Regulation of TORC1 by Rag GTPases in Nutrient Response

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2008 Jul 8

PMID 18604198

Citations 756

Authors

Eunjung Kim

Pankuri Goraksha-Hicks

Li Li

Thomas P Neufeld

Kun-Liang Guan

Affiliations

Soon will be listed here.

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.

Citing Articles

Retinoic Acid Promotes Neuronal Differentiation While Increasing Proteins and Organelles Related to Autophagy.

Lazzeri G, Lenzi P, Signorini G, Raffaelli S, Giammattei E, Natale G Int J Mol Sci. 2025; 26(4).

PMID: 40004155 PMC: 11855701. DOI: 10.3390/ijms26041691.

Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.

Kiraly S, Stanley J, Eden E Antioxidants (Basel). 2025; 14(2).

PMID: 40002312 PMC: 11852311. DOI: 10.3390/antiox14020125.

Determination of Nutrient Ligand-Sensor Binding Affinity.

Gu X Methods Mol Biol. 2025; 2882:163-178.

PMID: 39992509 DOI: 10.1007/978-1-0716-4284-9_8.

Energy metabolism in health and diseases.

Liu H, Wang S, Wang J, Guo X, Song Y, Fu K Signal Transduct Target Ther. 2025; 10(1):69.

PMID: 39966374 PMC: 11836267. DOI: 10.1038/s41392-025-02141-x.

STAT6 mutations compensate for CREBBP mutations and hyperactivate IL4/STAT6/RRAGD/mTOR signaling in follicular lymphoma.

Shao Q, Bedi K, Malek I, Shedden K, Malek S Leukemia. 2025; .

PMID: 39910284 DOI: 10.1038/s41375-025-02525-6.

References

Thomas G . The S6 kinase signaling pathway in the control of development and growth. Biol Res. 2002; 35(2):305-13. DOI: 10.4067/s0716-97602002000200022. View

Shigemitsu K, Tsujishita Y, Hara K, NANAHOSHI M, Avruch J, Yonezawa K . Regulation of translational effectors by amino acid and mammalian target of rapamycin signaling pathways. Possible involvement of autophagy in cultured hepatoma cells. J Biol Chem. 1999; 274(2):1058-65. DOI: 10.1074/jbc.274.2.1058. View

Oldham S, Montagne J, Radimerski T, Thomas G, Hafen E . Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev. 2000; 14(21):2689-94. PMC: 317036. DOI: 10.1101/gad.845700. View

Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg M, Hall A . Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004; 6(11):1122-8. DOI: 10.1038/ncb1183. View

Potter C, Pedraza L, Xu T . Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol. 2002; 4(9):658-65. DOI: 10.1038/ncb840. View

Long X, Ortiz-Vega S, Lin Y, Avruch J . Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J Biol Chem. 2005; 280(25):23433-6. DOI: 10.1074/jbc.C500169200. View

Gingras A, Kennedy S, OLeary M, Sonenberg N, Hay N . 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev. 1998; 12(4):502-13. PMC: 316523. DOI: 10.1101/gad.12.4.502. View

Byfield M, Murray J, Backer J . hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem. 2005; 280(38):33076-82. DOI: 10.1074/jbc.M507201200. View

Radimerski T, Montagne J, Hemmings-Mieszczak M, Thomas G . Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. Genes Dev. 2002; 16(20):2627-32. PMC: 187466. DOI: 10.1101/gad.239102. View

10.

Sekiguchi T, Hirose E, Nakashima N, Ii M, Nishimoto T . Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J Biol Chem. 2000; 276(10):7246-57. DOI: 10.1074/jbc.M004389200. View

11.

Sarbassov D, Guertin D, Ali S, Sabatini D . Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307(5712):1098-101. DOI: 10.1126/science.1106148. View

12.

Wullschleger S, Loewith R, Hall M . TOR signaling in growth and metabolism. Cell. 2006; 124(3):471-84. DOI: 10.1016/j.cell.2006.01.016. View

13.

Noda T, Ohsumi Y . Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998; 273(7):3963-6. DOI: 10.1074/jbc.273.7.3963. View

14.

Hay N, Sonenberg N . Upstream and downstream of mTOR. Genes Dev. 2004; 18(16):1926-45. DOI: 10.1101/gad.1212704. View

15.

Britton J, Lockwood W, Li L, Cohen S, Edgar B . Drosophila's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Dev Cell. 2002; 2(2):239-49. DOI: 10.1016/s1534-5807(02)00117-x. View

16.

Blommaart E, Luiken J, Blommaart P, Van Woerkom G, Meijer A . Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem. 1995; 270(5):2320-6. DOI: 10.1074/jbc.270.5.2320. View

17.

Juhasz G, Erdi B, Sass M, Neufeld T . Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev. 2007; 21(23):3061-6. PMC: 2081972. DOI: 10.1101/gad.1600707. View

18.

Hara K, Yonezawa K, Weng Q, Kozlowski M, Belham C, Avruch J . Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem. 1998; 273(23):14484-94. DOI: 10.1074/jbc.273.23.14484. View

19.

Schurmann A, Brauers A, Massmann S, Becker W, Joost H . Cloning of a novel family of mammalian GTP-binding proteins (RagA, RagBs, RagB1) with remote similarity to the Ras-related GTPases. J Biol Chem. 1995; 270(48):28982-8. DOI: 10.1074/jbc.270.48.28982. View

20.

Nakashima N, Noguchi E, Nishimoto T . Saccharomyces cerevisiae putative G protein, Gtr1p, which forms complexes with itself and a novel protein designated as Gtr2p, negatively regulates the Ran/Gsp1p G protein cycle through Gtr2p. Genetics. 1999; 152(3):853-67. PMC: 1460653. DOI: 10.1093/genetics/152.3.853. View