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Activation-coupled membrane-type 1 matrix metalloproteinase membrane trafficking

Yi I Wu1, Hidayatullah G Munshi, Scott J Snipas

  • 1Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

The Biochemical Journal
|July 26, 2007
PubMed

Insights

A novel alpha1-proteinase inhibitor (alpha1-PI(MT1)) effectively blocks membrane-type 1 matrix metalloproteinase (MT1-MMP) activation by inhibiting furin. This leads to reduced MT1-MMP activity, collagen invasion, and altered intracellular localization of proMT1-MMP.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) is crucial for development and cancer progression.
  • MT1-MMP activity is tightly regulated at the post-translational level, particularly during zymogen activation.
  • Inhibiting MT1-MMP activation is a potential therapeutic strategy for cancers.

Purpose of the Study:

  • To design and evaluate a novel alpha1-proteinase inhibitor (alpha1-PI(MT1)) targeting MT1-MMP activation.
  • To investigate the effects of alpha1-PI(MT1) on proMT1-MMP activation, MT1-MMP activity, and cell-surface localization.
  • To compare the efficacy of alpha1-PI(MT1) with wild-type alpha1-PI (alpha1-PI(WT)) and a furin inhibitory mutant alpha1-PI(PDX).

Main Methods:

  • Engineered alpha1-PI(MT1) by incorporating the MT1-MMP propeptide cleavage sequence into the alpha1-PI reactive-site loop.
  • Assessed the interaction of alpha1-PI(MT1) with furin and its effect on proMT1-MMP activation using SDS-stable complex formation.
  • Evaluated MT1-MMP-mediated collagen invasion and the subcellular localization of proMT1-MMP in cells expressing alpha1-PI(MT1).

Main Results:

  • Alpha1-PI(MT1) formed an SDS-stable complex with furin, effectively inhibiting proMT1-MMP activation.
  • MT1-MMP activity was reduced, leading to decreased MT1-MMP-mediated collagen invasion and proMMP-2 activation.
  • Expression of alpha1-PI(MT1) caused intracellular accumulation of a glycosylated proMT1-MMP species, retaining it in the perinuclear region and reducing cell-surface presence.

Conclusions:

  • Alpha1-PI(MT1) is a potent inhibitor of MT1-MMP zymogen activation by targeting furin.
  • MT1-MMP activity and subcellular localization are coordinately regulated, with intracellular retention of proMT1-MMP prior to activation.
  • Targeting MT1-MMP activation and localization presents a promising strategy for controlling cancer progression and invasion.

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