AKT-independent phosphorylation of TSC2 and activation of mTOR and ribosomal protein S6 kinase signaling by prostaglandin F2α
AKT-independent phosphorylation of TSC2 and activation of mTOR and ribosomal protein S6 kinase signaling by prostaglandin F2α
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DOI：
10.1074/jbc.m605371200
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发表时间：
2006-09-15
影响因子：
4.8
通讯作者：
Davis, John S.
中科院分区：
文献类型：
--
作者：
Arvisais, Edward W.;Romanelli, Angela;Davis, John S.
前列腺素F2 α（PGF 2 α）是黄体（CL）消退的重要介质，尽管介导这一过程的细胞信号事件尚未明确确定。已确定PGF 2 α与G蛋白偶联受体（GPCR）结合，刺激黄体细胞中的蛋白激酶C（PKC）和Raf-MEK-Erk信号传导。进行本实验以确定PGF 2 α是否刺激类固醇生成黄体细胞中的哺乳动物雷帕霉素靶蛋白（mTOR）/核糖体蛋白S6激酶1（S6 K1）信号通路。我们证明，PGF 2 α治疗的结果在时间和浓度依赖性刺激的磷酸化和激活的S6 K1。mTOR抑制剂雷帕霉素消除了对PGF 2 α处理的S6 K1刺激。用PGF 2 α治疗没有增加AKT磷酸化，但增加了Erk和肿瘤抑制蛋白结节性硬化症复合物2（TSC 2）的磷酸化，TSC 2是mTOR的上游调节因子。PGF 2 α的作用被PKC激活剂PMA模拟，并被MEK 1抑制剂U 0126抑制。mTOR/S6 K1的激活和假定的涉及翻译装置的下游过程（即4 EBP 1磷酸化、m（7）G帽结合试验中4 EBP 1结合的释放以及S6的磷酸化和合成）对雷帕霉素处理完全敏感，表明mTOR参与PGF 2 α的作用。综上所述，我们的数据表明，GPCR激活响应PGF 2 α刺激mTOR途径，增加黄体细胞中的翻译机制。在mTOR控制下的蛋白质翻译可能对黄体发育和退化有影响，并为PGF 2 α靶组织的治疗干预提供了新的策略。
Prostaglandin F2 alpha (PGF2 alpha) is an important mediator of corpus luteum (CL) regression, although the cellular signaling events that mediate this process have not been clearly identified. It is established that PGF2 alpha binds to a G-protein-coupled receptor (GPCR) to stimulate protein kinase C (PKC) and Raf-MEK-Erk signaling in luteal cells. The present experiments were performed to determine whether PGF2 alpha stimulates the mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase 1 (S6K1) signaling pathway in steroidogenic luteal cells. We demonstrate that PGF2 alpha treatment results in a time- and concentration-dependent stimulation of the phosphorylation and activation of S6K1. The stimulation of S6K1 in response to PGF2 alpha treatment was abolished by the mTOR inhibitor rapamycin. Treatment with PGF2 alpha did not increase AKT phosphorylation but increased the phosphorylation of Erk and the tumor suppressor protein tuberous sclerosis complex 2 (TSC2), an upstream regulator of mTOR. The effects of PGF2 alpha were mimicked by the PKC activator PMA and inhibited by U0126, a MEK1 inhibitor. The activation of mTOR/S6K1 and putative down stream processes involving the translational apparatus (i.e. 4EBP1 phosphorylation, release of 4EBP1 binding in m(7)G cap binding assays, and the phosphorylation and synthesis of S6) were completely sensitive to treatment with rapamycin, implicating mTOR in the actions of PGF2 alpha. Taken together, our data suggest that GPCR activation in response to PGF2 alpha stimulates the mTOR pathway which increases the translational machinery in luteal cells. The translation of proteins under the control of mTOR may have implications for luteal development and regression and offer new strategies for therapeutic intervention in PGF2 alpha-target tissues.