title: Activation-coupled membrane-type 1 matrix metalloproteinase membrane trafficking.
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 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.
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Yi I
authors.initials: YI
authors.lastname: Wu
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Snipas
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Rafael
authors.initials: R
authors.lastname: Fridman
authors.forename: M Sharon
authors.initials: MS
authors.lastname: Stack
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003094:Collagen / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D015202:Protein Engineering; D021381:Protein Transport; D014162:Transfection
chemical_list: D004792:Enzyme Precursors; D011480:Protease Inhibitors; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14