Prostaglandin E(2) inhibits fibroblast migration by E-prostanoid 2 receptor-mediated increase in PTEN activity.
Prostaglandin E(2) inhibits fibroblast migration by E-prostanoid 2 receptor-mediated increase in PTEN activity.
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DOI：
10.1165/rcmb.2004-0126oc
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发表时间：
2005-02
影响因子：
6.4
通讯作者：
E. White;Rachelle G Atrasz;E. G. Dickie;D. Aronoff;V. Stambolic;T. Mak;B. Moore;M. Peters-Golden
中科院分区：
文献类型：
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作者：
E. White;Rachelle G Atrasz;E. G. Dickie;D. Aronoff;V. Stambolic;T. Mak;B. Moore;M. Peters-Golden
在来自纤维增生性肺病患者的肺成纤维细胞中存在增加的迁移表型。前列腺素E（2）（PGE（2））抑制成纤维细胞迁移，但受体和介导这种作用的机制尚不清楚。我们的数据证实，用PGE（2）处理人肺成纤维细胞抑制迁移。布他前列素（一种E-前列腺素（EP）2受体特异性配体）的类似作用表明EP 2受体参与了迁移抑制信号传导。此外，缺乏EP 2受体的成纤维细胞的迁移不能被PGE（2）或布他前列素抑制，证实了EP 2在介导这些效应中的核心作用。我们以前的数据表明，磷酸酶和张力蛋白同源物的染色体10（PTEN），磷酸酶，反对磷脂酰肌醇-3-激酶（PI 3 K）的行动，可能是重要的调节肺成纤维细胞的运动。我们现在报道PGE（2）和布他前列素都增加了PTEN磷酸酶活性，而没有伴随着PTEN蛋白水平的增加。这有助于EP 2介导的迁移抑制，因为PTEN缺失的成纤维细胞中的迁移同样不受EP 2受体信号传导的影响。响应于EP 2刺激而增加的PTEN活性与PTEN上的酪氨酸磷酸化降低相关，这是已知的调节酶活性的机制。总的来说，这些数据描述了新的机制发现，即PGE（2）通过EP 2受体降低PTEN上的酪氨酸磷酸化，导致PTEN酶活性增加和成纤维细胞迁移的抑制。
An increased migratory phenotype exists in lung fibroblasts derived from patients with fibroproliferative lung disease. Prostaglandin E(2) (PGE(2)) suppresses fibroblast migration, but the receptor(s) and mechanism(s) mediating this action are unknown. Our data confirm that treatment of human lung fibroblasts with PGE(2) inhibits migration. Similar effects of butaprost, an E-prostanoid (EP) 2 receptor-specific ligand, implicate the EP2 receptor in migration-inhibitory signaling. Further, migration in fibroblasts deficient for the EP2 receptor cannot be inhibited by PGE(2) or butaprost, confirming the central role of EP2 in mediating these effects. Our previous data suggested that phosphatase and tensin homolog on chromosome ten (PTEN), a phosphatase that opposes the actions of phosphatidylinositol-3-kinase (PI3K), may be important in regulating lung fibroblast motility. We now report that both PGE(2) and butaprost increase PTEN phosphatase activity, without a concomitant increase in PTEN protein levels. This contributes to EP2-mediated migration inhibition, because migration in PTEN-null fibroblasts is similarly unaffected by EP2 receptor signaling. Increased PTEN activity in response to EP2 stimulation is associated with decreased tyrosine phosphorylation on PTEN, a mechanism known to regulate enzyme activity. Collectively, these data describe the novel mechanistic finding that PGE(2), via the EP2 receptor, decreases tyrosine phosphorylation on PTEN, resulting in increased PTEN enzyme activity and inhibition of fibroblast migration.