Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Tadayuki ShimadaEmail author
  • Hiroko Sugiura
  • Kanato Yamagata
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101555


Historical Background

Rheb (Ras homologue enriched in brain) was originally identified as a small guanosine triphosphate (GTP)-binding protein upregulated in the brain in response to electroconvulsive shock (Yamagata et al. 1994). Despite its name, Rheb protein is ubiquitously expressed in a variety of tissues. Rheb is evolutionarily conserved between yeast and humans, and it belongs to the Ras subfamily. In mammals, two different Rheb genes have been identified: Rheb and RhebL (also called Rheb1 and Rheb2, respectively). Since the Rheb GTPase was found to be regulated by the Tsc1 and Tsc2 proteins, which are responsible for the tuberous sclerosis complex (TSC) (Pan et al. 2004), Rheb functions have been extensively investigated. Moreover, Rheb has been demonstrated to activate the mammalian target of rapamycin (mTOR) signaling pathway and to regulate protein translation, cell proliferation, cell size, and metabolism.

Protein and Gene Structure

This is a preview of subscription content, log in to check access.


  1. Alves MM, Fuhler GM, Queiroz KC, Scholma J, Goorden S, Anink J, et al. PAK2 is an effector of TSC1/2 signaling independent of mTOR and a potential therapeutic target for Tuberous Sclerosis Complex. Sci Rep. 2015;5:14534. doi:10.1038/srep14534.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science (New York, NY). 2007;318:977–80. doi:10.1126/science.1147379.CrossRefGoogle Scholar
  3. Cao Y, Tao L, Shen S, Xiao J, Wu H, Li B, et al. Cardiac ablation of Rheb1 induces impaired heart growth, endoplasmic reticulum-associated apoptosis and heart failure in infant mice. Int J Mol Sci. 2013;14:24380–98. doi:10.3390/ijms141224380.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ghosh AP, Marshall CB, Coric T, Shim EH, Kirkman R, Ballestas ME, et al. Point mutations of the mTOR-RHEB pathway in renal cell carcinoma. Oncotarget. 2015;6:17895–910. doi:10.18632/oncotarget.4963.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Goorden SM, Hoogeveen-Westerveld M, Cheng C, van Woerden GM, Mozaffari M, Post L, et al. Rheb is essential for murine development. Mol Cell Biol. 2011;31:1672–8. doi:10.1128/mcb.00985-10.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Goorden SM, Abs E, Bruinsma CF, Riemslagh FW, van Woerden GM, Elgersma Y. Intact neuronal function in Rheb1 mutant mice: implications for TORC1-based treatments. Hum Mol Genet. 2015;24:3390–8. doi:10.1093/hmg/ddv087.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Gracias NG, Shirkey-Son NJ, Hengst U. Local translation of TC10 is required for membrane expansion during axon outgrowth. Nat Commun. 2014;5:3506. doi:10.1038/ncomms4506.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Heard JJ, Fong V, Bathaie SZ, Tamanoi F. Recent progress in the study of the Rheb family GTPases. Cell Signal. 2014;26:1950–7. doi:10.1016/j.cellsig.2014.05.011.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Jewell JL, Russell RC, Guan KL. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol. 2013;14:133–9. doi:10.1038/nrm3522.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Lee MN, Koh A, Park D, Jang JH, Kwak D, Jeon H, et al. Deacetylated alphabeta-tubulin acts as a positive regulator of Rheb GTPase through increasing its GTP-loading. Cell Signal. 2013;25:539–51. doi:10.1016/j.cellsig.2012.11.006.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Li YH, Werner H, Puschel AW. Rheb and mTOR regulate neuronal polarity through Rap1B. J Biol Chem. 2008;283:33784–92. doi:10.1074/jbc.M802431200.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Pan D, Dong J, Zhang Y, Gao X. Tuberous sclerosis complex: from Drosophila to human disease. Trends Cell Biol. 2004;14:78–85. doi:10.1016/j.tcb.2003.12.006.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25:903–15. doi:10.1016/j.molcel.2007.03.003.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Sugiura H, Yasuda S, Katsurabayashi S, Kawano H, Endo K, Takasaki K, et al. Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex. Nat Commun. 2015;6:6842. doi:10.1038/ncomms7842.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Tamai T, Yamaguchi O, Hikoso S, Takeda T, Taneike M, Oka T, et al. Rheb (Ras homologue enriched in brain)-dependent mammalian target of rapamycin complex 1 (mTORC1) activation becomes indispensable for cardiac hypertrophic growth after early postnatal period. J Biol Chem. 2013;288:10176–87. doi:10.1074/jbc.M112.423640.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Yamagata K, Sanders LK, Kaufmann WE, Yee W, Barnes CA, Nathans D, et al. rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. J Biol Chem. 1994;269:16333–9.PubMedPubMedCentralGoogle Scholar
  17. Yasuda S, Sugiura H, Katsurabayashi S, Shimada T, Tanaka H, Takasaki K, et al. Activation of Rheb, but not of mTORC1, impairs spine synapse morphogenesis in tuberous sclerosis complex. Sci Rep. 2014;4:5155. doi:10.1038/srep05155.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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. doi:10.1074/jbc.M501253200.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Zou J, Zhou L, Du XX, Ji Y, Xu J, Tian J, et al. Rheb1 is required for mTORC1 and myelination in postnatal brain development. Dev Cell. 2011;20:97–108. doi:10.1016/j.devcel.2010.11.020.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Zou Y, Jiang W, Wang J, Li Z, Zhang J, Bu J, et al. Oligodendrocyte precursor cell-intrinsic effect of Rheb1 controls differentiation and mediates mTORC1-dependent myelination in brain. J Neurosci. 2014;34:15764–78. doi:10.1523/jneurosci.2267-14.2014.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Tadayuki Shimada
    • 1
    Email author
  • Hiroko Sugiura
    • 1
  • Kanato Yamagata
    • 1
    • 2
  1. 1.Synaptic Plasticity ProjectTokyo Metropolitan Institute of Medical ScienceSetagayaJapan
  2. 2.Department of PharmacologyShukutoku UniversityChibaJapan