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Science 294 (5548): 1942-1945

Copyright © 2001 by the American Association for the Advancement of Science

Phosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling

Yimin Fang, Montserrat Vilella-Bach, Rebecca Bachmann, Asa Flanigan, Jie Chen*

The mammalian target of rapamycin (mTOR) governs cell growth and proliferation by mediating the mitogen- and nutrient-dependent signal transduction that regulates messenger RNA translation. We identified phosphatidic acid (PA) as a critical component of mTOR signaling. In our study, mitogenic stimulation of mammalian cells led to a phospholipase D-dependent accumulation of cellular PA, which was required for activation of mTOR downstream effectors. PA directly interacted with the domain in mTOR that is targeted by rapamycin, and this interaction was positively correlated with mTOR's ability to activate downstream effectors. The involvement of PA in mTOR signaling reveals an important function of this lipid in signal transduction and protein synthesis, as well as a direct link between mTOR and mitogens. Furthermore, these studies suggest a potential mechanism for the in vivo actions of the immunosuppressant rapamycin.

Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, 601 South Goodwin Avenue, B107, Urbana, IL 61801, USA.
*   To whom correspondence should be addressed. E-mail: jiechen{at}uiuc.edu

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Understanding phospholipase D (PLD) using leukocytes: PLD involvement in cell adhesion and chemotaxis.
J. Gomez-Cambronero, M. Di Fulvio, and K. Knapek (2007)
J. Leukoc. Biol. 82, 272-281
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Lipin1 Regulation by Estrogen in Uterus and Liver: Implications for Diabetes and Fertility.
P. M. Gowri, S. Sengupta, S. Bertera, and B. S. Katzenellenbogen (2007)
Endocrinology 148, 3685-3693
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Systemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs p53-Deficient Tumor Cell Growth.
M. Buzzai, R. G. Jones, R. K. Amaravadi, J. J. Lum, R. J. DeBerardinis, F. Zhao, B. Viollet, and C. B. Thompson (2007)
Cancer Res. 67, 6745-6752
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The Mammalian Target of Rapamycin Pathway as a Potential Target for Cancer Chemoprevention.
L. Kopelovich, J. R. Fay, C. C. Sigman, and J. A. Crowell (2007)
Cancer Epidemiol. Biomarkers Prev. 16, 1330-1340
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Interleukin-8 Signaling Promotes Translational Regulation of Cyclin D in Androgen-Independent Prostate Cancer Cells.
C. F. MacManus, J. Pettigrew, A. Seaton, C. Wilson, P. J. Maxwell, S. Berlingeri, C. Purcell, M. McGurk, P. G. Johnston, and D. J.J. Waugh (2007)
Mol. Cancer Res. 5, 737-748
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Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia.
S. M. Chan, A. P. Weng, R. Tibshirani, J. C. Aster, and P. J. Utz (2007)
Blood 110, 278-286
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Phospholipase D2-derived phosphatidic acid binds to and activates ribosomal p70 S6 kinase independently of mTOR.
N. Lehman, B. Ledford, M. Di Fulvio, K. Frondorf, L. C. McPhail, and J. Gomez-Cambronero (2007)
FASEB J 21, 1075-1087
   Abstract »    Full Text »    PDF »
Insulin Controls Subcellular Localization and Multisite Phosphorylation of the Phosphatidic Acid Phosphatase, Lipin 1.
T. E. Harris, T. A. Huffman, A. Chi, J. Shabanowitz, D. F. Hunt, A. Kumar, and J. C. Lawrence Jr. (2007)
J. Biol. Chem. 282, 277-286
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