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Regulation of membrane-type 1 matrix metalloproteinase activity by vacuolar H+-ATPases

Erik Maquoi1, Karine Peyrollier, Agnès Noël

  • 1Laboratory of Tumor and Development Biology, University of Liège, Tour de Pathologie (B23), Sart Tilman, B-4000 Liège, Belgium.

The Biochemical Journal
|April 2, 2003
PubMed

Insights

The cell surface activity of membrane-type 1 matrix metalloproteinase (MT1-MMP) is regulated by degradation. Blocking this process with bafilomycin-A(1) increases active MT1-MMP and pro-MMP-2 activation.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Membrane-type 1 matrix metalloproteinase (MT1-MMP) is crucial for development and cancer.
  • MT1-MMP activity is regulated by processing, TIMP binding, and internalization.
  • The fate of internalized MT1-MMP and its regulation remain unclear.

Purpose of the Study:

  • To investigate the role of vacuolar H(+)-ATPase in MT1-MMP regulation.
  • To determine the effect of inhibiting vacuolar acidification on MT1-MMP activity and processing.
  • To elucidate the degradation pathway of internalized MT1-MMP.

Main Methods:

  • Treatment of human tumor cell lines expressing MT1-MMP with bafilomycin-A(1).
  • Analysis of MT1-MMP activity, internalization, and processing.
  • Assessment of pro-MMP-2 activation.

Main Results:

  • MT1-MMP activity is constitutively downregulated via vacuolar H(+)-ATPase-dependent degradation.
  • Inhibition of degradation leads to accumulation of active MT1-MMP on the cell surface.
  • Internalization of MT1-MMP is unaffected by blocking degradation.
  • Impaired degradation enhances pro-MMP-2 activation.

Conclusions:

  • Cell surface MT1-MMP activity is regulated by a vacuolar H(+)-ATPase-dependent degradation pathway.
  • This pathway controls the availability of active MT1-MMP and influences pro-MMP-2 activation.
  • Targeting this degradation process may offer therapeutic strategies for diseases involving MT1-MMP.

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