Differential roles of TIMP-4 and TIMP-2 in pro-MMP-2 activation by MT1-MMP

Biochem Biophys Res Commun. 2001 Feb 16;281(1):126-30. doi: 10.1006/bbrc.2001.4323.


The tissue inhibitors of metalloproteinases (TIMPs) are specific inhibitors of MMP enzymatic activity. However, TIMP-2 can promote the activation of pro-MMP-2 by MT1-MMP. This process is mediated by the formation of a complex between MT1-MMP, TIMP-2, and pro-MMP-2. Binding of TIMP-2 to active MT1-MMP also inhibits the autocatalytic turnover of MT1-MMP on the cell surface. Thus, under certain conditions, TIMP-2 is a positive regulator of MMP activity. TIMP-4, a close homologue of TIMP-2 also binds to pro-MMP-2 and can potentially participate in pro-MMP-2 activation. We coexpressed MT1-MMP with TIMP-4 and investigated its ability to support pro-MMP-2 activation. TIMP-4, unlike TIMP-2, does not promote pro-MMP-2 activation by MT1-MMP. However, TIMP-4 binds to MT1-MMP inhibiting its autocatalytic processing. When coexpressed with TIMP-2, TIMP-4 competitively reduced pro-MMP-2 activation by MT1-MMP. A balance between TIMP-2 and TIMP-4 may be a critical factor in determining the degradative potential of cells in normal and pathological conditions.

Publication types

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

MeSH terms

  • Animals
  • Catalysis
  • Cell Line
  • Cell Membrane / metabolism
  • Enzyme Activation
  • Enzyme Precursors / metabolism*
  • Gelatinases / metabolism*
  • Genetic Vectors / metabolism
  • Haplorhini
  • Humans
  • Immunoblotting
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / metabolism*
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / physiology*
  • Tissue Inhibitor of Metalloproteinases / physiology*
  • Transfection
  • Vaccinia virus / metabolism


  • Enzyme Precursors
  • Recombinant Proteins
  • Tissue Inhibitor of Metalloproteinases
  • tissue inhibitor of metalloproteinase-4
  • Tissue Inhibitor of Metalloproteinase-2
  • Gelatinases
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • progelatinase