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Molecular and Cellular Biology, August 2009, p. 4308-4324, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01665-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Site-Specific mTOR Phosphorylation Promotes mTORC1-Mediated Signaling and Cell Growth {triangledown}

Hugo A. Acosta-Jaquez,1 Jennifer A. Keller,1 Kathryn G. Foster,1 Bilgen Ekim,1 Ghada A. Soliman,1,2 Edward P. Feener,4 Bryan A. Ballif,3 and Diane C. Fingar1,2*

Department of Cell and Developmental Biology,1 Department of Medicine, Division of Metabolism, Endocrinology, and Diabetes, 109 Zina Pitcher Place, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200,2 Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215,4 Department of Biology and Vermont Genetics Network Proteomics Facility, University of Vermont, 311 March Life Science Building, Burlington, Vermont 054053

Received 27 October 2008/ Returned for modification 15 December 2008/ Accepted 22 May 2009

The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) functions as a rapamycin-sensitive environmental sensor that promotes cellular biosynthetic processes in response to growth factors and nutrients. While diverse physiological stimuli modulate mTORC1 signaling, the direct biochemical mechanisms underlying mTORC1 regulation remain poorly defined. Indeed, while three mTOR phosphorylation sites have been reported, a functional role for site-specific mTOR phosphorylation has not been demonstrated. Here we identify a new site of mTOR phosphorylation (S1261) by tandem mass spectrometry and demonstrate that insulin-phosphatidylinositol 3-kinase signaling promotes mTOR S1261 phosphorylation in both mTORC1 and mTORC2. Here we focus on mTORC1 and show that TSC/Rheb signaling promotes mTOR S1261 phosphorylation in an amino acid-dependent, rapamycin-insensitive, and autophosphorylation-independent manner. Our data reveal a functional role for mTOR S1261 phosphorylation in mTORC1 action, as S1261 phosphorylation promotes mTORC1-mediated substrate phosphorylation (e.g., p70 ribosomal protein S6 kinase 1 [S6K1] and eukaryotic initiation factor 4E binding protein 1) and cell growth to increased cell size. Moreover, Rheb-driven mTOR S2481 autophosphorylation and S6K1 phosphorylation require S1261 phosphorylation. These data provide the first evidence that site-specific mTOR phosphorylation regulates mTORC1 function and suggest a model whereby insulin-stimulated mTOR S1261 phosphorylation promotes mTORC1 autokinase activity, substrate phosphorylation, and cell growth.

* Corresponding author. Mailing address: Department of Cell and Developmental Biology, 109 Zina Pitcher Place, University of Michigan Medical School, Ann Arbor, MI 48109-2200. Phone: (734) 763-7541. Fax: (734) 763-1166. E-mail: dfingar{at}umich.edu

{triangledown} Published ahead of print on 1 June 2009.

Molecular and Cellular Biology, August 2009, p. 4308-4324, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01665-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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