Activation-Coupled Membrane Type 1 Matrix Metalloproteinase Membrane Trafficking.

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 α1-PI reactive-site loop (designated α1-PIMT1) and this was compared with wild-type α1-PI (α1-PIWT) and the furin inhibitory mutant α1-PIPDX. 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 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.