Prointegrin maturation follows rapid trafficking and processing of MT1-MMP in furin-negative colon carcinoma LoVo cells
Prointegrin maturation follows rapid trafficking and processing of MT1-MMP in furin-negative colon carcinoma LoVo cells
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DOI：
10.1111/j.1600-0854.2004.00206.x
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发表时间：
2004-08-01
期刊：
影响因子：
4.5
通讯作者：
Strongin, AY
中科院分区：
文献类型：
--
作者：
Deryugina, EI;Ratnikov, BI;Strongin, AY
了解促进肿瘤侵袭的1型基质金属蛋白酶（MT1-MMP）的功能对了解肿瘤生物学至关重要。MT1-MMP作为一种潜伏的酶原在细胞中合成，需要裂解其原域才能发挥蛋白水解活性。成熟的alphav整合素亚基也可以通过对alphav亚基前体（前alphav）的蛋白内溶裂解产生。furin的裂解被认为是MT1-MMP和pro-alphav激活的主要事件。为了阐明MT1-MMP和pro-alphav的替代激活途径，我们使用了furin阴性的LoVo细胞，它们共同表达MT1-MMP和整合素alphavbeta3。在这些细胞中，MT1-MMP前酶通过非常规的Brefeldin a抗性途径迅速运输到质膜上，然后在细胞表面进行自催化处理。接下来，MT1-MMP活性将细胞表面相关的前α - α转化为以二硫键重链和轻链为代表的成熟α - α整合素，并促进功能性整合素α - α β 3异源二聚体的形成。这些事件刺激了体外细胞的运动，以及体内恶性肿瘤的侵袭和肿瘤的生长。我们的数据表明，在furin阴性的结肠癌细胞中，MT1-MMP被自催化加工，活性蛋白酶随后作为整合素前转化酶起作用。我们的研究结果有力地证明furin的加工并不是MT1-MMP激活的先决条件。
Understanding the function of invasion-promoting membrane type-1 matrix metalloproteinase (MT1-MMP) is of paramount importance for understanding cancer biology. MT1-MMP is synthesized in cells as a latent zymogen that requires the cleavage of its prodomain to exert the proteolytic activity. The mature alphav integrin subunit is also generated by endoproteolytic cleavage of the alphav subunit precursor (pro-alphav). Cleavage by furin is considered to be a principal event in the activation of both MT1-MMP and pro-alphav. To elucidate the alternative activation pathway of MT1-MMP and pro-alphav, we employed furin-negative LoVo cells, which co-express MT1-MMP with integrin alphavbeta3. In these cells the MT1-MMP proenzyme was rapidly trafficked to the plasma membrane via an unconventional Brefeldin A-resistant pathway and, then, autocatalytically processed on the cell surface. Next, the MT1-MMP activity converted the cell surface-associated pro-alphav into the mature alphav integrin, represented by the disulfide-bonded heavy and light chains, and promoted the formation of the functional integrin alphavbeta3 heterodimer. These events stimulated cell motility in vitro, and malignant invasion and tumor growth in vivo. Our data suggest that in furin-negative colon carcinoma cells MT1-MMP is autocatalytically processed and the active protease then operates as a prointegrin convertase. Our findings argue strongly that the processing by furin is not a prerequisite for the activation of MT1-MMP.