Prostaglandin E2 induced functional expression of early growth response factor-1 by EP4, but not EP2, prostanoid receptors via the phosphatidylinositol 3-kinase and extracellular signal-regulated kinases
Prostaglandin E2 induced functional expression of early growth response factor-1 by EP4, but not EP2, prostanoid receptors via the phosphatidylinositol 3-kinase and extracellular signal-regulated kinases
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DOI：
10.1074/jbc.m212665200
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发表时间：
2003-04-04
影响因子：
4.8
通讯作者：
Regan, JW
中科院分区：
文献类型：
--
作者：
Fujino, H;Xu, W;Regan, JW
前列腺素E - 2（PGE(2)）通过与称为EP受体的G蛋白偶联受体亚家族相互作用来介导其生理效应。这些受体由四种主要亚型组成，分别命名为EP1、EP2、EP3和EP4。已知EP2和EP4亚型与Gα(s)偶联并刺激细胞内环3,5 - 腺苷一磷酸的形成，而EP1和EP3受体分别已知与Gα(q)和Gα(i)偶联。最近我们发现EP2和EP4受体能够激活T细胞因子信号传导；然而，EP2受体主要通过一种依赖环腺苷酸依赖性蛋白激酶的途径来实现这一点，而EP4受体则主要利用一种依赖磷脂酰肌醇3 - 激酶（PI3K）的途径（藤野，H.，韦斯特，K.A.，和里根，J.W.（2002年）《生物化学杂志》277卷，2614 - 2619页）。我们现在报道，PGE(2)对EP4受体（而非EP2受体）的刺激通过一种依赖PI3K的机制导致细胞外信号调节激酶（ERKs）的磷酸化。此外，EP4受体对PI3K/ERK信号传导的这种激活诱导早期生长反应因子 - 1（EGR - 1）的功能性表达。在相同条件下，PGE(2)刺激EP2受体后未观察到EGR - 1蛋白表达的诱导。这些发现指出了EP2和EP4受体在信号传导潜能方面的重要差异，这对于EP4受体在炎症和癌症中的潜在参与可能具有重要意义。
Prostaglandin E-2 (PGE(2)) mediates its physiological effects by interactions with a subfamily of G-protein-coupled receptors known as EP receptors. These receptors consist of four primary subtypes named EP, EP2, EP3, and EP4. The EP2 and EP4 subtypes are known to couple to Galpha(s) and stimulate intracellular cyclic 3,5-adenosine monophosphate formation, whereas the EP1 and EP3 receptors are known to couple to Galpha(q) and Galpha(i), respectively. Recently we found that EP2 and EP4 receptors can activate T-cell factor signaling; however, EP2 receptors did this primarily through a cAMP-dependent protein kinase-dependent pathway, whereas EP4 receptors primarily utilized a phosphatidylinositol 3-kinase (PI3K)-dependent pathway (Fujino, H., West, K. A., and Regan, J. W. (2002) J. Biol. Chem. 277, 2614-2619). We now report that PGE(2) stimulation of EP4 receptors, but not EP2 receptors, leads to phosphorylation of the extracellular signal-regulated kinases (ERKs) through a PI3K-dependent mechanism. Furthermore, this activation of PI3K/ERK signaling by the EP4 receptors induces the functional expression of early growth response factor-1 (EGR-1). Under the same conditions induction of EGR-1 protein expression was not observed following PGE(2) stimulation of EP2 receptors. These findings point to important differences in the signaling potential of the EP2 and EP4 receptors, which could be significant with respect to the potential involvement of EP4 receptors in inflammation and cancer.