MT1-MMP initiates activation of pro-MMP-2 and integrin αvβ3 promotes maturation of MMP-2 in breast carcinoma cells
MT1-MMP initiates activation of pro-MMP-2 and integrin αvβ3 promotes maturation of MMP-2 in breast carcinoma cells
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DOI：
10.1006/excr.2000.5118
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发表时间：
2001-02-15
影响因子：
3.7
通讯作者：
Strongin, AY
中科院分区：
文献类型：
--
作者：
Deryugina, EI;Ratnikov, B;Strongin, AY
我们评估了参与基质金属蛋白酶原-2（pro-MMP-2）激活途径的细胞机制，该酶与许多肿瘤类型的恶性进展有关。膜1型基质金属蛋白酶（MT 1-MMP）切割pro-NIMP-2的N-末端前结构域，从而产生活化中间体，然后成熟为MMP-2的完全活性酶。我们的研究结果提供的证据如何MT 1-MMP和整合素α v β 3之间的合作，促进更有效的激活和特定的，瞬时对接的激活中间体，并进一步，成熟的，活性酶的MMP-2在离散区域的细胞。我们发现MT 1-MMP和整合素α v β 3在MCF 7乳腺癌细胞中的共表达特异性地增强了MMP-2的反式自催化成熟。MMP-2的C-末端血红素样结构域与MT 1-MMP近端的整合素α v β 3分子的结合促进MMP-2成熟。玻连蛋白，整合素α v β 3的特异性配体，竞争性阻断MMP-2的整合素依赖性成熟。免疫荧光和免疫沉淀研究支持MT 1-MMP和整合素α v β 3聚集在细胞表面的离散区域。显然，所鉴定的机制似乎有助于将活性MMP-2直接聚集在表达α v β 3的细胞的侵袭伪足和侵袭前沿或其附近，从而加速肿瘤细胞运动。(C)北京：科学出版社.
We evaluated cellular mechanisms involved in the activation pathway of matrix prometalloproteinase-2 (pro-MMP-2), an enzyme implicated in the malignant progression of many tumor types. Membrane type-1 matrix metalloproteinase (MT1-MMP) cleaves the N-terminal prodomain of pro-NIMP-2 thus generating the activation intermediate that then matures into the fully active enzyme of MMP-2. Our results provide evidence on how a collaboration between MT1-MMP and integrin alphav beta3 promotes more efficient activation and specific, transient docking of the activation intermediate and, further, the mature, active enzyme of MMP-2 at discrete regions of cells. We show that coexpression of MT1-MMP and integrin alphav beta3 in MCF7 breast carcinoma cells specifically enhances in trans autocatalytic maturation of MMP-2. The association of MMP-2's C-terminal hemopexin-like domain with those molecules of integrin alphav beta3 which are proximal to MT1-MMP facilitates MMP-2 maturation. Vitronectin, a specific ligand of integrin alphav beta3, competitively blocked the integrin-dependent maturation of MMP-2. Immunofluorescence and immunoprecipitation studies supported clustering of MT1-MMP and integrin alphav beta3 at discrete regions of the cell surface. Evidently, the identified mechanisms appear to be instrumental to clustering active MMP-2 directly at the invadopodia and invasive front of alphav beta3-expressing cells or in their close vicinity, thereby accelerating tumor cell locomotion. (C) 2001 Academic Press.