Selective involvement of TIMP-2 in the second activational cleavage of pro-MMP-2: refinement of the pro-MMP-2 activation mechanism

FEBS Lett. 2003 Oct 23;553(3):457-63. doi: 10.1016/s0014-5793(03)01094-9.

Abstract

A tissue inhibitor of metalloproteinases-2 (TIMP-2)-independent mechanism for generating the first activational cleavage of pro-matrix metalloproteinase-2 (MMP-2) was identified in membrane type-1 MMP (MT1-MMP)-transfected MCF-7 cells and confirmed in TIMP-2-deficient fibroblasts. In contrast, the second MMP-2-activational step was found to be TIMP-2 dependent in both systems. MMP-2 hemopexin C-terminal domain was found to be critical for the first step processing, confirming a need for membrane tethering. We propose that the intermediate species of MMP-2 forms the well-established trimolecular complex (MT1-MMP/TIMP-2/MMP-2) for further TIMP-2-dependent autocatalytic cleavage to the fully active species. This alternate mechanism may supplement the traditional TIMP-2-mediated first step mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Breast Neoplasms / metabolism
  • Catalytic Domain
  • Cell Line
  • Enzyme Activation
  • Enzyme Precursors / chemistry
  • Enzyme Precursors / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gelatinases / chemistry
  • Gelatinases / metabolism*
  • Humans
  • Matrix Metalloproteinase 14
  • Matrix Metalloproteinase 2 / chemistry
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / chemistry
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / chemistry
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Enzyme Precursors
  • Mmp14 protein, mouse
  • Recombinant Proteins
  • Tissue Inhibitor of Metalloproteinase-2
  • Gelatinases
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • progelatinase
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14