Activation-coupled membrane-type 1 matrix metalloproteinase membrane trafficking

Yi I. Wu, Hidayatullah G. Munshi, Scott J. Snipas, Guy S. Salvesen, Rafael Fridman, M. Sharon Stack*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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 α1-PI (α1-proteinase inhibitor)-based inhibitor was designed by incorporating the MT1-MMP propeptide cleavage sequence into the γ-PI reactive-site loop (designated α1-PIMT1) and this was compared with wild-type α1-PI (α1-PIWT) and the furin inhibitory mutant α1-PI PDX. α1-PIMT1 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. α1-PIMT1 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 co-ordinated 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.

Original languageEnglish (US)
Pages (from-to)171-177
Number of pages7
JournalBiochemical Journal
Volume407
Issue number2
DOIs
StatePublished - Oct 15 2007

Keywords

  • Furin
  • MT1-MMP (membrane-type 1 matrix metalloproteinase)
  • Trafficking
  • α1-PI (α1-proteinase inhibitor)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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