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Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-alpha convertase activity but does not

W R English1, X S Puente, J M Freije

  • 1School of Biological Sciences, University of East Anglia, University Plain, Norwich, Norfolk NR4 7TJ, United Kingdom.

The Journal of Biological Chemistry
|May 9, 2000
PubMed

Insights

Mouse MT4-MMP (membrane type 4 matrix metalloproteinase) exhibits unique functions, efficiently degrading fibrinogen and shedding pro-tumor necrosis factor alpha (TNFalpha). This suggests a potential role for MT4-MMP in inflammatory processes.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Membrane type 4 matrix metalloproteinase (MT4-MMP) is structurally distinct from other MT-MMPs.
  • Previous studies lacked a complete cDNA for human MT4-MMP, hindering functional analysis.

Purpose of the Study:

  • To isolate and characterize the complete mouse homologue of MT4-MMP (mMT4-MMP).
  • To investigate the enzymatic activity and cellular localization of mMT4-MMP.
  • To explore the potential role of mMT4-MMP in biological processes.

Main Methods:

  • Isolation of complete mouse MT4-MMP cDNA.
  • Expression of mMT4-MMP in COS-7 cells and purification of its catalytic domain from E. coli.
  • Enzyme activity assays using synthetic peptides, extracellular matrix components, and pro-tumor necrosis factor alpha (TNFalpha).
  • Western blot analysis of MT4-MMP in cell lines.

Main Results:

  • Complete mMT4-MMP cDNA was isolated, including signal peptide and pro-domain.
  • Recombinant mMT4-MMP localized to the cell surface but did not activate pro-MMP2.
  • The catalytic domain was inhibited by TIMP1, -2, and -3.
  • mMT4-MMP efficiently hydrolyzed fibrinogen/fibrin and processed pro-TNFalpha, shedding it from cells.
  • MT4-MMP was detected in monocyte/macrophage cell lines.

Conclusions:

  • Mouse MT4-MMP possesses distinct enzymatic properties, including fibrinolytic and TNFalpha-converting activity.
  • Its ability to process pro-TNFalpha and its presence in immune cells suggest a role in inflammation.
  • MT4-MMP represents a potential therapeutic target in inflammatory diseases.

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