMP-2, and the proposed mechanism involves two molecules of MT1-MMP in complex with one TIMP-2 molecule. We provide positive evidence that proMMP-2 activation is governed by dimerization of MT1-MMP on the surface of fibroblasts and fibrosarcoma cells. Even in the absence of transfection and overexpression, dimerization of MT1-MMP markedly stimulated the formation of active MMP-2 products. The effect demonstrated here was brought about by a monoclonal antibody that binds specifically to MT1-MMP as shown by immunofluorescence experiments. The antibody has no effect on the catalytic activity. The effect on proMMP-2 activation involves MT1-MMP dimerization because it requires the divalent monoclonal antibody, with no effect obtained with monovalent Fab fragments. Since only a negligible level of proMMP-2 activation was obtained with MT1-MMP-expressing cells in the absence of dimerization, our results identify the dimerization event as a critical level of proteolytic cascade regulation.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Cattle
  • Cell Line, Tumor
  • Dimerization
  • Enzyme Activation
  • Enzyme Precursors / metabolism*
  • Fibroblasts / metabolism*
  • Hemopexin / metabolism
  • Humans
  • Immunization
  • Matrix Metalloproteinase 14 / chemistry*
  • Matrix Metalloproteinase 14 / immunology
  • Matrix Metalloproteinase 14 / metabolism*
  • Matrix Metalloproteinase 2 / metabolism*
  • Mice
  • Molecular Weight
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary


  • Antibodies, Monoclonal
  • Enzyme Precursors
  • Mmp14 protein, mouse
  • Hemopexin
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14