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Gene Review

RHEB  -  Ras homolog enriched in brain

Homo sapiens

Synonyms: GTP-binding protein Rheb, RHEB2
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Disease relevance of RHEB

  • Mutational analysis performed on DNA from these eight angiomyolipomas plus five additional sporadic angiomyolipomas did not reveal mutations in exons 3 and 4 (homologous sites of Ras activating mutations) of either Rheb or RhebL1 [1].
  • In this study, we show that Rheb like-1 protein (RhebL1) rescues mTOR signaling during nutrient withdrawal and that tuberous sclerosis complex-1 (TSC) and TSC2 impairs RhebL1-mediated signaling through mTOR [2].
  • Taken together, these data reveal that the TSC/Rheb/mTOR pathway plays a critical role in the regulation of E(2)-induced proliferation, and highlight Rheb as a novel molecular target for breast cancer therapy [3].
  • The well-conserved Rheb-Target-of-rapamycin (TOR)-S6-kinase (S6K) signaling pathway regulates several cellular processes and has been shown to influence lifespan and diseases such as cancer and neurodegenerative disorders [4].
  • Mutational analysis of Rheb and RhebL1 was performed on DNA from phospho-mTOR/phospho-S6 positive clear cell renal cell carcinoma [5].
  • We demonstrate that Rheb overexpression promotes hyperplasia and a low-grade neoplastic phenotype in the mouse prostate while eliciting a concomitant senescence response and a negative feedback loop limiting Akt activation [6].

Psychiatry related information on RHEB


High impact information on RHEB


Biological context of RHEB

  • The polypeptide, consisting of 184 amino acids deduced from nucleotide sequences, contains five repeats of the Ras-related GTP-binding region and is highly homologous to the rat RHEB (Ras homologue enriched in brain) gene, which encodes a Ras-related growth factor- and synaptic activity-regulated protein, with 98.9% amino acid identity [12].
  • Using fluorescence in situ hybridization, we concluded that this human RHEB gene was localized to band q36 on chromosome 7 [12].
  • The small GTPase Rheb displays unique biological and biochemical properties different from other small GTPases and functions as an important mediator between the tumor suppressor proteins TSC1 and TSC2 and the mammalian target of rapamycin to stimulate cell growth [13].
  • RESULTS: Here, we show that Rheb binds to the TOR complex specifically, independently of its ability to bind TSC2, through separate interactions with the mTOR catalytic domain and with LST8 [14].
  • The unique switch II conformation results in a displacement of Gln64 (equivalent to the catalytic Gln61 of Ras), making it incapable of participating in GTP hydrolysis and thus accounting for the low intrinsic GTPase activity of Rheb [13].

Anatomical context of RHEB

  • IRS1 is preferentially depleted from the high-speed pellet fraction in TSC1/2-deficient mouse embryo fibroblasts or in HEK293/293T cells overexpressing Rheb [15].
  • Expression of wild type or mutant Rheb did not alter the morphology or growth properties of NIH 3T3 cells [16].
  • We found that Rheb and Rheb2 mRNA were elevated in various tumor cell lines relative to normal cells [17].
  • The vacuole formation required the GTP form of Rheb, but not the activation of the downstream mTOR kinase [18].
  • Here we identified that Rheb expression in cultured cells induces the formation of large cytoplasmic vacuoles, which are characterized as late endocytic (late endosome- and lysosome-like) components [18].

Associations of RHEB with chemical compounds

  • Unlike Ras, the phosphate moiety of GTP in Rheb is shielded by the conserved Tyr35 of switch I, leading to the closure of the GTP-binding site, which appears to prohibit the insertion of a potential arginine finger from its GTPase-activating protein [13].
  • We report here the three-dimensional structures of human Rheb in complexes with GDP, GTP, and GppNHp (5'-(beta,gamma-imide)triphosphate), which reveal novel structural features of Rheb and provide a molecular basis for its distinct properties [13].
  • Inhibition of Rheb is important for the regulation of mTOR pathway, while mutation of hamartin or tuberin results in uncontrolled cell cycle progression [19].
  • Candidates for mediating the action of leucine to stimulate signaling through the mTOR pathway include TSC2, Rheb, and raptor [20].
  • The second involves the measurement of Rheb-associated guanine nucleotides as measure of TSC2 GAP activity on Rheb in vivo [21].

