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J. Biol. Chem., Vol. 280, Issue 27, 25485-25490, July 8, 2005
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From the Program in Signal Transduction Research, The Burnham Institute, La Jolla, California 92037
The mammalian target of rapamycin (mTOR) coordinates cell growth with the growth factor and nutrient/energy status of the cell. The phosphatidylinositol 3-kinase-AKT pathway is centrally involved in the transmission of mitogenic signals to mTOR. Previous studies have shown that mTOR is a direct substrate for the AKT kinase and identified Ser-2448 as the AKT target site in mTOR. In this study, we demonstrate that rapamycin, a specific inhibitor of mTOR function, blocks serum-stimulated Ser-2448 phosphorylation and that this drug effect is not explained by the inhibition of AKT. Furthermore, the phosphorylation of Ser-2448 was dependent on mTOR kinase activity, suggesting that mTOR itself or a protein kinase downstream from mTOR was responsible for the modification of Ser-2448. Here we show that p70S6 kinase phosphorylates mTOR at Ser-2448 in vitro and that ectopic expression of rapamycin-resistant p70S6 kinase restores Ser-2448 phosphorylation in rapamycin-treated cells. In addition, we show that cellular amino acid status, which modulates p70S6 kinase (S6K1) activity via the TSC/Rheb pathway, regulates Ser-2448 phosphorylation. Finally, small interfering RNA-mediated depletion of p70S6 kinase reduces Ser-2448 phosphorylation in cells. Taken together, these results suggest that p70S6 kinase is a major effector of mTOR phosphorylation at Ser-2448 in response to both mitogen- and nutrient-derived stimuli.
Received for publication, February 15, 2005 , and in revised form, April 26, 2005.
* This work was supported in part by Grants CA76193 and CA52995 (to R. T. A.) from the NCI, National Institutes of 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.
Supported by a Kirschstein-NRSA Fellowship F32 CA099354 from the NCI, National
Institutes of Health. To whom correspondence should be addressed: Program in
Signal Transduction Research, The Burnham Institute, 10901 N. Torrey Pines
Road, La Jolla, CA 92037. Tel.: 858-646-3100 (ext. 3943); Fax: 858-713-6274;
E-mail:
gchiang{at}burnham.org.
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