Willson J A, Muir C A, Evered C L, Cepeda M A, Damjanovski S
Department of Biology, University of Western Ontario, 1151 Richmond St. N, London, ON, N6A 5B7, Canada.
Ontario Veterinary College, University of Guelph, 50 Stone Rd. E, Guelph, ON, N1G 2W1, Canada.
J Cell Commun Signal. 2018 Jun;12(2):479-488. doi: 10.1007/s12079-017-0407-5. Epub 2017 Aug 29.
The membrane bound matrix metalloproteinase MT1-MMP plays roles in modulating cell movement, independent of its abilities to remodel the extracellular matrix. Unlike many MMPs, MT1-MMP is activated in the Golgi prior to secretion by a pro-protein convertase, primarily furin. Regulation of the activation of pro-MT1-MMP has been methodically investigated, as altering the level of the active protein has broad implications in both activating other pro-MMPs, including pro-MMP-2, and many subsequent remodelling events. Our previous work in MCF-7 cells has demonstrated that modest, and not extremely high, levels of active MT1-MMP manifests into altered cell morphology and movement. At this low but optimal amount of MT1-MMP protein, changes to MT1-MMP levels are always mirrored by MMP-9 and pERK levels, and always opposite to MMP-2 levels. In this study, stable expression of the furin inhibitor α1-antitrypsin Portland (α1-PDX) in MDA-MB-231 cells increased overall MT1-MMP levels, but cells maintained a 21% proportion of pro-MT1-MMP. The increase in MT1-MMP was mirrored by increases in MMP-9 and pERK, but a decrease in MMP-2. These changes were associated with increased NF-κB transcription. In vitro analysis showed that α1-PDX decreased cell protrusions and migration, and this manifested as decreased tumourigenesis when examined in vivo using a chick CAM assay.
膜结合基质金属蛋白酶MT1-MMP在调节细胞运动中发挥作用，与其重塑细胞外基质的能力无关。与许多基质金属蛋白酶不同，MT1-MMP在分泌前于高尔基体中被一种前体蛋白转化酶（主要是弗林蛋白酶）激活。对前体MT1-MMP激活的调节已得到系统研究，因为改变活性蛋白的水平在激活包括前体MMP-2在内的其他前体MMP以及许多后续重塑事件中都具有广泛影响。我们之前在MCF-7细胞中的研究表明，适度而非极高水平的活性MT1-MMP会导致细胞形态和运动发生改变。在这个低但最佳量的MT1-MMP蛋白水平下，MT1-MMP水平的变化总是与MMP-9和pERK水平相对应，且总是与MMP-2水平相反。在本研究中，在MDA-MB-231细胞中稳定表达弗林蛋白酶抑制剂α1-抗胰蛋白酶波特兰（α1-PDX）可提高总体MT1-MMP水平，但细胞中前体MT1-MMP的比例仍保持在21%。MT1-MMP的增加与MMP-9和pERK的增加相对应，但与MMP-2的减少相对应。这些变化与NF-κB转录增加有关。体外分析表明，α1-PDX减少了细胞突起和迁移，在体内使用鸡胚绒毛尿囊膜试验检测时，这表现为肿瘤发生减少。
