Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

GTP-Binding Protein Rheb

  • Jeffrey J. HeardEmail author
  • Fuyuhiko Tamanoi
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101614



Historical Background

Ras homolog enriched in brain (Rheb) plays a significant role in regulating protein synthesis, cell growth, cell cycle, and autophagy (Aspuria and Tamanoi 2004; Heard et al. 2014). Deregulation of Rheb signaling has been shown to cause diseases ranging from developmental disorders to cancer. Rheb was initially discovered as a protein sharing strong homology with Ras and whose expression was rapidly induced in brain neuronal cell by increased synaptic activity (Yamagata et al. 1994). Since then, Rheb has been shown to be widely expressed and to be conserved in eukaryotes from yeast to human. Higher eukaryotes express two Rheb proteins, Rheb1 and Rheb2 (RhebL1). Two separate genes encode these proteins that share 74% similarity. Their functions appear similar, but their tissue expression profiles differ significantly. Rheb is a member of the Ras superfamily of GTP-binding proteins that act as molecular switches in the cell to...

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  1. Aspuria PJ, Tamanoi F. The Rheb family of GTP-binding proteins. Cell Signal. 2004;16:1105–12.PubMedCrossRefGoogle Scholar
  2. Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE [Internet]. 2004;2004(250):RE13.Google Scholar
  3. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell. 2003;11:1457–66.PubMedCrossRefGoogle Scholar
  4. Grabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, et al. A diverse array of cancer-associated mTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 2014;4:554–63.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Heard JJ, Fong V, Bathaie SZ, Tamanoi F. Recent progress in the study of the Rheb family GTPases. Cell Signal. 2014;26:1950–7.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Hsu YC, Chern JJ, Cai Y, Liu M, Choi KW. Drosphila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature. 2007;445:785–8.PubMedCrossRefGoogle Scholar
  7. Im E, von Lintig FC, Chen J, Zhuang S, Qui W, Chowdhury S, et al. Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene. 2002;21:6356–65.PubMedCrossRefGoogle Scholar
  8. Inoki K, Li Y, Xu T, Guan K-L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17:1829–34.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Karbowniczek M, Cash T, Cheung M, Robertson GP, Astrinidis A, Henske EP. Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. J Biol Chem. 2004;279:29930–7.PubMedCrossRefGoogle Scholar
  10. Lacher MD, Pincheira R, Zhu Z, Camoretti-Mercado B, Matli M, Warren RS, et al. Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis. Oncogene. 2010;29:6543–56.PubMedCrossRefGoogle Scholar
  11. Mazhab-Jafari MT, Marshall CB, Ishiyama N, Ho J, Di Palma V, Stambolic V, et al. An autoinhibited noncanonical mechanism of GTP hydrolysis by Rheb maintains mTORC1 homeostasis. Structure. 2012;20:1528–39.PubMedCrossRefGoogle Scholar
  12. Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ, Takahashi H, et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell. 2014;156:771–85.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Patel PH, Thapar N, Guo L, Martinez M, Maris J, Gau C-L, et al. Drosophila Rheb GTPase is required for cell cycle progression and cell growth. J Cell Sci. 2003;116:3601–10.PubMedCrossRefGoogle Scholar
  14. Sato T, Nakashima A, Guo L, Tamanoi F. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J Biol Chem. 2009;284:12783–91.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Sato T, Akasu H, Shimono W, Matsu C, Fujiwara Y, Shibagaki Y, et al. Rheb protein binds CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase) protein in a GTP- and effector domain-dependent manner and influences its cellular localization and carbamoyl-phosphate synthetase (CPSase) activity. J Biol Chem. 2015;290:1096–105.PubMedCrossRefGoogle Scholar
  16. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol. 2003;5:566–71.PubMedCrossRefGoogle Scholar
  17. Urano J, Tabancay AP, Yang W, Tamanoi F. The Saccharomyces cerevisiae Rheb G-protein is involved in regulating canavanine resistance and arginine uptake. J Biol Chem. 2000;275:11198–206.PubMedCrossRefGoogle Scholar
  18. Wang Y, Hong X, Wang J, Yin Y, Zhang Y, Zhou Y, et al. Inhibition of MAPK pathway is essential for suppressing Rheb-Y35N driven tumor growth. Oncogene. 2017;36:756–65.PubMedCrossRefGoogle Scholar
  19. Yamagata K, Sanders LK, Kaufmannn WE, Yee W, Barnes CA, Nathans D, et al. Rheb, a growth factor- and synaptic acticity-regulated gene, encodes a novel Ras-related protein. J Biol Chem. 1994;269:16333–9.PubMedPubMedCentralGoogle Scholar
  20. Yu Y, Li S, Xu X, Li Y, Guan K, Arnold E, et al. Structural basis for the unique biological function of small GTPase RHEB. J Biol Chem. 2005;280:17093–100.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Molecular Biology Institute, University of CaliforniaLos AngelesUSA
  2. 2.Department of Microbiology, Immunology and Molecular GeneticsUniversity of CaliforniaLos AngelesUSA