IndraLab
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"An important regulator of RHEB activity is the TSC complex which inactivates RHEB by accelerating GTP hydrolysis, and it has been reported that the TSC2 protein cycles on and off the lysosomal surface in response to amino acid levels : when amino acids are withdrawn TSC2 translocates to the lysosomal surface where it inactivates RHEB causing the subsequent mTOR inactivation."
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"XREF_BIBR Given that Rheb is able to bind the kinase domain of other phosphatidylinositol-3 kinase like kinase (PIKK) family members such as ataxia telangiecstasia mutated (ATM) and ataxia telangiecstasia and Rad3 related (ATR), XREF_BIBR structural studies examining the physical interaction between Rheb and mTOR could provide helpful insight into how Rheb activates mTOR."
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"Hamartin and tuberin are involved in the regulation of cell proliferation and differentiation, forming a physical and functional complex that activates GTPase, keeping the protein Ras homolog enriched in brain protein (RHEB) inactive in order to inhibit the mammalian target of rapamycin (mTOR) pathway."
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"Our mechanistic studies demonstrate that the inhibition of PPT1 initiates a cascade, beginning with the lysosomal displacement of vATPase subunits, which disrupts the function of Ragulator and Rag GTPase machinery, impairing lysosomal recruitment of mTORC1, and preventing Rheb-dependent activation of mTOR."
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"On the other hand, ATF6 activation is crucial to long-term survival of tumors by augmenting resistance to chemotherapy, nutrient starvation and stress in quiescent squamous carcinoma cells, where ATF6 increases Rheb expression, which in turn activates mTOR activity in an Akt independent manner."
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"This may be due to reduction in AMP-activated protein kinase signaling [ xref ] or due to the decreased interaction of glyceraldehyde 3-phosphate dehydrogenase and Rheb [ xref ], each of which would promote mTOR activation (specifically, the mTORC1 complex) by the small GTPase Rheb ( xref )."
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"AMPK has been shown to inhibit mTORC1 activity by two different mechanisms : one through activation of the TSC2, which promotes downstream inhibition of the mTOR activator Rheb [XREF_BIBR, XREF_BIBR], and the other through direct phosphorylation of Raptor at Ser792 blocking mTORC1 activation [XREF_BIBR]."
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"Although it is unknown how Prom1 negatively regulates mTOR signaling in the RPE, previous studies demonstrated that inhibition of mTOR signaling increased the CD133 + subpopulations in vitro and in vivo, whereas activation of mTOR by Rheb significantly decreased CD133 expression. xref In cancer cells, a mechanistic relationship exists between CD133 and the hypoxia-inducible factor-1α, a downstream target in the mTOR signaling pathway. xref These previous observations support the presence of a molecular cross talk between Prom1 and mTOR signaling in the regulation of autophagy flux in the RPE."
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"On the other hand, ATF6α prolongs survival of dormant tumor cells, but not proliferative squamous carcinoma cells, through transactivation of the Ras homolog enriched in brain (Rheb; a critical activator of the mammalian target of rapamycin [mTOR]) and thus activation of mTOR signaling (Schewe and Aguirre-Ghiso 2008)."
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"Hamartin and tuberin are involved in the regulation of cell proliferation and differentiation, forming a physical and functional complex that activates guanosine triphosphatase (GTPase), keeping the protein Ras homolog enriched in brain protein (RHEB) inactive in order to inhibit the mammalian target of rapamycin (mTOR) pathway."
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"Based on these findings, Rheb farnesylation-mediated lysosome translocation and thereafter the direct binding of mTOR are two important steps for mTORC1 activation.Similar to all small GTPase, Rheb has two forms of inactive GDP-bound and active GTP-bound states, which enables Rheb as a switch modulator of mTORC1 ."
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"Rheb is unique among members of the small GTPase family in that the regulation of its function occurs predominately through its inactivation by Rheb GAPs (e.g., TSC2) rather than its activation by Rheb guanidine exchange factors (GEFs); thus, overexpression of Rheb bypasses the requirement for PI3K activation of Akt to promote mTOR activity."
