Activation-coupled membrane-type 1 matrix metalloproteinase membrane trafficking

Biochem J. 2007 Oct 15;407(2):171-7. doi: 10.1042/BJ20070552.


The transmembrane collagenase MT1-MMP (membrane-type 1 matrix metalloproteinase), also known as MMP-14, has a critical function both in normal development and in cancer progression, and is subject to extensive controls at the post-translational level which affect proteinase activity. As zymogen activation is crucial for MT1-MMP activity, an alpha1-PI (alpha1-proteinase inhibitor)-based inhibitor was designed by incorporating the MT1-MMP propeptide cleavage sequence into the alpha1-PI reactive-site loop (designated alpha1-PI(MT1)) and this was compared with wild-type alpha1-PI (alpha1-PI(WT)) and the furin inhibitory mutant alpha1-PI(PDX). Alpha1-PI(MT1) formed an SDS-stable complex with furin and inhibited proMT1-MMP activation. A consequence of the loss of MT1-MMP activity was the activation of proMMP-2 and the inhibition of MT1-MMP-mediated collagen invasion. alpha1-PI(MT1) expression also resulted in the intracellular accumulation of a glycosylated species of proMT1-MMP that was retained in the perinuclear region, leading to significantly decreased cell-surface accumulation of proMT1-MMP. These observations suggest that both the subcellular localization and the activity of MT1-MMP are regulated in a coordinated fashion, such that proMT1-MMP is retained intracellularly until activation of its zymogen, then proMT1-MMP traffics to the cell surface in order to cleave extracellular substrates.

Publication types

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

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Collagen / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Precursors / metabolism
  • Glycosylation
  • Humans
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / metabolism*
  • Matrix Metalloproteinase 2 / metabolism
  • Protease Inhibitors / pharmacology
  • Protein Engineering
  • Protein Transport
  • Transfection


  • Enzyme Precursors
  • Protease Inhibitors
  • Collagen
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14