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Regulation of TORC1 by Rag GTPases in nutrient response

Nature Cell Biology volume 10, pages 935–945 (2008)Cite this article

Abstract

TORC1 (target of rapamycin complex 1) has a crucial role in the regulation of cell growth and size. A wide range of signals, including amino acids, is known to activate TORC1. Here, we report the identification of Rag GTPases as activators of TORC1 in response to amino acid signals. Knockdown of Rag gene expression suppressed the stimulatory effect of amino acids on TORC1 in Drosophila melanogaster S2 cells. Expression of constitutively active (GTP-bound) Rag in mammalian cells activated TORC1 in the absence of amino acids, whereas expression of dominant-negative Rag blocked the stimulatory effects of amino acids on TORC1. Genetic studies in Drosophila also show that Rag GTPases regulate cell growth, autophagy and animal viability during starvation. Our studies establish a function of Rag GTPases in TORC1 activation in response to amino acid signals.

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Figure 1: dRagA and dRagC are activators of TORC1 in Drosophila S2 cells.
Figure 2: Mammalian Rag GTPases regulate TORC1 activity.
Figure 3: Rag GTPases are involved in the response to amino acids.
Figure 4: dRagA and dRagC promote cell and organ growth in Drosophila.
Figure 5: Relationship between Rag and components of the TOR pathway.
Figure 6: Rag GTPases act in parallel with Rheb to promote fat body cell growth.
Figure 7: Regulation of autophagy by Rag.
Figure 8: High dRagA activity sensitizes Drosophila to starvation.

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Acknowledgements

The authors wish to thank Ken Inoki for discussions and Mary Stewart for the dS6K antibody. This work is supported by NIH grants to K.L.G. (GM62694 and CA108941) and T.P.N. (GM62509).

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Author notes

  1. Eunjung Kim

    Present address: Current address: Department of Food Sciences and Nutrition, Catholic University of Daegu, Gyeongsan, Korea.,

  2. Eunjung Kim and Pankuri Goraksha-Hicks: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, 92093-081, CA, USA

    Eunjung Kim, Li Li & Kun-Liang Guan

  2. Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    Pankuri Goraksha-Hicks & Thomas P. Neufeld

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Contributions

K.L.G. conceived the idea of GTPase screen; K.L.G. and E.K. designed, and E.K. performed, the screen and mammalian experiments; P.G.H. and T.P.N. designed and performed the Drosophila experiments with the assistance of E.K.; L.L. performed the LC3 experiments; K.L.G. and T.P.N. coordinated the study; K.L.G., E.K., P.G.H. and T.P.N. wrote the paper; all authors commented on the manuscript.

Note: Supplementary Information is available on the Nature Cell Biology website.

Corresponding authors

Correspondence to Thomas P. Neufeld or Kun-Liang Guan.

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Supplementary Figures S1, S2, S3, S4, S5, S6 and Supplementary Methods (PDF 2401 kb)

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Kim, E., Goraksha-Hicks, P., Li, L. et al. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10, 935–945 (2008). https://doi.org/10.1038/ncb1753

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