White Eric S, Atrasz Rachelle G, Dickie Emily G, Aronoff David M, Stambolic Vuk, Mak Tak W, Moore Bethany B, Peters-Golden Marc
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, 6301 MSRB III/0642, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0642, USA.
Am J Respir Cell Mol Biol. 2005 Feb;32(2):135-41. doi: 10.1165/rcmb.2004-0126OC. Epub 2004 Nov 11.
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.
在纤维增生性肺病患者的肺成纤维细胞中存在增强的迁移表型。前列腺素E(2)（PGE(2)）可抑制成纤维细胞迁移，但介导此作用的受体和机制尚不清楚。我们的数据证实，用PGE(2)处理人肺成纤维细胞可抑制其迁移。E-前列腺素（EP）2受体特异性配体布他前列素的类似作用表明，EP2受体参与迁移抑制信号传导。此外，EP2受体缺陷的成纤维细胞的迁移不能被PGE(2)或布他前列素抑制，这证实了EP2在介导这些效应中的核心作用。我们之前的数据表明，10号染色体上的磷酸酶和张力蛋白同源物（PTEN），一种对抗磷脂酰肌醇-3-激酶（PI3K）作用的磷酸酶，可能在调节肺成纤维细胞运动中起重要作用。我们现在报告，PGE(2)和布他前列素均可增加PTEN磷酸酶活性，而PTEN蛋白水平并未随之增加。这有助于EP2介导的迁移抑制，因为PTEN基因敲除的成纤维细胞中的迁移同样不受EP2受体信号传导的影响。对EP2刺激的反应中PTEN活性增加与PTEN上酪氨酸磷酸化减少有关，这是一种已知的调节酶活性的机制。总的来说，这些数据描述了一个新的机制发现，即PGE(2)通过EP2受体降低PTEN上的酪氨酸磷酸化，导致PTEN酶活性增加并抑制成纤维细胞迁移。
