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Originally published In Press as doi:10.1074/jbc.M504045200 on May 19, 2005

J. Biol. Chem., Vol. 280, Issue 28, 26089-26093, July 15, 2005
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Identification of S6 Kinase 1 as a Novel Mammalian Target of Rapamycin (mTOR)-phosphorylating Kinase*

Marina K. Holz and John Blenis{ddagger}

From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Here we demonstrate that mammalian target of rapamycin (mTOR) is phosphorylated in a rapamycin-sensitive manner. We show that S6 kinase 1 (S6K1), but not Akt, directly phosphorylates mTOR in cell-free in vitro system and in cells. Expression of a constitutively active, rapamycin- and wortmannin-resistant S6K1 leads to constitutive phosphorylation of mTOR, whereas knock-down of S6K1 using small inhibitory RNA greatly reduces mTOR phosphorylation despite elevated Akt activity. Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 gene, but not in a less tumorigenic cell line, MCF10a. Many models for Akt signaling to mTOR have been presented, suggesting direct phosphorylation by Akt. These models must be reconsidered in light of the present findings.

Received for publication, April 13, 2005 , and in revised form, May 17, 2005.

* This work was supported by National Institutes of Health Grants GM051405 and CA046595. 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.

{ddagger} To whom correspondence should be addressed: Dept. of Cell Biology, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115. Tel.: 617-432-4848; Fax: 617-432-1144; E-mail: jblenis{at}hms.harvard.edu.


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