Membrane-type 1 matrix metalloproteinase modulates focal adhesion stability and cell migration
Membrane-type 1 matrix metalloproteinase modulates focal adhesion stability and cell migration
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DOI：
10.1016/j.yexcr.2006.01.008
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发表时间：
2006-05-01
影响因子：
3.7
通讯作者：
Sato, H
中科院分区：
文献类型：
--
作者：
Takino, T;Watanabe, Y;Sato, H
膜1型基质金属蛋白酶（MT 1-MMP）在细胞外基质诱导的细胞迁移和细胞外信号调节激酶（ERK）的激活中起重要作用。我们在这里表明，MT 1-MMP基因转染到HeLa细胞促进纤连蛋白诱导的细胞迁移，这是伴随着纤连蛋白降解和减少稳定的局灶性粘连，其功能作为锚肌动蛋白应力纤维。MT 1-MMP表达减弱了细胞与纤连蛋白粘附诱导的整合素聚集。通过用合成MMP抑制剂BB 94抑制MT 1-MMP来消除整联蛋白聚集的衰减。当培养在纤连蛋白上时，内源性表达MT 1-MMP的HT 1080细胞表现出所谓的运动形态，具有组织良好的粘着斑形成、定向良好的肌动蛋白-应力纤维形成以及通过细胞迁移的踪迹的纤连蛋白溶解。内源性MT 1-MMP的抑制BB 94治疗或表达的MT 1-MMP羧基末端结构域，负调节MT 1-MMP的活性，导致纤连蛋白溶解和细胞迁移的抑制。BB 94处理促进了稳定的粘着斑形成，伴随着粘着斑激酶（FAK）酪氨酸397磷酸化的增强和ERK活化的减少。这些结果表明，MT 1-MMP的细胞外基质裂解促进粘着斑周转和随后的ERK激活，这反过来又刺激细胞迁移。(c)2006年爱思唯尔公司All rights reserved.
Membrane-type 1 matrix metalloproteinase (MT1-MMP) plays an important role in extracellular matrix-induced cell migration and the activation of extracellular signal-regulated kinase (ERK). We showed here that transfection of the MT1-MMP gene into HeLa cells promoted fibronectin-induced cell migration, which was accompanied by fibronectin degradation and reduction of stable focal adhesions, which function as anchors for actin-stress fibers. MT1-MMP expression attenuated integrin clustering that was induced by adhesion of cells to fibronectin. The attenuation of integrin clustering was abrogated by MT1-MMP inhibition with a synthetic MMP inhibitor, BB94. When cultured on fibronectin, HT1080 cells, which endogenously express MT1-MMP, showed so-called motile morphology with well-organized focal adhesion formation, well-oriented actin-stress fiber formation, and the lysis of fibronectin through trails of cell migration. Inhibition of endogenous MT1-MMP by BB94 treatment or expression of the MT1-MMP carboxyl-terminal domain, which negatively regulates MT1-MMP activity, resulted in the suppression of fibronectin lysis and cell migration. BB94 treatment promoted stable focal adhesion formation concomitant with enhanced phosphorylation of tyrosine 397 of focal adhesion kinase (FAK) and reduced ERK activation. These results suggest that lysis of the extracellular matrix by MT1-MMP promotes focal adhesion turnover and subsequent ERK activation, which in turn stimulates cell migration. (c) 2006 Elsevier Inc. All rights reserved.