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Molecular and Cellular Biology, June 2008, p. 4104-4115, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.00289-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The TSC1-TSC2 Complex Is Required for Proper Activation of mTOR Complex 2{triangledown}

Jingxiang Huang, Christian C. Dibble, Mika Matsuzaki, and Brendan D. Manning*

Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115

Received 20 February 2008/ Returned for modification 18 March 2008/ Accepted 1 April 2008

The mammalian target of rapamycin (mTOR) is a protein kinase that forms two functionally distinct complexes important for nutrient and growth factor signaling. Both complexes phosphorylate a hydrophobic motif on downstream protein kinases, which contributes to the activation of these kinases. mTOR complex 1 (mTORC1) phosphorylates S6K1, while mTORC2 phosphorylates Akt. The TSC1-TSC2 complex is a critical negative regulator of mTORC1. However, how mTORC2 is regulated and whether the TSC1-TSC2 complex is involved are unknown. We find that mTORC2 isolated from a variety of cells lacking a functional TSC1-TSC2 complex is impaired in its kinase activity toward Akt. Importantly, the defect in mTORC2 activity in these cells can be separated from effects on mTORC1 signaling and known feedback mechanisms affecting insulin receptor substrate-1 and phosphatidylinositol 3-kinase. Our data also suggest that the TSC1-TSC2 complex positively regulates mTORC2 in a manner independent of its GTPase-activating protein activity toward Rheb. Finally, we find that the TSC1-TSC2 complex can physically associate with mTORC2 but not mTORC1. These data demonstrate that the TSC1-TSC2 complex inhibits mTORC1 and activates mTORC2, which through different mechanisms promotes Akt activation.

* Corresponding author. Mailing address: Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. Phone: (617) 432-5614. Fax: (617) 432-5236. E-mail: bmanning{at}hsph.harvard.edu

{triangledown} Published ahead of print on 14 April 2008.

Molecular and Cellular Biology, June 2008, p. 4104-4115, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.00289-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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