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"Akt activation phosphorylates and inactivates tuberous sclerosis complex 2 (TSC2), which promotes the activation of mammalian target of rapamycin complex 1 (mTORC1) by Ras homolog enriched in brain (Rheb), 70 kDa ribosomal protein S6 kinase (p70S6K) phosphorylation, and ribosomal protein S6, consequently promoting protein synthesis ( xref )."
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"Additionally, AKT phosphorylates and activates the mTOR protein kinase by circumventing the inhibitory GTPase activity of the TSC2 tumor suppressor, tuberin, for the small G protein, Rheb, which binds directly to the kinase domain and activates mTOR in a GTP dependent manner [XREF_BIBR - XREF_BIBR]."
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"AMPK can induce autophagy by acting via two different pathways, directly, by phosphorylating the proautophagic factor ULK1 [XREF_BIBR, XREF_BIBR], and indirectly, by negatively regulating the mTOR complex targeting them TOR inhibitors tuberous sclerosis complex 1 and 2 (TSC1/2) and the mTOR activator Rheb, a Ras homologue GTP binding protein enriched in the brain [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"Hamartin and tuberin, the protein products of TSC1 and TSC2 , respectively, form a functional heterodimer that negatively
regulates cell growth via tuberin's GTPase Activating Protein activity toward the small
GTPase Rheb, which in turn activates the mechanistic target of rapamycin complex 1 (mTORC1)."
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"Activated mTOR further phosphorylates ribosomal p70 S6 kinase (S6K1), eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), and Akt, controlling cell proliferation, growth, and survival. xref , xref Activated PDK1 also positively regulates S6K1. xref Studies have placed tuberous sclerosis complex (TSC) 1/2 as a modulator between PI3K/Akt and mTOR. xref - xref The TSC1/2 complex acts as a repressor of mTOR function. xref - xref TSC2 has GTPase-activating protein (GAP) activity towards the Ras family small GTPase Rheb (Ras homolog enriched in brain), and TSC1/2 antagonizes the mTOR signaling pathway via stimulation of GTP hydrolysis of Rheb. xref - xref Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38, xref though this remains controversial. xref The TSC can also be activated by energy depletion through the activation of AMP-activated kinase (AMPK). xref AMPK responds both to changes in AMP concentration and to changes in the ratio of AMP to ATP. xref An increased AMP to ATP ratio allows AMPK phosphorylation and activation. xref This, in turn, activates the TSC, which catalyzes the conversion of Rheb-GTP to Rheb-GDP and thus inhibits mTOR. xref AMPK can also be phosphorylated and activated by the calcium- and calmodulin-dependent protein kinase kinase-β (CaMKK-β) in response to alterations in intracellular calcium homeostasis. xref In addition, AMPK may be activated by oxidative stress. xref "
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"We also used IUE, which allows us to express a plasmid of our choice that encodes constitutively active Rheb to increase mTOR activity, as reported in several neurodevelopmental disorders, and assess the impact of drug treatment on neuron morphology.We validated our experimental paradigm by successfully measuring and quantifying changes in neurite outgrowth over time and following Torin 1 treatment using the CellProfiler pipeline."
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"However, Rheb-mediated activation of mTOR requires Rheb to be GTP-bound,20 which suggest that regulation of mTOR kinase activity can occur through modulating Rheb's GTP-binding status.Growth factor activation of mTORC1 occurs through insulin or IGF-1 signalling, both of which activate their respective receptor tyrosine kinases."
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"Disruption of the mTOR pathway in adult mouse HSCs by the introduction of loss-of-function alleles of Pten or Tsc1 (both negative regulators of mTOR) or gain-of-function mutations in the mTOR activators RHEB2 or AKT leads to depletion of HSC recycling and long-term reconstitution activity ."
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"Renal mTOR activation in poorly controlled diabetes may result from a combination of AKT inhibition of tuberous sclerosis complex 2, hyperglycemia induced AMPK inhibition, and increased glucose uptake through glucose transporter 1, in which the resulting increased glycolysis and activation of GAPDH can lead directly to Rheb activation of mTOR by reducing Rheb binding to GAPDH."
