Epidermal growth factor-regulated activation of Rac GTPase enhances CD44 cleavage by metalloproteinase disintegrin ADAM10
Epidermal growth factor-regulated activation of Rac GTPase enhances CD44 cleavage by metalloproteinase disintegrin ADAM10
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DOI：
10.1042/bj20050582
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发表时间：
2006-04-01
影响因子：
4.1
通讯作者：
Sako, Y
中科院分区：
文献类型：
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作者：
Murai, T;Miyauchi, T;Sako, Y
侵袭性肿瘤细胞，如胶质瘤，经常高水平表达EGF(表皮生长因子)受体，它们对EGF的反应表现出增强的细胞迁移。我们先前报道，肿瘤细胞的迁移与CD44的胞外裂解有关，CD44是参与肿瘤侵袭和转移的主要黏附分子，而CD44的连接促进了这种裂解。在目前的研究中，我们发现EGF促进CD44的裂解和CD44依赖的细胞迁移。导入显性负突变的小GTP酶rac1或RNAi(RNA干扰)耗尽rac1可阻断EGF诱导的CD44裂解。用MEK(丝裂原活化蛋白激酶/细胞外信号调节激酶)的抑制剂PD98059处理也能抑制CD44的裂解。此外，RNAi研究表明，EGF诱导了依赖于CD44的ADAM 10(一种去整合素和金属蛋白酶10)的切割和细胞迁移。这些结果表明，EGF通过激活Rac1和丝裂原活化蛋白激酶，诱导ADAM10介导的CD44裂解，从而促进肿瘤细胞的迁移和侵袭。
Invasive tumour cells, such as gliomas, frequently express EGF (epidermal growth factor) receptor at a high level and they exhibit enhanced cell migration in response to EGF We reported previously that tumour cell migration is associated with ectodomain cleavage of CD44, the major adhesion molecule that is implicated in tumour invasion and metastasis, and that the cleavage is enhanced by ligation of CD44. In the present Study, we show that EGF promotes CD44 cleavage and CD44-dependent cell migration. Introduction of a dominant-negative mutant of the small GTPase Rac1 or depletion of Rac1 by RNAi (RNA interference) abrogated CD44 cleavage induced by EGF. Treatment with PD98059, an inhibitor for MEK (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase), also suppressed the CD44 cleavage. Furthermore, RNAi studies showed that EGF induced ADAM 10 (a disintegrin and metalloproteinase 10)-dependent CD44 cleavage and cell migration. These results indicate that EGF induces ADAM10-mediated CD44 cleavage through Rac1 and mitogen-activated protein kinase activation, and thereby promotes tumour cell migration and invasion.