TIMP-2 Interaction with MT1-MMP Activates the AKT Pathway and Protects Tumor Cells from Apoptosis.
TIMP-2 Interaction with MT1-MMP Activates the AKT Pathway and Protects Tumor Cells from Apoptosis.
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DOI：
10.1371/journal.pone.0136797
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Mignatti P
中科院分区：
文献类型：
--
作者：
Valacca C;Tassone E;Mignatti P
膜1型基质金属蛋白酶（MT 1-MMP）是一种具有细胞外催化结构域和短胞质尾区的跨膜蛋白酶，可降解多种细胞外基质（ECM）成分。此外，MT 1-MMP通过蛋白水解依赖性和非依赖性机制激活细胞内信号传导。我们以前已经表明，结合的组织抑制剂的金属蛋白酶-2（TIMP-2）的MT 1-MMP控制细胞增殖和迁移，以及在体内肿瘤的生长，通过激活Ras-细胞外信号调节激酶-1和-2（ERK 1/2）途径，通过一种机制，需要的细胞质，而不是MT 1-MMP的蛋白水解结构域。在这里，我们表明，在MT 1-MMP表达细胞TIMP-2也诱导快速和持续激活AKT的剂量和时间依赖性的方式，并通过一种机制，独立于MT 1-MMP的蛋白水解活性。成纤维细胞生长因子受体-1介导TIMP-2诱导ERK 1/2，但不诱导AKT活化;然而，Ras活化是将TIMP-2活化信号传递给ERK 1/2和AKT途径所必需的。通过TIMP-2与MT 1-MMP结合激活ERK 1/2和AKT保护肿瘤细胞免受血清饥饿诱导的凋亡。相反，TIMP-2上调上皮癌细胞中三维I型胶原诱导的凋亡。因此，TIMP-2与MT 1-MMP的相互作用为肿瘤细胞提供了促凋亡或抗凋亡信号，这取决于细胞外环境和凋亡刺激。
Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane proteinase with an extracellular catalytic domain and a short cytoplasmic tail, degrades a variety of extracellular matrix (ECM) components. In addition, MT1-MMP activates intracellular signaling through proteolysis-dependent and independent mechanisms. We have previously shown that binding of tissue inhibitor of metalloproteinases-2 (TIMP-2) to MT1-MMP controls cell proliferation and migration, as well as tumor growth in vivo by activating the Ras—extracellular signal regulated kinase-1 and -2 (ERK1/2) pathway through a mechanism that requires the cytoplasmic but not the proteolytic domain of MT1-MMP. Here we show that in MT1-MMP expressing cells TIMP-2 also induces rapid and sustained activation of AKT in a dose- and time-dependent manner and by a mechanism independent of the proteolytic activity of MT1-MMP. Fibroblast growth factor receptor-1 mediates TIMP-2 induction of ERK1/2 but not of AKT activation; however, Ras activation is necessary to transduce the TIMP-2-activated signal to both the ERK1/2 and AKT pathways. ERK1/2 and AKT activation by TIMP-2 binding to MT1-MMP protects tumor cells from apoptosis induced by serum starvation. Conversely, TIMP-2 upregulates apoptosis induced by three-dimensional type I collagen in epithelial cancer cells. Thus, TIMP-2 interaction with MT1-MMP provides tumor cells with either pro- or anti-apoptotic signaling depending on the extracellular environment and apoptotic stimulus.