Membrane type-1 matrix metalloproteinase (MT1-MMP, MMP-14) is a unique protease that cleaves extracellular proteins, activates proMMPs, and initiates intra'/> Inhibition of MT1-MMP proteolytic function and ERK1/2 signalling influences cell migration and invasion through changes in MMP-2 and MMP-9 levels
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Inhibition of MT1-MMP proteolytic function and ERK1/2 signalling influences cell migration and invasion through changes in MMP-2 and MMP-9 levels

机译：抑制MT1-MMP蛋白水解功能和ERK1 / 2信号传导通过MMP-2和MMP-9水平的变化影响细胞迁移和侵袭

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Abstract Membrane type-1 matrix metalloproteinase (MT1-MMP, MMP-14) is a unique protease that cleaves extracellular proteins, activates proMMPs, and initiates intracellular signalling. MCF-7 cells are non-invasive and deficient in MT1-MMP, MMP-2, and MMP-9 expression. We created an MCF-7 cell line (C2) that stably produces active MT1-MMP and demonstrated increased ERK1/2 phosphorylation. MAPK inhibition in this cell line showed an inverse relationship in MMP-2 and MMP-9 transcripts where levels of these genes increased and decreased, respectively. Using invasive MDA-MB 231 cells that endogenously produce MT1-MMP and have naturally high pERK levels, we demonstrated the identical inverse relationship between MMP-2 and -9 transcript and protein levels, suggesting that this novel relationship is conserved amongst MT1-MMP positive breast cancer cells. To further analyze the relationship between MMP-2 and -9 levels, we chemically inhibited activation and catalytic activity of MT1-MMP using a furin and MMP inhibitor, respectively, to show that interference with the functions of MT1-MMP induced changes in MMP-2 and 9 transcript levels that were always inverse of each other, and likely mediated by differential transcriptional activity of the NF-κB transcription factor. Furthermore, we analyzed the functional consequences of these expression changes to show MMP, and in particular ERK, inhibition decreased migration and invasion using 2D culture, and inhibits the formation of an invasive phenotype in Matrigel 3D culture. This study demonstrated a novel inverse transcriptional relationship between MMP-2 and -9 levels and MT1-MMP activity that have functional consequences, and also showed that increases in the levels of MMPs does not necessarily correlate with an invasive phenotype.
机译：<标题>抽象 ara Id =“par1”>膜型-1矩阵金属蛋白酶（MT1-MMP，MMP-14）是一种独特的蛋白酶，可切割细胞外蛋白，激活PROMMP，并启动细胞内信号。 MCF-7细胞在MT1-MMP，MMP-2和MMP-9表达中是非侵入性的并且缺乏。我们创建了一种MCF-7细胞系（C2），其稳定地产生活性MT1-MMP，并证明ERK1 / 2磷酸化增加。 MAPK抑制在该细胞系中显示出在MMP-2和MMP-9转录物中的反比关系，其中这些基因的水平分别增加和降低。使用内源性产生MT1-MMP的侵袭性MDA-MB 231细胞并具有天然高的Perk水平，我们证明了MMP-2和-9转录物和蛋白质水平之间的相同逆关系，表明这种新的关系在MT1-MMP阳性中被保守乳腺癌细胞。为了进一步分析MMP-2和-9水平之间的关系，我们可以分别使用Furin和MMP抑制剂进行化学抑制MT1-MMP的活化和催化活性，表明干扰MT1-MMP诱导的MMP中变化的功能2和9种转录水平始终彼此反比，并且可能通过NF-κB转录因子的差分转录活性介导。此外，我们分析了这些表达变化的功能后果，以显示MMP，特别是ERK，抑制使用2D培养的迁移和侵袭，并抑制Matrigel 3D培养中的侵入性表型的形成。该研究表明了MMP-2和-9水平与具有功能后果的MT1-MMP活性的新型逆转录关系，并且还显示MMP水平的增加不一定与侵入性表型相关。

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