This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Toschi, A.
Right arrow Articles by Foster, D. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Toschi, A.
Right arrow Articles by Foster, D. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2009, p. 1411-1420, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.00782-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Regulation of mTORC1 and mTORC2 Complex Assembly by Phosphatidic Acid: Competition with Rapamycin{triangledown}

Alfredo Toschi, Evan Lee, Limei Xu, Avalon Garcia, Noga Gadir, and David A. Foster*

Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065

Received 15 May 2008/ Returned for modification 14 July 2008/ Accepted 17 December 2008

mTOR, the mammalian target of rapamycin, is a critical node for control of cell growth and survival and has widely been implicated in cancer survival signals. mTOR exists in two complexes: mTORC1 and mTORC2. Phospholipase D (PLD) and its metabolite phosphatidic acid (PA) have been implicated in the regulation of mTOR; however, their role has been controversial. We report here that suppression of PLD prevents phosphorylation of the mTORC1 substrate S6 kinase (S6K) at Thr389 and the mTORC2 substrate Akt at Ser473. Suppression of PLD also blocked insulin-stimulated Akt phosphorylation at Ser473 and the mTORC2-dependent phosphorylation of PRAS40. Importantly, PA was required for the association of mTOR with Raptor to form mTORC1 and that of mTOR with Rictor to form mTORC2. The effect of PA was competitive with rapamycin—with much higher concentrations of rapamycin needed to compete with the PA-mTORC2 interaction than with PA-mTORC1. Suppressing PA production substantially increased the sensitivity of mTORC2 to rapamycin. Data provided here demonstrate a PA requirement for the stabilization of both mTORC1 and mTORC2 complexes and reveal a mechanism for the inhibitory effect of rapamycin on mTOR. This study also suggests that by suppressing PLD activity, mTORC2 could be targeted therapeutically with rapamycin.

* Corresponding author. Mailing address: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY 10065. Phone: (212) 772-4075. Fax: (212) 772-5227. E-mail: foster{at}genectr.hunter.cuny.edu

{triangledown} Published ahead of print on 29 December 2008.

Molecular and Cellular Biology, March 2009, p. 1411-1420, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.00782-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Laplante, M., Sabatini, D. M. (2009). mTOR signaling at a glance. J. Cell Sci. 122: 3589-3594 [Full Text]  
  • Jin, N., Jiang, T., Rosen, D. M., Nelkin, B. D., Ball, D. W. (2009). Dual Inhibition of Mitogen-Activated Protein Kinase Kinase and Mammalian Target of Rapamycin in Differentiated and Anaplastic Thyroid Cancer. J. Clin. Endocrinol. Metab. 94: 4107-4112 [Abstract] [Full Text]  
  • Yu, K., Toral-Barza, L., Shi, C., Zhang, W.-G., Lucas, J., Shor, B., Kim, J., Verheijen, J., Curran, K., Malwitz, D. J., Cole, D. C., Ellingboe, J., Ayral-Kaloustian, S., Mansour, T. S., Gibbons, J. J., Abraham, R. T., Nowak, P., Zask, A. (2009). Biochemical, Cellular, and In vivo Activity of Novel ATP-Competitive and Selective Inhibitors of the Mammalian Target of Rapamycin. Cancer Res. 69: 6232-6240 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»