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MTOR RHEB (1 - 10 of 10)
PMID: 16757352
Rheb activation of mTOR and S6K1 signaling.
Rheb activation of mTOR and ...   (details)

MTOR RHEB

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 16757352

Rheb activation of mTOR and S6K1 signaling.
Source

Methods in enzymology (2006)

Abstract

Rheb activation of mTOR and S6K1 signaling. More than 10 years ago, Rheb (Ras homolog enriched in brain) was identified as a highly conserved protein that is a member of the Ras superfamily of small GTPases, which play critical roles in cell growth and proliferation. Recently, a convergence of genetic and biochemical evidence from yeast, Drosophila, and mammalian cells has placed Rheb upstream of the mammalian target of rapamycin (mTOR) and immediately downstream of the tumor suppressors TSC1 (hamartin) and TSC2 (tuberin). Rheb plays a key role in the regulation of cell growth in response to growth factors, nutrients, and amino acids linking PI3K and TOR signaling. Rheb activation of the nutrient and energy-sensitive TOR pathway leads to the direct phosphorylation of two known downstream translational control targets by mTOR, the 40S ribosomal S6 kinase 1 (S6K1) and the eukaryotic translation initiation factor 4E (eIF4E) - binding protein 1 (4E-BP1). Appropriate regulation of this pathway is crucial for the proper control of cell growth, proliferation, survival, and differentiation. Inappropriate regulation of these signaling molecules, therefore, can lead to a variety of human diseases. In this chapter, we describe cell biological and biochemical methods commonly used to study Rheb activation and dissect its role in the mTOR-signaling pathway.

PMID: 16803888
Rheb inhibits C-raf activity and B-raf/C-raf heterodimerization.
... of Rheb activation of the mammalian target of rapamycin-Raptor complex ...   (details)

MTOR RHEB

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 16803888

Rheb inhibits C-raf activity and B-raf/C-raf heterodimerization.
Source

The Journal of biological chemistry (9/1/2006)

Abstract

Rheb inhibits C-raf activity and B-raf/C-raf heterodimerization. The Ras-Raf-MEK signaling cascade is critical for normal development and is activated in many forms of cancer. We have recently shown that B-Raf kinase interacts with and is inhibited by Rheb, the target of the GTPase-activating domain of the tuberous sclerosis complex 2 gene product tuberin. Here, we demonstrate for the first time that activation of Rheb is associated with decreased B-Raf and C-Raf phosphorylation at residues Ser-446 and Ser-338, respectively, concomitant with a decrease in the activities of both kinases and decreased heterodimerization of B-Raf and C-Raf. Importantly, the impact of Rheb on B-Raf/C-Raf heterodimerization and kinase activity are rapamycin-insensitive, indicating that they are independent of Rheb activation of the mammalian target of rapamycin-Raptor complex. In addition, we found that Rheb inhibits the association of B-Raf with H-Ras. Taken together, these results support a central role of Rheb in the regulation of the Ras/B-Raf/C-Raf/MEK signaling network.

PMID: 17502379
Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif.
... that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression ...   (details)

MTOR RHEB

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 17502379

Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif.
Source

The Journal of biological chemistry (7/13/2007)

Abstract

Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF) -mediated transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor (VEGF) -A secretion during hypoxia, which is reversed with rapamycin. Mutants of Rheb, which do not bind guanine nucleotide (D60K, D60V, N119I, and D122N) and are unable to activate mTOR, inhibit the activity of HIF when overexpressed. We show that regulatory associated protein of mTOR (Raptor) interacts with HIF1alpha and requires an mTOR signaling (TOS) motif located in the N terminus of HIF1alpha. Furthermore, a mutant of HIF1alpha lacking this TOS motif dominantly impaired HIF activity during hypoxia and was unable to bind to the co-activator CBP/p300. Rapamycin treatments do not affect the stability of HIF1alpha and modulate HIF activity via a Von Hippel-Lindau (VHL) -independent mechanism. We demonstrate that the high levels of HIF activity in cells devoid of TSC2 can be reversed by treatments with rapamycin or the readdition of TSC2. Our work explains why human cancers with aberrant mTOR signaling are prone to angiogenesis and suggests that inhibition of mTOR with rapamycin might be a suitable therapeutic strategy.