Physical interactions of RHEB

  • TSC2 was found to bind to Rheb-GTP in vitro and to reduce Rheb GTP levels in vivo [22].
  • Rheb interacts with Raf-1 kinase and may function to integrate growth factor- and protein kinase A-dependent signals [23].
  • We show that Rheb interacts with FKBP38 through a section within its switch I region that is equivalent to the effector domain of other Ras-like small GTPases [24].

Regulatory relationships of RHEB

  • Here we demonstrate that Rheb interacts with and appears to regulate Raf-1 kinase, an essential component of the H-Ras signaling pathway [23].

Other interactions of RHEB

  • Further experiments show that H-Ras, Rheb, Rho6 and G alpha(i1) interact with PDE delta and that, at least for H-Ras, the intact C-terminus is required [25].
  • Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1 [2].
  • In direct contrast to H-Ras, however, the interaction of Rheb with Raf-1 is potentiated by growth factors in combination with agents that increase cyclic AMP (cAMP) levels [23].
  • In this study, we identified and characterized a novel member of Ras family named RHEBL1, belonging to the Rheb branch of small GTPase proteins [26].

Analytical, diagnostic and therapeutic context of RHEB

  • Here we describe the detection of M-Ras and Rap1 activity by GST-RBD pull-down as well as that of Rheb and epitope-tagged R-Ras by classical metabolic labeling and immunoprecipitation [27].


