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Integrity of mTORC2 is dependent on the rictor Gly-934 site

Oncogene volume 31, pages 2115–2120 (2012)Cite this article

Abstract

Growth factor signaling coupled to activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway plays a crucial role in the regulation of cell proliferation and survival. The key regulatory kinase of Akt has been identified as mammalian target of rapamycin complex 2 (mTORC2), which functions as the PI3K-dependent Ser-473 kinase of Akt. This kinase complex is assembled by mTOR and its essential components rictor, Sin1 and mLST8. The recent genetic screening study in Caenorhabditis elegans has linked a specific point mutation of rictor to an elevated storage of fatty acids that resembles the rictor deficiency phenotype. In our study, we show that in mammalian cells the analogous single rictor point mutation (G934E) prevents the binding of rictor to Sin1 and the assembly of mTORC2, but this mutation does not interfere with the binding of the rictor-interacting protein Protor. A substitution of the rictor Gly-934 residue to a charged amino acid prevents formation of the rictor/Sin1 heterodimer. The cells expressing the rictor G934E mutant remain deficient in the mTORC2 signaling, as detected by the reduced phosphorylation of Akt on Ser-473 and a low cell proliferation rate. Thus, although a full length of rictor is required to interact with its binding partner Sin1, a single amino acid of rictor Gly-934 controls its interaction with Sin1 and assembly of mTORC2.

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Acknowledgements

This study was supported by the MD Anderson Trust Fellow Fund and NIH grant CA133522 (DDS). R Aimbetov and O Bulgakova have been partially supported by the Ph.D. training grants from Kazakhstan. We are thankful to our laboratory member Dr Tattym Shaikenov for providing the Akt substrate. We are also thankful to Dr Dario Alessi (University of Dundee, Dundee, England) for providing the Protor 1α expression plasmid.

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    R Aimbetov, C-H Chen, O Bulgakova, D Abetov & D D Sarbassov

  2. Department of Genetics and Molecular Biology, al-Farabi Kazakh National University, Almaty, Kazakhstan

    R Aimbetov, D Abetov & A K Bissenbaev

  3. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    C-H Chen & D D Sarbassov

  4. Department of Natural Sciences, The LN Gumilyov Eurasian National University, Astana, Kazakhstan

    O Bulgakova & R I Bersimbaev

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  1. R Aimbetov
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  2. C-H Chen
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  3. O Bulgakova
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  4. D Abetov
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  5. A K Bissenbaev
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  6. R I Bersimbaev
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  7. D D Sarbassov
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Correspondence to D D Sarbassov.

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Aimbetov, R., Chen, CH., Bulgakova, O. et al. Integrity of mTORC2 is dependent on the rictor Gly-934 site. Oncogene 31, 2115–2120 (2012). https://doi.org/10.1038/onc.2011.404

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