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"Our results suggest that the clear resistance of LD muscle to insulin and marginal baseline resistance to leucine, and amino acids more broadly, does not fully translate to a reduction in LD muscle protein synthesis.Insulin signaling in the gastrocnemius muscle, from Akt phosphorylation through Rheb-mediated mTOR activation, was blunted in preterm pigs after feeding."
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"While constitutively active AKT is as capable as PTEN −/− xref , xref , recent data demonstrate that direct activation of mTOR by constitutively active Rheb or downstream modulation of the mTORC1 effectors E4BP or S6K1 fail to fully mimic the regenerative effect xref , xref , xref , xref ."
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"In addition, from a methodologic perspective, Rheb CA expression rapidly (6-8 hours) activates the mTOR pathway as compared to other experimental strategies such as conditional transgenic mice, small hairpin RNA (shRNA), or CRISPR and Cas9 vectors because the timing of mTORC1 activation depends on the half-life of the KD/KO protein of interest."
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"Among the downstream targets of Akt is the tuberous sclerosis complex 2 (TSC2), which is—together with TSC1—located on the lysosomal membrane, from which it subsequently dissociates to act as a GAP for the Ras-related small GTPase, Rheb, which in turn activates mammalian target of rapamycin complex 1 (mTORC1)."
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"This metabolic switch could potentially be linked to reduced PI3K/AKT/mTOR signaling indicated by the GSEA in NCI-H1975 and NCI-H2009 cells as mTOR is a driver of the Warburg effect.41 Previous studies have indicated the mTOR-activating protein RHEB as a central downstream target of FTI treatment that results in inhibition of RHEB farnesylation and reduced mTOR signaling.11 42 43 RHEB is a known substrate of FTase, and like HRAS, the localization of RHEB is exclusively dependent on farnesylation."
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"MTOR signaling, including Ras homolog enriched in brain (Rheb), rapamycin insensitive companion of mTOR (Rictor) and ribosomal protein S6 kinase B2 (S6K2), was investigated by western blotting and qPCR, and insulin responsiveness was evaluated by glucose uptake and phosphorylation of insulin receptor substrate-1 (p-IRS1)."
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"To investigate whether the DDIT4 and mTOR signaling pathway is involved in regulating the proliferation of RMCs treated with 1,25 (OH) 2 D 3, we examined the expression of VDR, DDIT4, TSC1 and TSC2, the mTOR mediator Rheb, mTOR, and its downstream proteins 4E-BP1 and p70S6K by Western blot."
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"AKT is responsible for the inhibition of negative regulators of mTOR, such as tuberous sclerosis complex (TSC1/2), whilst pyruvate dehydrogenase kinase 1(PDK1) induces the mTOR activator Rheb (Ras homolog enriched in brain), thereby releasing the mTOR complex to phosphorylate its targets (Perluigi et al., 2015)."
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"The mechanisms by which mTORC1 is activated by amino acids are less clear but a number of studies have shown that the binding of Raptor to the Rag GTPases, a family of four related small GTPases XREF_BIBR, is necessary for mTOR to localize onto the lysosome where mTOR is activated by its upstream activator Rheb XREF_BIBR, XREF_BIBR,."
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"In many metazoan organisms, growth factor availability is also integrated into the activation of mTORC1 via regulation of the nucleotide binding state of Ras homolog enriched in brain (Rheb), a small GTPase that binds to and allosterically activates the mTOR kinase when it is part of mTORC1 XREF_BIBR, XREF_BIBR."
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"Another example of a non-canonical ATF6-regulated gene product is the small GTPase Ras homolog enriched in brain (Rheb), which, when induced by ATF6α in the heart, activates mammalian target of rapamycin complex 1 (mTORC1) and thus drives protein synthesis and hypertrophic cardiac myocyte growth [66]."
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"When compared to Rheb, the greater effect size of ca-Akt was also expected because ca-Akt has the potential to induce an increase in protein synthesis through the combined activation of mTOR signaling and the inhibition of glycogen synthase kinase-3 beta (GSK3beta), while Rheb only activates mTOR signaling."