PMID: 18650380
ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo.
... of Rheb and activation of mTOR signaling independent ...   (details)

MTOR RHEB

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTOR-signaling   (MLST8   RPTOR   MTOR )

PMID: 18650380

ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo.
Source

Proceedings of the National Academy of Sciences of the United States of America (7/29/2008)

Abstract

ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. The pathways that allow quiescent disseminated cancer cells to survive during prolonged dormancy periods are unknown. Here, we identify the transcription factor ATF6alpha as a pivotal survival factor for quiescent but not proliferative squamous carcinoma cells. ATF6alpha is essential for the adaptation of dormant cells to chemotherapy, nutritional stress, and, most importantly, the in vivo microenvironment. Mechanism analysis showed that MKK6 and p38alpha/beta contribute to regulating nuclear translocation and transcriptional activation of ATF6alpha in dormant cancer cells. Downstream, ATF6alpha induces survival through the up-regulation of Rheb and activation of mTOR signaling independent of Akt. Down-regulation of ATF6alpha or Rheb reverted dormant tumor cell resistance to rapamycin and induced pronounced killing only of dormant cancer cells in vivo. Knocking down ATF6alpha also prolonged the survival of nude mice bearing dormant tumor cells. Targeting survival signaling by the ATF6alpha-Rheb-mTOR pathway in dormant tumor cells may favor the eradication of residual disease during dormancy periods.

PMID: 18765678
Amino acid regulation of TOR complex 1.
... enabling Rheb-GTP activation of mTORC1.   (details)

MTOR RHEB

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 18765678

Amino acid regulation of TOR complex 1.
Source

American journal of physiology. Endocrinology and metabolism (April 2009)

Abstract

Amino acid regulation of TOR complex 1. TOR complex 1 (TORC1), an oligomer of the mTOR (mammalian target of rapamycin) protein kinase, its substrate binding subunit raptor, and the polypeptide Lst8/GbetaL, controls cell growth in all eukaryotes in response to nutrient availability and in metazoans to insulin and growth factors, energy status, and stress conditions. This review focuses on the biochemical mechanisms that regulate mTORC1 kinase activity, with special emphasis on mTORC1 regulation by amino acids. The dominant positive regulator of mTORC1 is the GTP-charged form of the ras-like GTPase Rheb. Insulin, growth factors, and a variety of cellular stressors regulate mTORC1 by controlling Rheb GTP charging through modulating the activity of the tuberous sclerosis complex, the Rheb GTPase activating protein. In contrast, amino acids, especially leucine, regulate mTORC1 by controlling the ability of Rheb-GTP to activate mTORC1. Rheb binds directly to mTOR, an interaction that appears to be essential for mTORC1 activation. In addition, Rheb-GTP stimulates phospholipase D1 to generate phosphatidic acid, a positive effector of mTORC1 activation, and binds to the mTOR inhibitor FKBP38, to displace it from mTOR. The contribution of Rheb's regulation of PL-D1 and FKBP38 to mTORC1 activation, relative to Rheb's direct binding to mTOR, remains to be fully defined. The rag GTPases, functioning as obligatory heterodimers, are also required for amino acid regulation of mTORC1. As with amino acid deficiency, however, the inhibitory effect of rag depletion on mTORC1 can be overcome by Rheb overexpression, whereas Rheb depletion obviates rag's ability to activate mTORC1. The rag heterodimer interacts directly with mTORC1 and may direct mTORC1 to the Rheb-containing vesicular compartment in response to amino acid sufficiency, enabling Rheb-GTP activation of mTORC1. The type III phosphatidylinositol kinase also participates in amino acid-dependent mTORC1 activation, although the site of action of its product, 3'OH-phosphatidylinositol, in this process is unclear.

PMID: 19272448
Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition.
... that activation of mTORC1 by both Rheb and ...   (details)

MTOR RHEB

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 19272448

Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition.
Source

Cellular signalling (July 2009)

