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J. Biol. Chem., Vol. 280, Issue 20, 19937-19947, May 20, 2005

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The Mammalian Target of Rapamycin-p70 Ribosomal S6 Kinase but Not Phosphatidylinositol 3-Kinase-Akt Signaling Is Responsible for Fibroblast Growth Factor-9-induced Cell Proliferation^*

Lih-Yuh C. Wing, Hsiu-Mei Chen, Pei-Chin Chuang¶, Meng-Hsing Wu||, and Shaw-Jenq Tsai¶**

From the Department of Physiology, the ^¶Institute of Basic Medical Sciences, and the ^||Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China

Fibroblast growth factor-9 (FGF9) is a potent mitogen that stimulates normal and cancer cell proliferation though the signaling mechanism is not fully understood. In this study, we aimed to unravel the signaling cascades mediate FGF9 actions in human uterine endometrial stromal cell. Our results demonstrate that the mitogenic effect of FGF9 is transduced via two parallel but additive signaling pathways involving mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase. Activation of mTOR by FGF9 induces p70 ribosomal S6 kinase (S6K1) phosphorylation, cyclin expression, and cell proliferation, which are independent of phosphatidylinositol 3-kinase and Akt. Coimmunoprecipitation analysis demonstrates that mTOR physically associates with S6K1 upon FGF9 treatment, whereas ablation of mTOR activity using RNA interference or pharmacological inhibitor blocks S6K1 phosphorylation and cell proliferation induced by FGF9. Further study demonstrates that activation of mTOR is regulated by a phospholipase C-controlled calcium signaling pathway. These studies provide evidence to demonstrate, for the first time, that a novel signaling cascade involving phospholipase C, calcium, mTOR, and S6K1 is activated by FGF9 in a receptor-specific manner.

Received for publication, October 19, 2004 , and in revised form, March 2, 2005.

^* This work was supported by National Science Council of the Republic of China, Taiwan, Grants NSC 92-2320-B006-080 (to S.-J. T.) and NSC 92-2320-B006-038 (to L.-Y. C. W.). 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.

To whom correspondence may be addressed: Dept. of Physiology, National Cheng Kung University Medical College, Tainan, Taiwan, Republic of China. Fax: 886-6-236-2780; E-mail: wing{at}mail.ncku.edu.tw. ** To whom correspondence may be addressed: Dept. of Physiology, National Cheng Kung University Medical College, Tainan 701, Taiwan, Republic of China. Fax: 886-6-236-2780; E-mail: seantsai{at}mail.ncku.edu.tw.

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