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"RHEB stimulates the protein kinase mTOR, which results in activating phosphorylation of the mTOR substrates S6 kinase (S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) XREF_BIBR, XREF_BIBR, which is consistent with RHEB being essential for cell growth and cell cycle progression in D. melanogaster 116."
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"[XREF_BIBR] This led us to propose that RHEB normally contacts and activates lysosome localized mTOR from a distinct endomembrane compartment (XREF_FIG) (a relationship which we termed " transendomembrane " to contrast to the prevailing " cis-" interaction in which both RHEB and mTOR are proposed to both be lysosomal)."
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"Renal mTOR activation in poorly controlled diabetes may result from a combination of AKT inhibition of tuberous sclerosis complex 2, hyperglycemia-induced AMPK inhibition, and increased glucose uptake through glucose transporter 1, in which the resulting increased glycolysis and activation of GAPDH can lead directly to Rheb activation of mTOR by reducing Rheb binding to GAPDH ( xref , xref )."
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"To determine whether the overexpression of Rheb could induce mTOR signaling in adult skeletal muscle in vivo, mouse TA muscles were transfected with Rheb, or GFP as a control condition, and the phosphorylation of the ribosomal S6 (S6) protein on the Ser235/236 residues (P-S6) was evaluated as a marker of mTOR signaling."
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"Under nutrient-rich conditions, mTOR is mainly activated through a signaling cascade involving activation of class I phosphinositol 3 kinase (PI3K)/protein kinase B (Akt), phosphorylation of tuberous sclerosis complex 2 (TSC2), and activation of the GTP-binding protein Rheb which in turn activates mTOR [ xref ]."
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"Combined, these results indicate that 1) Rheb induces hypertrophy through a rapamycin sensitive mechanism, 2) mTOR is the rapamycin sensitive element in skeletal muscle that confers Rheb induced hypertrophy, and 3) mTOR kinase activity is necessary for the Rheb induced hypertrophic response."
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"Among amino acids, Leu promotes mTORC1 activity and protein synthesis in skeletal muscle at physiologically relevant concentrations. xref , xref In muscle, Leu binding to Sestrin2, the key sensor for intracellular Leu, disrupts the interaction between Sestrin2 and GATOR2. xref The release of GATOR2 from Sestrin2 inhibits GATOR1, a protein with GTPase-activating protein activity for RagA. xref , xref In turn, the inhibition of GATOR1 facilitates mTOR association with GTP-bound RagA on the lysosomal surface, where mTOR is fully activated by Rheb. xref "
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"For example, the TSC1/TSC2 complex inhibits mTOR functions by inactivating Rheb; Rheb binds and activates mTOR only when the former is in its GTP-bound form. xref The phosphoinositide-3-kinase (PI3K)-Akt pathway activates mTOR by Akt-mediated phosphorylation of TSC2, followed by disassembly and inhibition of the TSC1/TSC2 complex. xref , xref The extracellular signal-related kinase (ERK) stimulates mTOR activation by either directly phosphorylating TSC2 or by inducing TSC2 phosphorylation via its two downstream effectors, ribosomal S6 kinase (RSK) and DAPK. xref – xref Finally, AMP-activated protein kinase (AMPK) phosphorylates TSC2 and stabilizes the TSC1/TSC2 complex, thereby inhibiting Rheb-mediated activation of mTOR. xref AMPK can also regulate mTOR function in a TSC-independent manner by directly phosphorylating Raptor, an essential component of mTORC1, to inhibit mTOR activity. xref Notably, TSC1 and 2, PI3K, and Akt are all subject to mutation in human tumors."
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"This conclusion is reinforced by supplementary data from two studies : mice with a neo-insertion in an Mtor intron that decreases Mtor mRNA approximately 70% show a similar selective lowering of CD44 on CD4 + T cells and CD44 levels are also reduced on naive, CD62L positive T cells that are deficient for the mTOR activator Rheb or deficient for the mTOR interacting protein Rictor."
