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Sci. Signal., 22 February 2011
Vol. 4, Issue 161, p. ra10
[DOI: 10.1126/scisignal.2001731]

RESEARCH ARTICLES

ER Stress Inhibits mTORC2 and Akt Signaling Through GSK-3β–Mediated Phosphorylation of Rictor

Chien-Hung Chen1,2, Tattym Shaikenov1, Timothy R. Peterson3,4, Rakhan Aimbetov1,5, Amangeldy K. Bissenbaev5, Szu-Wei Lee1,2, Juan Wu1, Hui-Kuan Lin1,2, and Dos D. Sarbassov1,2*

1 Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2 The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
3 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
4 Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
5 Department of Genetics and Molecular Biology, Al-Farabi Kazakh National University, Almaty 050038, Kazakhstan.

Abstract: In response to environmental cues, cells coordinate a balance between anabolic and catabolic pathways. In eukaryotes, growth factors promote anabolic processes and stimulate cell growth, proliferation, and survival through activation of the phosphoinositide 3-kinase (PI3K)–Akt pathway. Akt-mediated phosphorylation of glycogen synthase kinase–3β (GSK-3β) inhibits its enzymatic activity, thereby stimulating glycogen synthesis. We show that GSK-3β itself inhibits Akt by controlling the mammalian target of rapamycin complex 2 (mTORC2), a key activating kinase for Akt. We found that during cellular stress, GSK-3β phosphorylated the mTORC2 component rictor at serine-1235, a modification that interfered with the binding of Akt to mTORC2. The inhibitory effect of GSK-3β on mTORC2-Akt signaling and cell proliferation was eliminated by blocking phosphorylation of rictor at serine-1235. Thus, in response to cellular stress, GSK-3β restrains mTORC2-Akt signaling by specifically phosphorylating rictor, thereby balancing the activities of GSK-3β and Akt, two opposing players in glucose metabolism.

* To whom correspondence should be addressed. E-mail: dsarbass{at}mdanderson.org

Citation: C.-H. Chen, T. Shaikenov, T. R. Peterson, R. Aimbetov, A. K. Bissenbaev, S.-W. Lee, J. Wu, H.-K. Lin, D. D. Sarbassov, ER Stress Inhibits mTORC2 and Akt Signaling Through GSK-3β–Mediated Phosphorylation of Rictor. Sci. Signal. 4, ra10 (2011).

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