Activation-coupled membrane-type 1 matrix metalloproteinase membrane trafficking.
Activation-coupled membrane-type 1 matrix metalloproteinase membrane trafficking.
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激活耦合膜 1 型基质金属蛋白酶膜运输。
DOI：
10.1042/bj20070552
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Stack,MSharon
中科院分区：
文献类型：
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作者：
Wu,YiI;Munshi,HidayatullahG;Snipas,ScottJ;Salvesen,GuyS;Fridman,Rafael;Stack,MSharon
跨膜胶原酶MT 1-MMP（膜1型基质金属蛋白酶），也称为MMP-14，在正常发育和癌症进展中具有关键功能，并且在影响蛋白酶活性的翻译后水平受到广泛控制。由于酶原激活对MT 1-MMP活性至关重要，因此通过将MT 1-MMP前肽切割序列并入α1-PI反应位点环（称为α1-PIMT 1）来设计基于α1-PI（α1-蛋白酶抑制剂）的抑制剂，并将其与野生型α1-PI（α1-PIWT）和弗林蛋白酶抑制突变体α1-PIPDX进行比较。α1-PIMT 1与furin形成SDS稳定的复合物，抑制proMT 1-MMP的活化。MT 1-MMP活性丧失的结果是proMMP-2的活化和MT 1-MMP介导的胶原侵袭的抑制。α1-PIMT 1表达还导致proMT 1-MMP的糖基化物质在细胞内积聚，该物质保留在核周区域，导致proMT 1-MMP的细胞表面积聚显著减少。这些观察结果表明，MT 1-MMP的亚细胞定位和活性以协调的方式调节，使得proMT 1-MMP保留在细胞内直到其酶原活化，然后proMT 1-MMP运输到细胞表面以切割细胞外底物。
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-PIMT1formed 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-PIMT1expression 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.