  1. Frequent [corrected] hyperphosphorylation of ribosomal protein S6 [corrected] in lymphangioleiomyomatosis-associated angiomyolipomas. Robb, V.A., Astrinidis, A., Henske, E.P. Mod. Pathol. (2006) [Pubmed]
  2. Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1. Tee, A.R., Blenis, J., Proud, C.G. FEBS Lett. (2005) [Pubmed]
  3. Estrogen-Induced Activation of Mammalian Target of Rapamycin Is Mediated via Tuberin and the Small GTPase Ras Homologue Enriched in Brain. Yu, J., Henske, E.P. Cancer Res. (2006) [Pubmed]
  4. Increased Rheb-TOR signaling enhances sensitivity of the whole organism to oxidative stress. Patel, P.H., Tamanoi, F. J. Cell. Sci. (2006) [Pubmed]
  5. Activation of the mTOR signaling pathway in renal clear cell carcinoma. Robb, V.A., Karbowniczek, M., Klein-Szanto, A.J., Henske, E.P. J. Urol. (2007) [Pubmed]
  6. Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events. Nardella, C., Chen, Z., Salmena, L., Carracedo, A., Alimonti, A., Egia, A., Carver, B., Gerald, W., Cordon-Cardo, C., Pandolfi, P.P. Genes Dev. (2008) [Pubmed]
  7. TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth. Inoki, K., Ouyang, H., Zhu, T., Lindvall, C., Wang, Y., Zhang, X., Yang, Q., Bennett, C., Harada, Y., Stankunas, K., Wang, C.Y., He, X., Macdougald, O.A., You, M., Williams, B.O., Guan, K.L. Cell (2006) [Pubmed]
  8. PRAS40 Is an Insulin-Regulated Inhibitor of the mTORC1 Protein Kinase. Sancak, Y., Thoreen, C.C., Peterson, T.R., Lindquist, R.A., Kang, S.A., Spooner, E., Carr, S.A., Sabatini, D.M. Mol. Cell (2007) [Pubmed]
  9. TSC2: filling the GAP in the mTOR signaling pathway. Li, Y., Corradetti, M.N., Inoki, K., Guan, K.L. Trends Biochem. Sci. (2004) [Pubmed]
  10. TSC1-2 tumour suppressor and regulation of mTOR signalling: linking cell growth and proliferation? Findlay, G.M., Harrington, L.S., Lamb, R.F. Curr. Opin. Genet. Dev. (2005) [Pubmed]
  11. Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. Cai, S.L., Tee, A.R., Short, J.D., Bergeron, J.M., Kim, J., Shen, J., Guo, R., Johnson, C.L., Kiguchi, K., Walker, C.L. J. Cell Biol. (2006) [Pubmed]
  12. Isolation of cDNA and genomic clones of a human Ras-related GTP-binding protein gene and its chromosomal localization to the long arm of chromosome 7, 7q36. Mizuki, N., Kimura, M., Ohno, S., Miyata, S., Sato, M., Ando, H., Ishihara, M., Goto, K., Watanabe, S., Yamazaki, M., Ono, A., Taguchi, S., Okumura, K., Nogami, M., Taguchi, T., Ando, A., Inoko, H. Genomics (1996) [Pubmed]
  13. Structural basis for the unique biological function of small GTPase RHEB. Yu, Y., Li, S., Xu, X., Li, Y., Guan, K., Arnold, E., Ding, J. J. Biol. Chem. (2005) [Pubmed]
  14. Rheb binds and regulates the mTOR kinase. Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K., Avruch, J. Curr. Biol. (2005) [Pubmed]
  15. Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis. Shah, O.J., Hunter, T. Mol. Cell. Biol. (2006) [Pubmed]
  16. The Ras-related protein Rheb is farnesylated and antagonizes Ras signaling and transformation. Clark, G.J., Kinch, M.S., Rogers-Graham, K., Sebti, S.M., Hamilton, A.D., Der, C.J. J. Biol. Chem. (1997) [Pubmed]
  17. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. Basso, A.D., Mirza, A., Liu, G., Long, B.J., Bishop, W.R., Kirschmeier, P. J. Biol. Chem. (2005) [Pubmed]
  18. Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. Saito, K., Araki, Y., Kontani, K., Nishina, H., Katada, T. J. Biochem. (2005) [Pubmed]
  19. Hamartin and tuberin: working together for tumour suppression. Jozwiak, J. Int. J. Cancer (2006) [Pubmed]
  20. Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. Kimball, S.R., Jefferson, L.S. J. Nutr. (2006) [Pubmed]
  21. Measurements of TSC2 GAP Activity Toward Rheb. Li, Y., Inoki, K., Vikis, H., Guan, K.L. Meth. Enzymol. (2005) [Pubmed]
  22. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. Castro, A.F., Rebhun, J.F., Clark, G.J., Quilliam, L.A. J. Biol. Chem. (2003) [Pubmed]
  23. Rheb interacts with Raf-1 kinase and may function to integrate growth factor- and protein kinase A-dependent signals. Yee, W.M., Worley, P.F. Mol. Cell. Biol. (1997) [Pubmed]
  24. The switch I region of Rheb is critical for its interaction with FKBP38. Ma, D., Bai, X., Guo, S., Jiang, Y. J. Biol. Chem. (2008) [Pubmed]
  25. The complex of Arl2-GTP and PDE delta: from structure to function. Hanzal-Bayer, M., Renault, L., Roversi, P., Wittinghofer, A., Hillig, R.C. EMBO J. (2002) [Pubmed]
  26. Identification and characterization of RHEBL1, a novel member of Ras family, which activates transcriptional activities of NF-kappa B. Yuan, J., Shan, Y., Chen, X., Tang, W., Luo, K., Ni, J., Wan, B., Yu, L. Mol. Biol. Rep. (2005) [Pubmed]
  27. Measuring Ras-family GTP levels in vivo--running hot and cold. Castro, A.F., Rebhun, J.F., Quilliam, L.A. Methods (2005) [Pubmed]
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