Molecular mechanism of inhibition of cell motility

鞘氨醇-1-磷酸（S1 P）是一种具有生物活性的溶血磷脂，可在多种细胞类型中诱导多种生物学反应。这些反应中的许多由S1 P受体S1P_1/EDG 1、S1P_3/EDG 3和S1P_2/EDG 5介导。我们以前的研究表明，S1P_2/EDG_5通过G_1<12>和G_2<13>蛋白介导胰岛素样生长因子-I（IGF-I）诱导的Rac活化和细胞迁移，而S1P_1/EDG_1和S1P_3/EDG_3单独通过G_1蛋白介导Rac活化和细胞迁移。然而，G_1<12>和G_2<13>蛋白如何在S1P_2/EDG 5信号转导中介导Rac抑制和细胞迁移尚不清楚。我们发现，用C3毒素预处理（使Rho失活）和显性阴性Rho A的表达可以阻止S1 P_2/EDG 5介导的Rac抑制和细胞迁移。另一方面，组成型活性Rho的表达抑制IGF-I诱导的Rac活化和细胞迁移。然而，Rho激酶抑制剂不影响S1P_2/EDG 5介导的Rac抑制或细胞迁移。这些结果表明，Rho，而不是Rho激酶，介导抑制Rac活性和细胞运动性对刺激S1P_2/EDG 5。

Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that induces a variety of biological responses in diverse cell types. Many of these responses are mediated by S1P receptors, S1P_1/EDG1, S1P_3/EDG3, and S1P_2/EDG5. We previously showed that S1P_2/EDG5, via G_<12> and G_<13> proteins, mediated inhibiton of insulin-like growth factor-I (IGF-I)-induced Rac activation and cell migration, whereas S1P_1/EDG1 and S1P_3/EDG3 each alone, via G_1 protein, mediated Rac activation and stimulation of cell migration. However, it is not known how G_<12> and G_<13> proteins mediate inhibition of Rac and cell migration in S1P_2/EDG5 signaling. We found that the pretreatment with C3 toxin, which inactivates Rho, and the expresson of dominat negative Rho A prevented S1P_2/EDG5-mediated inhibition of Rac and cell migration. On other hand, the expression of constitutively active Rho inhibited IGF-I induced Rac activation and cell migration. However, Rho kinase inhibitors did not affect S1P_2/EDG5-mediated inhibition of Rac or cell migration. These results indicate that Rho, but not Rho kinase, mediates inhibition of Rac activity and cell mobility on stimulation of S1P_2/EDG5.