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J. Biol. Chem., Vol. 280, Issue 11, 10091-10099, March 18, 2005

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Modulation of the Mammalian Target of Rapamycin Pathway by Diacylglycerol Kinase-produced Phosphatidic Acid^*

Antonia Ávila-Flores, Teresa Santos, Esther Rincón, and Isabel Mérida

From the Department of Immunology and Oncology, National Centre for Biotechnology, Consejo Superior de Investigaciones Científicas, Campus Cantoblanco, E-28049 Madrid, Spain

The protein known as mammalian target of rapamycin (mTOR) regulates cell growth by integrating different stimuli, such as available nutrients and mitogenic factors. The lipid messenger phosphatidic acid (PA) binds and positively regulates the mitogenic response of mTOR. PA generator enzymes are consequently potential regulators of mTOR. Here we explored the contribution to this pathway of the enzyme diacylglycerol kinase (DGK), which produces PA through phosphorylation of diacylglycerol. We found that overexpression of the DGK, but not of the isoform, in serum-deprived HEK293 cells induced mTOR-dependent phosphorylation of p70S6 kinase (p70S6K). After serum addition, p70S6K phosphorylation was higher and more resistant to rapamycin treatment in cells overexpressing DGK. The effect of this DGK isoform on p70S6K hyperphosphorylation required the mTOR PA binding region. Down-regulation of endogenous DGK by small interfering RNA in HEK293 cells diminished serum-induced p70S6K phosphorylation, highlighting the role of this isoform in the mTOR pathway. Our results confirm a role for PA in mTOR regulation and describe a novel pathway in which DGK-derived PA acts as a mediator of mTOR signaling.

Received for publication, October 29, 2004 , and in revised form, December 28, 2004.

^* This work was supported by Grant BMC2001-1066 from the Spanish Ministry of Science and Technology, Grant 08.37002272002 from the Comunidad de Madrid, and Grant G037179 from the Instituto de Salud Carlos III. 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 should be addressed. Tel.: 34-91-585-4665; Fax: 34-91-372-0493; E-mail: imerida{at}cnb.uam.es.

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