Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta(1) integrin activity.
Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta(1) integrin activity.
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DOI：
10.1083/jcb.200508204
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发表时间：
2006-05-22
影响因子：
7.8
通讯作者：
Negishi, Manabu
中科院分区：
文献类型：
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作者：
Oinuma, Izumi;Katoh, Hironori;Negishi, Manabu
丛蛋白是信号蛋白的细胞表面受体，调节许多细胞类型的细胞迁移。我们最近报道了信号蛋白 4D (Sema4D) 受体 Plexin-B1 作为 R-Ras 的 GTP 酶激活蛋白 (GAP)，R-Ras 是 Ras 家族 GTP 酶的成员，参与整合素活性和细胞迁移的调节 (Oinuma, I., Y. Ishikawa, H. Katoh, and M. Negishi. 2004. Science. 305:862–865)。我们表征了 Sema4D/Plexin-B1 下游的 R-Ras 在细胞迁移中的作用。 Sema4D 激活 Plexin-B1 可抑制 ECM 依赖性 R-Ras 激活、R-Ras 介导的磷脂酰肌醇 3-激酶激活以及通过其 R-Ras GAP 结构域的 β1 整联蛋白激活，从而抑制细胞迁移。此外，通过 R-Ras 特异性 GAP 的过度表达或通过 RNA 干扰敲低 R-Ras 来灭活 R-Ras 足以抑制响应 ECM 刺激的 β1 整合素激活和细胞迁移。因此，我们得出结论，R-Ras 活性对于 ECM 介导的 β1 整联蛋白激活和细胞迁移至关重要，并且 Sema4D/Plexin-B1 介导的 R-Ras GAP 活性使 R-Ras 失活通过调节 β1 整联蛋白的活性来控制细胞迁移。
Plexins are cell surface receptors for semaphorins and regulate cell migration in many cell types. We recently reported that the semaphorin 4D (Sema4D) receptor Plexin-B1 functions as a GTPase-activating protein (GAP) for R-Ras, a member of Ras family GTPases implicated in regulation of integrin activity and cell migration (Oinuma, I., Y. Ishikawa, H. Katoh, and M. Negishi. 2004. Science. 305:862–865). We characterized the role of R-Ras downstream of Sema4D/Plexin-B1 in cell migration. Activation of Plexin-B1 by Sema4D suppressed the ECM-dependent R-Ras activation, R-Ras–mediated phosphatydylinositol 3-kinase activation, and β1 integrin activation through its R-Ras GAP domain, leading to inhibition of cell migration. In addition, inactivation of R-Ras by overexpression of the R-Ras–specific GAP or knockdown of R-Ras by RNA interference was sufficient for suppressing β1 integrin activation and cell migration in response to the ECM stimulation. Thus, we conclude that R-Ras activity is critical for ECM-mediated β1 integrin activation and cell migration and that inactivation of R-Ras by Sema4D/Plexin-B1–mediated R-Ras GAP activity controls cell migration by modulating the activity of β1 integrins.