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

• We find that mildly increasing systemic Rheb-TOR-S6K signaling sensitizes the whole organism to oxidative stress and promotes senescence of locomotor activity with age [4].

High impact information on RHEB

• TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth [7].
• 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 [8].
• Thus, TSC1/2 and Rheb have pivotal roles in mediating growth factors, nutrient and energy sensing signals to mTOR-dependent targets [9].
• However, Rheb-induced growth might not explain the additional effects of TSC1-2 upon cell proliferation [10].
• In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression [11].

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].

References