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Gene Review

RHEBP1  -  Ras-homolog enriched in brain pseudogene 1

Homo sapiens

Synonyms: RHEB, RHEB1
 
 
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Disease relevance of RHEBP1

  • 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 [1].
  • Mutational analysis of Rheb and RhebL1 was performed on DNA from phospho-mTOR/phospho-S6 positive clear cell renal cell carcinoma [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].
  • 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 [4].
 

Psychiatry related information on RHEBP1

 

High impact information on RHEBP1

  • Our data demonstrate that Rheb acts downstream of TSC1/TSC2 and upstream of mTOR to regulate cell growth [5].
  • PRAS40 inhibits cell growth, S6K1 phosphorylation, and rheb-induced activation of the mTORC1 pathway, and in vitro it prevents the great increase in mTORC1 kinase activity induced by rheb1-GTP [6].
  • IRS1 is preferentially depleted from the high-speed pellet fraction in TSC1/2-deficient mouse embryo fibroblasts or in HEK293/293T cells overexpressing Rheb [7].
  • Akt-dependent cell size regulation by the adhesion molecule on glia occurs independently of phosphatidylinositol 3-kinase and Rheb signaling [8].
  • We demonstrated a novel catalytic mechanism of the TSC2 GAP and Rheb that TSC2 uses a catalytic "asparagine thumb" instead of the arginine finger found in Ras-GAP [9].
 

Biological context of RHEBP1

  • A novel approach for expression cloning of small GTPases: identification, tissue distribution and chromosome mapping of the human homolog of rheb [10].
  • Increased Rheb-TOR signaling enhances sensitivity of the whole organism to oxidative stress [1].
  • However, no mutations in exons 3 and 4 (homologous sites of Ras activating mutations) in Rheb or RhebL1 were identified [2].
  • Similar to other members of the Ras superfamily, Rheb has a C-terminal CaaX box that is subject to farnesylation [11].
  • The human RHEB gene was mapped to chromosome 10q11 [10].
 

Anatomical context of RHEBP1

  • Using this procedure we have cloned several small GTP-binding proteins from human keratinocytes including the human homolog of rheb, a novel member of the ras-related GTP-binding proteins [10].
  • Northern analysis showed that human rheb is ubiquitously expressed, with the highest levels observed in skeletal and cardiac muscle, and not in brain, as it is the case for rat rheb [10].
  • Timed imaging of live cells expressing EGFP-Rheb reveals that following brief association with the ER, Rheb localizes to highly ordered, distinct structures within the cytoplasm that display characteristics of Golgi membranes [11].
  • We found that Rheb and Rheb2 mRNA were elevated in various tumor cell lines relative to normal cells [12].
  • MKP-1 and MKP-3 mRNAs, but not rheb mRNA, increased in the striatum, thalamus, and cortices, and in the striatum, hippocampus, and cortices, respectively, after a single methamphetamine [13].
 

Associations of RHEBP1 with chemical compounds

  • Consistent with the notion that the endomembrane may serve as a platform for the assembly of a functional Rheb/mTOR complex, treatment of cells with brefeldin A interferes with transmission of Rheb signals to p70S6K [11].
  • We hypothesized that tuberin and the small GTPase Ras homologue enriched in brain (Rheb), regulators of the mTOR pathway, mediate E(2)-induced activation of mTOR [3].
  • The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity [12].
  • Finally, overexpression of Rheb, a downstream target of Tuberin function and a positive upstream effector of mTOR, reverses the effect of dexamethasone on phosphorylation of mTOR substrates [14].
  • Herein we show that the binding of Rheb to endogenous and recombinant mTOR is reversibly inhibited by withdrawal of all extracellular amino acids or just leucine [15].
 

Analytical, diagnostic and therapeutic context of RHEBP1

References

  1. Increased Rheb-TOR signaling enhances sensitivity of the whole organism to oxidative stress. Patel, P.H., Tamanoi, F. J. Cell. Sci. (2006) [Pubmed]
  2. 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]
  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. Frequent [corrected] hyperphosphorylation of ribosomal protein S6 [corrected] in lymphangioleiomyomatosis-associated angiomyolipomas. Robb, V.A., Astrinidis, A., Henske, E.P. Mod. Pathol. (2006) [Pubmed]
  5. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Inoki, K., Li, Y., Xu, T., Guan, K.L. Genes Dev. (2003) [Pubmed]
  6. 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]
  7. 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]
  8. Akt-dependent cell size regulation by the adhesion molecule on glia occurs independently of phosphatidylinositol 3-kinase and Rheb signaling. Scheidenhelm, D.K., Cresswell, J., Haipek, C.A., Fleming, T.P., Mercer, R.W., Gutmann, D.H. Mol. Cell. Biol. (2005) [Pubmed]
  9. Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Li, Y., Inoki, K., Guan, K.L. Mol. Cell. Biol. (2004) [Pubmed]
  10. A novel approach for expression cloning of small GTPases: identification, tissue distribution and chromosome mapping of the human homolog of rheb. Gromov, P.S., Madsen, P., Tomerup, N., Celis, J.E. FEBS Lett. (1995) [Pubmed]
  11. Localization of Rheb to the endomembrane is critical for its signaling function. Buerger, C., Devries, B., Stambolic, V. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  12. 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]
  13. Gene expression related to synaptogenesis, neuritogenesis, and MAP kinase in behavioral sensitization to psychostimulants. Ujike, H., Takaki, M., Kodama, M., Kuroda, S. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  14. Dexamethasone Represses Signaling through the Mammalian Target of Rapamycin in Muscle Cells by Enhancing Expression of REDD1. Wang, H., Kubica, N., Ellisen, L.W., Jefferson, L.S., Kimball, S.R. J. Biol. Chem. (2006) [Pubmed]
  15. Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. Long, X., Ortiz-Vega, S., Lin, Y., Avruch, J. J. Biol. Chem. (2005) [Pubmed]
  16. Expression, purification, crystallization and preliminary structural characterization of the GTPase domain of human Rheb. Yu, Y., Chang, Y., Li, S., Hu, H., Huang, Q., Ding, J. Acta Crystallogr. D Biol. Crystallogr. (2004) [Pubmed]
 
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