PTEN as an effector in the signaling of antimigratory G protein-coupled receptor
PTEN as an effector in the signaling of antimigratory G protein-coupled receptor
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DOI：
10.1073/pnas.0409784102
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发表时间：
2005-03-22
影响因子：
11.1
通讯作者：
Hla, T
中科院分区：
文献类型：
--
作者：
Sanchez, T;Thangada, S;Hla, T
PTEN是一种肿瘤抑制性磷酸酶，在调节细胞迁移和侵袭中起重要作用。尚未描述细胞表面受体对PTEN（10号染色体上缺失的磷酸酶和张力蛋白同源物）的生理调节。在这里，我们表明，生物活性脂质鞘氨醇1-磷酸（S1 P），它通过S1 P2受体（S1 P2 R）G蛋白偶联受体（GPCR）抑制细胞迁移，利用PTEN作为信号中间体。S1 P2 R对细胞迁移的抑制被显性阴性的PTEN表达废除。S1 P不能有效地抑制Pten（Delta loxP/Delta loxP）小鼠胚胎成纤维细胞的迁移;然而，在PTEN表达后，恢复了抗迁移作用。Pten（Delta loxP/Delta loxP）细胞中Rho GTdR的S1 P2 R活化不受影响，显性阴性Rho GTdR逆转WT细胞中但Pten（Delta loxP/Delta loxP）细胞中细胞迁移的S1 P抑制，表明PTEN在Rho GTdR下游起作用。S1 P2 R受体的配体激活刺激S1 P2 R和PTEN的免疫共沉淀。有趣的是，S1 P2 R信号增加了膜组分中的PTEN磷酸酶活性。此外，S1 P2 R信号刺激了PTEN的酪氨酸磷酸化。这些数据表明，S1 P2 R受体通过Rho GTP酶依赖性途径主动调节PTEN磷酸酶以抑制细胞迁移。GPCR对PTEN的调控可能是细胞迁移和侵袭信号转导的一种普遍机制。
PTEN, a tumor suppressor phosphatase, is important in the regulation of cell migration and invasion. Physiological regulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) by cell surface receptors has not been described. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P), which acts through the S1P2 receptor (S1P2R) G protein-coupled receptor (GPCR) to inhibit cell migration, utilizes PTEN as a signaling intermediate. S1P2R inhibition of cell migration is abrogated by dominant-negative PTEN expression. S1P was unable to efficiently inhibit the migration of Pten(Delta loxP/Delta loxP) mouse embryonic fibroblasts; however, the antimigratory effect was restored upon the expression of PTEN. S1P2R activation of Rho GTPase is not affected in Pten(Delta loxP/Delta loxP) cells, and dominant-negative Rho GTPase reversed S1P inhibition of cell migration in WT cells but not in Pten(Delta loxP/Delta loxP) cells, suggesting that PTEN acts downstream of the Rho GTPase. Ligand activation of the S1P2R receptor stimulated the coimmunoprecipitation of S1P2R and PTEN. Interestingly, S1P2R signaling increased PTEN phosphatase activity in membrane fractions. Furthermore, tyrosine phosphorylation of PTEN was stimulated by S1P2R signaling. These data suggest that the S1P2R receptor actively regulates the PTEN phosphatase by a Rho GTPase-dependent pathway to inhibit cell migration. GPCR regulation of PTEN maybe a general mechanism in signaling events of cell migration and invasion.