Abstract

Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition. The mammalian target of rapamycin (mTOR) pathway is implicated in a number of human diseases, but the pathway details are not fully understood. Here we elucidate the interactions between various proteins involved in mTOR complex 1 (mTORC1). An in vitro mTORC1 kinase assay approach was used to probe the role of the mTORC1 component Raptor and revealed that certain Raptor mutations disrupt binding to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and prevent its subsequent phosphorylation by mTOR. Interestingly, we show that a point mutation in the highly conserved Raptor RNC domain still allows binding to mTOR but prevents Raptor association and mTOR-dependent phosphorylation of 4E-BP1, indicating that this Raptor domain facilitates substrate recognition by mTORC1. This Raptor RNC domain mutant also dominantly inhibits mTORC1 signalling to 4E-BP1, S6K1 and HIF1alpha in vivo. We further characterise the functions of the mTORC1 signalling (TOS) and RAIP motifs of 4E-BP1, which are involved in substrate recognition by Raptor and phosphorylation by mTORC1. We show that an mTOR mutant, L1460P, responds to insulin even in nutrient-deprived conditions and is resistant to inhibition by inactive RagB-RagC heterodimers that mimic nutrient withdrawal suggesting that this region of mTOR is involved in sensing the permissive amino acid input. We found that FKBP38 inhibits mTOR (L1460P), while the mTOR (E2419K) kinase domain mutant was resistant to FKBP38 inhibition. Finally, we show that activation of mTORC1 by both Rheb and RhebL1 is impaired by FKBP38. Our work demonstrates the value of an in vitro mTORC1 kinase assay to characterise cell signalling components of mTORC1 involved in recognition and phosphotransfer to mTORC1 substrates.

PMID: 19299511
Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein.
The activation of mTORC1 by Rheb can ...   (details)

MTOR RHEB

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 19299511

Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein.
Source

The Journal of biological chemistry (5/8/2009)

Abstract

Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. Rheb G-protein plays critical roles in the TSC/Rheb/mTOR signaling pathway by activating mTORC1. The activation of mTORC1 by Rheb can be faithfully reproduced in vitro by using mTORC1 immunoprecipitated by the use of anti-raptor antibody from mammalian cells starved for nutrients. The low in vitro kinase activity against 4E-BP1 of this mTORC1 preparation is dramatically increased by the addition of recombinant Rheb. On the other hand, the addition of Rheb does not activate mTORC2 immunoprecipitated from mammalian cells by the use of anti-rictor antibody. The activation of mTORC1 is specific to Rheb, because other G-proteins such as KRas, RalA/B, and Cdc42 did not activate mTORC1. Both Rheb1 and Rheb2 activate mTORC1. In addition, the activation is dependent on the presence of bound GTP. We also find that the effector domain of Rheb is required for the mTORC1 activation. FKBP38, a recently proposed mediator of Rheb action, appears not to be involved in the Rheb-dependent activation of mTORC1 in vitro, because the preparation of mTORC1 that is devoid of FKBP38 is still activated by Rheb. The addition of Rheb results in a significant increase of binding of the substrate protein 4E-BP1 to mTORC1. PRAS40, a TOR signaling (TOS) motif-containing protein that competes with the binding of 4EBP1 to mTORC1, inhibits Rheb-induced activation of mTORC1. A preparation of mTORC1 that is devoid of raptor is not activated by Rheb. Rheb does not induce autophosphorylation of mTOR. These results suggest that Rheb induces alteration in the binding of 4E-BP1 with mTORC1 to regulate mTORC1 activation.

PMID: 20068142
Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage.
Activation of mTORC1 signaling ... of Rheb inhibits ...   (details)

MTOR RHEB

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 20068142

Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage.
Source

Diabetes (April 2010)

Abstract

Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. [OBJECTIVE] In metazoans, target of rapamycin complex 1 (TORC1) plays the key role in nutrient- and hormone-dependent control of metabolism. However, the role of TORC1 in regulation of triglyceride storage and metabolism remains largely unknown. [RESEARCH DESIGN AND METHODS] In this study, we analyzed the effect of activation and inhibition of the mammalian TORC1 (mTORC1) signaling pathway on the expression of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), lipolysis, lipogenesis, and lipid storage in different mammalian cells. [RESULTS] Activation of mTORC1 signaling in 3T3-L1 adipocytes by ectopic expression of Rheb inhibits expression of ATGL and HSL at the level of transcription, suppresses lipolysis, increases de novo lipogenesis, and promotes intracellular accumulation of triglycerides. Inhibition of mTORC1 signaling by rapamycin or by knockdown of raptor stimulates lipolysis primarily via activation of ATGL expression. Analogous results have been obtained in C2C12 myoblasts and mouse embryonic fibroblasts with genetic ablation of tuberous sclerosis 2 (TSC2) gene. Overexpression of ATGL in these cells antagonized the lipogenic effect of TSC2 knockout. [CONCLUSIONS] Our findings demonstrate that mTORC1 promotes fat storage in mammalian cells by suppression of lipolysis and stimulation of de novo lipogenesis.

