Proteolytic action of kallikrein-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal hemopexin domains.
Proteolytic action of kallikrein-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal hemopexin domains.
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DOI：
10.1016/j.bbamcr.2011.05.007
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Haun RS
中科院分区：
文献类型：
--
作者：
Ramani VC;Kaushal GP;Haun RS
明胶酶、基质金属蛋白酶 (MMP)-9 和 -2 是作为潜在的、无活性的酶产生的，可以被许多蛋白酶通过蛋白水解激活。在许多正常和病理条件下，MMP 的表达失调，其他蛋白酶的表达也会发生变化。人激肽释放酶相关肽酶 7 (KLK7) 是一种类似胰凝乳蛋白酶的丝氨酸蛋白酶，在许多不同类型的肿瘤病症中过度表达，并且还显示出高水平的 MMP-9 和 -2 表达。由于从未检查过 KLK7 对 MMP 的激活，因此我们试图确定 KLK7 是否可以激活这些 MMP。为了检验这一假设，将 KLK7 与重组 MMP 一起孵育，并分析反应产物的活性。 proMMP-9 与 KLK7 一起孵育，产生了一种新型截短的活性 MMP-9，缺乏 C 端血红素结合蛋白结构域。相反，KLK7 降解但不激活 proMMP-2。使用由表达 MMP-9 的细胞系 MDA-MMP-9 制备的条件培养基进一步证实了 KLK7 对 proMMP-9 的新激活。我们的结果清楚地表明，KLK7 激活 proMMP-9 以产生其他蛋白酶不产生的新型截短的活性 MMP-9 产物。这些发现表明，KLK7 可能在表达高水平这两种蛋白酶的肿瘤中的 MMP-9 激活中发挥重要作用，并且与其他蛋白酶激活的全长 MMP-9 相比，所得截短的 MMP 可能具有改变的底物特异性。
The gelatinases, matrix metalloproteinase (MMP)-9 and -2, are produced as latent, inactive enzymes that can be proteolytically activated by a number of proteases. In many normal and pathological conditions, where the expression of MMPs is deregulated, changes in the expression of other proteases have also been reported. Human kallikrein-related peptidase 7 (KLK7), a chymotryptic-like serine protease, is overexpressed in many different types of neoplastic conditions, which have also been shown to express high levels of both MMP-9 and -2. Since the activation of MMPs by KLK7 has never been examined, we sought to determine whether KLK7 can activate these MMPs. To test this hypothesis KLK7 was incubated with the recombinant MMPs and the products of the reaction were analyzed for their activity. Incubation of proMMP-9 with KLK7 resulted in the production of a novel truncated, active MMP-9 lacking the C-terminal hemopexin domains. In contrast, KLK7 degraded, but did not activate, proMMP-2. The novel activation of proMMP-9 by KLK7 was further confirmed using conditioned medium prepared from an MMP-9-expressing cell line, MDA-MMP-9. Our results clearly establish that KLK7 activates proMMP-9 to produce a novel truncated, active MMP-9 product not generated by other proteases. These findings suggest that KLK7 may play an important role in the activation of MMP-9 in tumors that express high levels of both these proteases and the resulting truncated MMP may possess altered substrate specificities compared with full-length MMP-9 activated by other proteases.
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