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J. Biol. Chem., Vol. 281, Issue 37, 26904-26913, September 15, 2006
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AKT-independent Phosphorylation of TSC2 and Activation of mTOR and Ribosomal Protein S6 Kinase Signaling by Prostaglandin F2
*
¶1
From the
Olson Center for Women's Health, Departments of Obstetrics and Gynecology, and Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3255, the Serono Research Institute, Rockland, Massachusetts 02370, and the ¶Department of Veterans Affairs Medical Center, Omaha, Nebraska 68105
Prostaglandin F2
(PGF2) 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 binds to a G-proteincoupled 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 stimulates the mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase 1 (S6K1) signaling pathway in steroidogenic luteal cells. We demonstrate that PGF2 treatment results in a timeand concentration-dependent stimulation of the phosphorylation and activation of S6K1. The stimulation of S6K1 in response to PGF2 treatment was abolished by the mTOR inhibitor rapamycin. Treatment with PGF2 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 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 m7G cap binding assays, and the phosphorylation and synthesis of S6) were completely sensitive to treatment with rapamycin, implicating mTOR in the actions of PGF2. Taken together, our data suggest that GPCR activation in response to PGF2 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-target tissues.
Received for publication, June 5, 2006
* This work was supported in part by the Dept. of Veterans Affairs, National Institutes of Health Grant RO1HD38813, and the Olson Center for Women's Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: 983255 Nebraska Medical Center, Omaha, NE 68189-3255. Tel.: 402-559-9079; Fax: 402-559-7126; E-mail: jsdavis{at}unmc.edu.
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