科研之友
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摘要
The transmembrane collagenase MT1-MMP (membrane-type I 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 alpha 1-PI (alpha 1-protemase inhibitor)-based inhibitor was designed by incorporating the MT1-MMP propeptide cleavage sequence into the alpha 1-PI reactive-site loop (designated alpha 1-PIMT1) and this was compared with wild-type alpha 1-PI (alpha 1-PIWT) and the furin inhibitory mutant alpha 1-PIPDX. alpha 1-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. alpha 1-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.
- 出版日期2007-10-15
- 单位西北大学
