Fridman R, Toth M, Peña D, Mobashery S
Department of Pathology, Wayne State University, Detroit, Michigan 48201, USA.
Cancer Res. 1995 Jun 15;55(12):2548-55.
The M(r) 72,000 (MMP-2; gelatinase A) and M(r) 92,000 (MMP-9; gelatinase B) gelatinases are two members of the family of matrix metalloproteinases (MMPs). These proteinases are thought to play a critical role in tumor cell invasion and are frequently coexpressed in human cancers. Gelatinases are secreted in a latent inactive form, and their conversion to the active species can be accomplished by other proteolytic enzymes, including other MMPs. We report herein that organomercurial or plasma membrane-activated M(r) 72,000 gelatinase A activates progelatinase B to an M(r) 82,000 active form in a process inhibited by tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Progelatinase B activation was accomplished by the two active species of gelatinase A, the M(r) 62,000 and M(r) 45,000 forms, generated after plasma membrane or organomercurial activation of TIMP-2-free progelatinase A. The M(r) 45,000 species of gelatinase A lacks both the NH2-terminal profragment and the COOH-terminal domain known to play a role in plasma membrane activation and the regulation of TIMP-2 inhibition. These results suggest a novel mechanism of activation of progelatinase B mediated by gelatinase A species that may be localized in the surface of tumor cells and enhance matrix degradation during cancer metastasis.
分子量为72,000（基质金属蛋白酶-2；明胶酶A）和分子量为92,000（基质金属蛋白酶-9；明胶酶B）的明胶酶是基质金属蛋白酶（MMPs）家族的两个成员。这些蛋白酶被认为在肿瘤细胞侵袭中起关键作用，且在人类癌症中经常共同表达。明胶酶以潜在的无活性形式分泌，它们向活性形式的转化可由其他蛋白水解酶完成，包括其他基质金属蛋白酶。我们在此报告，有机汞或质膜激活的分子量为72,000的明胶酶A在金属蛋白酶组织抑制剂（TIMP）-1和TIMP-2抑制的过程中将前明胶酶B激活为分子量为82,000的活性形式。前明胶酶B的激活是由明胶酶A的两种活性形式完成的，即无TIMP-2的前明胶酶A经质膜或有机汞激活后产生的分子量为62,000和分子量为45,000的形式。分子量为45,000的明胶酶A既缺乏已知在质膜激活和TIMP-2抑制调节中起作用的NH2末端前肽段，也缺乏COOH末端结构域。这些结果提示了一种由可能定位于肿瘤细胞表面的明胶酶A介导的前明胶酶B激活的新机制，该机制可能在癌症转移过程中增强基质降解。
