Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase

J. Avruch, K. Hara, Y. Lin, M. Liu, X. Long, S. Ortiz-Vega, K. Yonezawa

Research output: Contribution to journalReview article

234 Citations (Scopus)

Abstract

Target of Rapamycin (TOR), a giant protein kinase expressed by all eucaryotic cells, controls cell size in response to nutrient signals. In metazoans, cell and organismal growth is controlled by nutrients and the insulin/insulin-like growth factor (IGF) system, and the understanding of how these inputs coordinately regulate TOR signaling has advanced greatly in the past 5 years. In single-cell eucaryotes and Caenorhabditis elegans, TOR is a dominant regulator of overall mRNA translation, whereas in higher metazoans, TOR controls the expression of a smaller fraction of mRNAs that is especially important to cell growth. TOR signals through two physically distinct multiprotein complexes, and the control of cell growth is mediated primarily by TOR complex 1 (TORC1), which contains the polypeptides raptor and LST8. Raptor is the substrate binding element of TORC1, and the ability of raptor to properly present substrates, such as the translational regulators 4E-BP and p70 S6 kinase, to the TOR catalytic domain is essential for their TOR-catalysed phosphorylation, and is inhibited by the Rapamycin/FKBP-12 complex. The dominant proximal regulator of TORC1 signaling and kinase activity is the ras-like small GTPase Rheb. Rheb binds directly to the mTOR catalytic domain, and Rheb-GTP enables TORC1 to attain an active configuration. Insulin/IGF enhances Rheb GTP charging through the ability of activated Akt to inhibit the Rheb-GTPase-activating function of the tuberous sclerosis heterodimer (TSC1/TSC2). Conversely, energy depletion reduces Rheb-GTP charging through the ability of the adenosine monophosphate-activated protein kinase to phosphorylate TSC2 and stimulate its Rheb-GTPase activating function, as well as by HIFα-mediated transcriptional responses that act upstream of the TSC1/2 complex. Amino-acid depletion inhibits TORC1 acting predominantly downstream of the TSC complex, by interfering with the ability of Rheb to bind to mTOR. The components of the insulin/IGF pathway to TORC1 are now well established, whereas the elements mediating the more ancient and functionally dominant input of amino acids remain largely unknown.

Original languageEnglish
Pages (from-to)6361-6372
Number of pages12
JournalOncogene
Volume25
Issue number48
DOIs
Publication statusPublished - 2006 Oct 16

Fingerprint

GTP Phosphohydrolases
Sirolimus
Phosphotransferases
Insulin
Amino Acids
Raptors
Somatomedins
Guanosine Triphosphate
Protein Kinases
Catalytic Domain
Growth
Tacrolimus Binding Protein 1A
70-kDa Ribosomal Protein S6 Kinases
Multiprotein Complexes
Food
Tuberous Sclerosis
Monomeric GTP-Binding Proteins
Caenorhabditis elegans
Protein Biosynthesis
Adenosine Monophosphate

Keywords

  • Leucine
  • Raptor
  • Rheb
  • S6K
  • TOR
  • TSC

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Avruch, J., Hara, K., Lin, Y., Liu, M., Long, X., Ortiz-Vega, S., & Yonezawa, K. (2006). Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene, 25(48), 6361-6372. https://doi.org/10.1038/sj.onc.1209882

Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. / Avruch, J.; Hara, K.; Lin, Y.; Liu, M.; Long, X.; Ortiz-Vega, S.; Yonezawa, K.

In: Oncogene, Vol. 25, No. 48, 16.10.2006, p. 6361-6372.

Research output: Contribution to journalReview article

Avruch, J, Hara, K, Lin, Y, Liu, M, Long, X, Ortiz-Vega, S & Yonezawa, K 2006, 'Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase', Oncogene, vol. 25, no. 48, pp. 6361-6372. https://doi.org/10.1038/sj.onc.1209882
Avruch, J. ; Hara, K. ; Lin, Y. ; Liu, M. ; Long, X. ; Ortiz-Vega, S. ; Yonezawa, K. / Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. In: Oncogene. 2006 ; Vol. 25, No. 48. pp. 6361-6372.
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