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TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling

Nature Cell Biology volume 4, pages 648–657 (2002)Cite this article

Abstract

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the formation of hamartomas in a wide range of human tissues. Mutation in either the TSC1 or TSC2 tumour suppressor gene is responsible for both the familial and sporadic forms of this disease. TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1–TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1–TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). Furthermore, TSC2 is directly phosphorylated by Akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. TSC2 is inactivated by Akt-dependent phosphorylation, which destabilizes TSC2 and disrupts its interaction with TSC1. Our data indicate a molecular mechanism for TSC2 in insulin signalling, tumour suppressor functions and in the inhibition of cell growth.

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Figure 1: Inhibition of S6K by TSC1–TSC2.
Figure 2: Effects of endogenous TSC2 and disease-derived mutations on phosphorylation of S6K.
Figure 3: Phosphorylation of TSC2 by Akt.
Figure 4: Determination of Akt-dependent phosphorylation sites in TSC2.
Figure 5: Mutation of Akt phosphorylation sites alters TSC2 activity.
Figure 6: TSC1–TSC2 inhibits nutrient-stimulated phosphorylation of S6K and 4E-BP1.
Figure 7: TSC1–TSC2 functions through mTOR to inhibit S6K.

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Acknowledgements

We are indebted to J. Blenis, Y. Xiong, and S. Schreiber for providing cDNAs. We thank T. Xu for personal communication. We also thank E. Tang and H.G. Vikis for critical reading of the manuscript, and B. Chia for construction of TSC2 fragment 1 and fragment 2 plasmids. This work was supported by grants from the National Institutes of Health and the Walther Cancer Institute.

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  1. Department of Biological Chemistry, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, 48109, MI, USA

    Ken Inoki, Yong Li, Tianquan Zhu, Jun Wu & Kun-Liang Guan

  2. The Institute of Gerontology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, 48109, MI, USA

    Kun-Liang Guan

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Inoki, K., Li, Y., Zhu, T. et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4, 648–657 (2002). https://doi.org/10.1038/ncb839

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