MT1-MMP initiates activation of pro-MMP-2 and integrin alphavbeta3 promotes maturation of MMP-2 in breast carcinoma cells

Exp Cell Res. 2001 Feb 15;263(2):209-23. doi: 10.1006/excr.2000.5118.


We evaluated cellular mechanisms involved in the activation pathway of matrix prometalloproteinase-2 (pro-MMP-2), an enzyme implicated in the malignant progression of many tumor types. Membrane type-1 matrix metalloproteinase (MT1-MMP) cleaves the N-terminal prodomain of pro-MMP-2 thus generating the activation intermediate that then matures into the fully active enzyme of MMP-2. Our results provide evidence on how a collaboration between MT1-MMP and integrin alphavbeta3 promotes more efficient activation and specific, transient docking of the activation intermediate and, further, the mature, active enzyme of MMP-2 at discrete regions of cells. We show that coexpression of MT1-MMP and integrin alphavbeta3 in MCF7 breast carcinoma cells specifically enhances in trans autocatalytic maturation of MMP-2. The association of MMP-2's C-terminal hemopexin-like domain with those molecules of integrin alphavbeta3 which are proximal to MT1-MMP facilitates MMP-2 maturation. Vitronectin, a specific ligand of integrin alphavbeta3, competitively blocked the integrin-dependent maturation of MMP-2. Immunofluorescence and immunoprecipitation studies supported clustering of MT1-MMP and integrin alphavbeta3 at discrete regions of the cell surface. Evidently, the identified mechanisms appear to be instrumental to clustering active MMP-2 directly at the invadopodia and invasive front of alphavbeta3-expressing cells or in their close vicinity, thereby accelerating tumor cell locomotion.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal / metabolism
  • Blotting, Western
  • Breast Neoplasms / enzymology*
  • Carcinoma / enzymology
  • Cell Movement
  • Culture Media, Serum-Free
  • Enzyme Activation
  • Female
  • Fibrosarcoma / enzymology
  • Flow Cytometry
  • Glioma / enzymology
  • Humans
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / metabolism*
  • Microscopy, Confocal
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • Protease Inhibitors / metabolism
  • Protein Precursors / metabolism*
  • Proteins / metabolism
  • Receptors, Vitronectin / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism
  • Transfection
  • Tumor Cells, Cultured
  • Vitronectin / metabolism


  • Antibodies, Monoclonal
  • Culture Media, Serum-Free
  • Protease Inhibitors
  • Protein Precursors
  • Proteins
  • Receptors, Vitronectin
  • Recombinant Fusion Proteins
  • Vitronectin
  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • PHEX protein, human
  • Matrix Metalloproteinase 2