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"MTORC1 activation requires dual inputs, one from the extracellular environment, typically mediated by growth factor-PI3K-Akt-TSC1/2-Rheb signaling, and a second from intracellular nutrient availability, typically conveyed by amino acid-mediated activation of the Ragulator-Rag complex that recruits mTORC1 to lysosomal membranes, where mTOR is activated by GTP-binding protein Rheb ( xref )."
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"Moreover, genes that negatively regulate the mammalian target of rapamycin (mTOR), the main regulator of autophagy, such as AMPK, LKB1, PTEN and TSC1/2 induce autophagy while, conversely, oncogenes that promote mTOR signaling, such as class I PI3K, AKT, Ras and RHEB inhibit autophagy [XREF_BIBR, XREF_BIBR]."
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"Furthermore, significant enrichment of MAPK and PI3K/AKT signaling pathways in our KEGG analysis ( xref ) may in part explain the hyperproliferative phenotype exhibited by cells lining the cysts, where kinases from both pathways are known for mediating the phosphorylation and inactivation of TSC2, which in turn will allow RHEB to activate mTOR and drive cell proliferation [ xref , xref ]."
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"In conclusion, dissociation of PRAS40 from mTORC1 and enhanced mTORC1 substrate binding results from Akt and mTORC1 activation and makes little or no contribution to mTORC1 signaling, which rather is determined by Rheb activation of mTOR catalytic activity, through mechanisms that remain to be fully elucidated."
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"AKT phosphorylates and inactivates nodular sclerosing factor 2, thus inducing the formation of active Rheb ( xref ), and Rheb in turn phosphorylates and activates mammalian target of rapamycin (mTOR) ( xref ), mTOR can directly enhance the transcriptional activity of hypoxia inducible factor-1α (HIF-1α), leading to its metastasis to the nucleus and activation with the structural subunit HIF-1β to form the HIF-1 heterodimer complex, and then in combination with a hypoxia response element in the HIF-1α target gene, the transcriptional activity of the target gene is regulated ( xref )."
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"Renal mTOR activation in poorly controlled diabetes may result from a combination of AKT inhibition of TSC2, hyperglycemia-induced AMP kinase inhibition and increased glucose uptake through glucose transporter 1 (GLUT1), in which the resulting increased glycolysis and activation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) can lead directly to Rheb activation of mTOR by reducing Rheb binding to GAPDH [ xref , xref ]."
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"TSC knockout cells, which have increased mTORC1 activity, have a reduced mature miRNA level.52 Accordingly, mTOR activation by Rheb can bring down the maturation process and also recycle existing miRNPs, and both of these pathways may contribute to the miRNA activity rescue process."
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"Moreover, RHEB p.Y35L-expressing, GFP-positive neurons featured enhanced phosphorylated S6 staining (Fig. 3c, e) and an increased soma size (Fig. 3c, d, f, g), indicating that the RHEB p.Y35L mutation induces aberrant mTOR activation and cytomegalic neurons in vivo.Importantly, 1-month-old mice subjected to embryonic expression of RHEB p.Y35L exhibited spontaneous tonic-clonic seizures (Supplementary Video 1), whereas mice with embryonic expression of the control vehicle vector or wild-type RHEB demonstrated no such phenomena."
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"Tuberous sclerosis complexes 1 and 2 (TSC1 and TSC2; also known as Hamartin and Tuberin) form a heterodimeric protein complex to control mTOR signalling by integrating different signalling pathways : TSC1 and TSC2 complex functions as a GTPase activating protein to inhibit the activity of Rheb, a small GTPase protein that activates mTOR activation XREF_BIBR XREF_BIBR."
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"Some studies have shown that Rheb can respond to growth factor stimuli and available nutrients, antagonizing the mTOR endogenous inhibitor, FKBP38, in a GTP-dependent manner (Bai et al., 2007), and bind to the carboxyl terminal of the mTOR catalytic domain to regulate its kinase activity using phospholipase D1 (PLD1) (Long et al., 2005a; Sancak et al., 2007; Sun et al., 2008)."