PMID: 20375271
Lovastatin induces VSMC differentiation through inhibition of Rheb and mTOR.
Rheb overexpression induced mTORC1 activity ...   (details)

MTOR RHEB

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 20375271

Lovastatin induces VSMC differentiation through inhibition of Rheb and mTOR.
Source

American journal of physiology. Cell physiology (July 2010)

Abstract

Lovastatin induces VSMC differentiation through inhibition of Rheb and mTOR. It is becoming increasingly clear that cholesterol-independent effects of statins also contribute to the cardioprotective effects, but these mechanisms remain poorly understood. We investigated the effects of lovastatin on vascular smooth muscle phenotype. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) inhibition with rapamycin induces vascular smooth muscle cell (VSMC) differentiation. We found that lovastatin also inhibits mTORC1 signaling and that this inhibition is required for VSMC differentiation. Lovastatin inhibition of mTORC1 was farnesylation dependent, suggesting the farnesylated G protein Rheb (Ras homologue enriched in brain), a known upstream activator of mTORC1. Rheb overexpression induced mTORC1 activity and repressed contractile protein expression, but a farnesylation-deficient mutant (C18S) elicited the opposite effect. Rheb knockdown with small interfering RNA was also sufficient to inhibit mTORC1 and induce contractile protein expression, and it prevented statin-induced VSMC differentiation. Notably, mTORC1 activity was elevated in VSMC isolated from an intimal hyperplastic patient lesion compared with normal media, and lovastatin treatment inhibited mTORC1 activity in these cultures. Furthermore, lovastatin inhibited mTORC1 activity and prevented the downregulation of contractile protein expression in an ex vivo angioplasty model. In conclusion, these findings illustrate a mechanism for the cardioprotective effects of lovastatin through inhibition of Rheb and mTORC1 and promotion of a differentiated VSMC phenotype.

PMID: 21914810
The mechanism of insulin-stimulated 4E-BP protein binding to mammalian target of rapamycin (mTOR) complex 1 and its contribution to mTOR complex 1 signaling.
... by Rheb activation of mTOR catalytic ...   (details)

MTOR RHEB

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 21914810

The mechanism of insulin-stimulated 4E-BP protein binding to mammalian target of rapamycin (mTOR) complex 1 and its contribution to mTOR complex 1 signaling.
Source

The Journal of biological chemistry (11/4/2011)

Abstract

The mechanism of insulin-stimulated 4E-BP protein binding to mammalian target of rapamycin (mTOR) complex 1 and its contribution to mTOR complex 1 signaling. Insulin activation of mTOR complex 1 is accompanied by enhanced binding of substrates. We examined the mechanism and contribution of this enhancement to insulin activation of mTORC1 signaling in 293E and HeLa cells. In 293E, insulin increased the amount of mTORC1 retrieved by the transiently expressed nonphosphorylatable 4E-BP [5A] to an extent that varied inversely with the amount of PRAS40 bound to mTORC1. RNAi depletion of PRAS40 enhanced 4E-BP [5A] binding to ~70% the extent of maximal insulin, and PRAS40 RNAi and insulin together did not increase 4E-BP [5A] binding beyond insulin alone, suggesting that removal of PRAS40 from mTORC1 is the predominant mechanism of an insulin-induced increase in substrate access. As regards the role of increased substrate access in mTORC1 signaling, RNAi depletion of PRAS40, although increasing 4E-BP [5A] binding, did not stimulate phosphorylation of endogenous mTORC1 substrates S6K1 (Thr (389)) or 4E-BP (Thr (37) /Thr (46)), the latter already ~70% of maximal in amino acid replete, serum-deprived 293E cells. In HeLa cells, insulin and PRAS40 RNAi also both enhanced the binding of 4E-BP [5A] to raptor but only insulin stimulated S6K1 and 4E-BP phosphorylation. Furthermore, Rheb overexpression in 293E activated mTORC1 signaling completely without causing PRAS40 release. In the presence of Rheb and insulin, PRAS40 release is abolished by Akt inhibition without diminishing mTORC1 signaling. 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.