Huttenlocher A, Palecek S P, Lu Q, Zhang W, Mellgren R L, Lauffenburger D A, Ginsberg M H, Horwitz A F
Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
J Biol Chem. 1997 Dec 26;272(52):32719-22. doi: 10.1074/jbc.272.52.32719.
Integrin receptors play an important role during cell migration by mediating linkages and transmitting forces between the extracellular matrix and the actin cytoskeleton. The mechanisms by which these linkages are regulated and released during migration are not well understood. We show here that cell-permeable inhibitors of the calcium-dependent protease calpain inhibit both beta1 and beta3 integrin-mediated cell migration. Calpain inhibition specifically stabilizes peripheral focal adhesions, increases adhesiveness, and decreases the rate of cell detachment. Furthermore, these inhibitors alter the fate of integrin receptors at the rear of the cell during migration. A Chinese hamster ovary cell line expressing low levels of calpain I also shows reduced migration rates with similar morphological changes, further implicating calpain in this process. Taken together, the data suggest that calpain inhibition modulates cell migration by stabilizing cytoskeletal linkages and decreasing the rate of retraction of the cell's rear. Inhibiting calpain-mediated proteolysis may therefore be a potential therapeutic approach to control pathological cell migration such as tumor metastasis.
整合素受体在细胞迁移过程中通过介导细胞外基质与肌动蛋白细胞骨架之间的连接并传递力发挥重要作用。在迁移过程中这些连接如何被调节和释放的机制尚未完全了解。我们在此表明，钙依赖性蛋白酶钙蛋白酶的细胞可渗透抑制剂抑制β1和β3整合素介导的细胞迁移。钙蛋白酶抑制特异性地稳定外周粘着斑，增加粘附性，并降低细胞脱离速率。此外，这些抑制剂在迁移过程中改变细胞后部整合素受体的命运。表达低水平钙蛋白酶I的中国仓鼠卵巢细胞系也显示出迁移速率降低并伴有类似的形态学变化，进一步表明钙蛋白酶参与此过程。综上所述，数据表明钙蛋白酶抑制通过稳定细胞骨架连接和降低细胞后部回缩速率来调节细胞迁移。因此，抑制钙蛋白酶介导的蛋白水解可能是控制病理性细胞迁移如肿瘤转移的潜在治疗方法。
