Expanding mTOR signaling

Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Research (Impact Factor: 12.41). 09/2007; 17(8):666-81. DOI: 10.1038/cr.2007.64
Source: PubMed


The mammalian target of rapamycin (mTOR) has drawn much attention recently because of its essential role in cell growth control and its involvement in human tumorigenesis. Great endeavors have been made to elucidate the functions and regulation of mTOR in the past decade. The current prevailing view is that mTOR regulates many fundamental biological processes, such as cell growth and survival, by integrating both intracellular and extracellular signals, including growth factors, nutrients, energy levels, and cellular stress. The significance of mTOR has been highlighted most recently by the identification of mTOR-associated proteins. Amazingly, when bound to different proteins, mTOR forms distinctive complexes with very different physiological functions. These findings not only expand the roles that mTOR plays in cells but also further complicate the regulation network. Thus, it is now even more critical that we precisely understand the underlying molecular mechanisms in order to directly guide the development and usage of anti-cancer drugs targeting the mTOR signaling pathway. In this review, we will discuss different mTOR-associated proteins, the regulation of mTOR complexes, and the consequences of mTOR dysregulation under pathophysiological conditions.

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    • "Moreover, mTOR-selective inhibitor rapamycin seems to suppress additive effects of HPEinduced phosphorylation of S6K rather than MTA alone. Because S6K1 is a positive regulator of protein synthesis downstream of mTOR,[41]the mTOR pathway seems to be a master mediator of MTA and HPE-induced odontoblastic differentiation. Collectively, mTOR, MAPK and NF-kB pathways, that are engaged in stimulating growth, differentiation and angiogenesis of HDPCs via MTA and HPE, are schematically drawn based on the current findings, as depicted in Figure 4. "
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    ABSTRACT: Objective The aim of this study was to evaluate the combined effects of mineral trioxide aggregate (MTA) and human placental extract (HPE) on cell growth, differentiation and in vitro angiogenesis of human dental pulp cells (HDPCs) and to identify underlying signal transduction mechanisms. In vivo dental pulp responses in rats for a pulp-capping agent were examined. Materials and methods MTS assay. ALP activity test, alizarin red S staining and RT-PCR for marker genes were carried out to evaluate cell growth and differentiation. HUVEC migration, mRNA expression and capillary tube formation were measured to evaluate angiogenesis. Signal transduction was analysed using Western blotting and confocal microscopy. The pulps of rat maxillary first molars were exposed and capped with either MTA or MTA plus HPE. Histologic observation and scoring were performed. Results Compared to treatment of HDPCs with either HPE or MTA alone, the combination of HPE and MTA increased cell growth, ALP activity, mineralized nodules and expression of marker mRNAs. Combination HPE and MTA increased migration, capillary tube formation and angiogenic gene expression compared with MTA alone. Activation of Akt, mammalian target of rapamycin (mTOR), p38, JNK and ERK MAPK, Akt, and NF-κB were significantly increased by combining HPE and MTA compared with MTA alone. Pulp capping with MTA plus HPE in rats showed superior dentin bridge formation, odontoblastic layers and dentinal tubules and lower inflammatory cell response, compared to the MTA alone group. Conclusions This study demonstrates for the first time that the use of MTA with HPE promotes cell growth, differentiation and angiogenesis in HDPCs, which were associated with mTOR, MAPK and NF-κB pathways. Direct pulp capping with HPE plus MTA showed superior results when compared with MTA alone. Thus, the combination of MTA and HPE may be useful for regenerative endodontics.
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    • "This phosphorylation blocks the ability of TSC2, while residing within the TSC1eTSC2 tumor suppressor dimmer to act as a GTPase-activating protein (GAP) for Rheb (Ras-homolog enriched in brain), thereby allowing Rheb-GTP to accumulate and operate as an activator of the rapamycin-sensitive mammalian TOR complex 1 (mTORC1) (Avruch et al., 2006). The latter is consisting of target of rapamycin (TOR), RAPTOR (regulatory associated protein of TOR) LST8 (also known as GbL), and PRAS40 (proline-rich Akt substrate 40 kDa) (Bhaskar and Hay, 2007; Yang and Guan, 2007). Since it is mTORC1 that conveys signals to S6Ks and rpS6, it will be mentioned in the remainder of this review, rather than mTOR, when transduction of signals is discussed. "
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    ABSTRACT: The phosphorylation of ribosomal protein S6 (rpS6) has been described for the first time about four decades ago. Since then, numerous studies have shown that this modification occurs in response to a wide variety of stimuli on five evolutionarily conserved serine residues. However, despite a large body of information on the respective kinases and the signal transduction pathways, the physiological role of rpS6 phosphorylation remained obscure until genetic manipulations were applied in both yeast and mammals in an attempt to block this modification. Thus, studies based on both mice and cultured cells subjected to disruption of the genes encoding rpS6 and the respective kinases, as well as the substitution of the phosphorylatable serine residues in rpS6, have laid the ground for the elucidation of the multiple roles of this protein and its posttranslational modification. This review focuses primarily on newly identified kinases that phosphorylate rpS6, pathways that transduce various signals into rpS6 phosphorylation, and the recently established physiological functions of this modification. It should be noted, however, that despite the significant progress made in the last decade, the molecular mechanism(s) underlying the diverse effects of rpS6 phosphorylation on cellular and organismal physiology are still poorly understood.
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    • "However, recent data suggested that cellular outcome in tumor cell treatment cannot be predicted by changes in the phosphorylation status of AKT as induction of its phosphorylation in the presence of the broad anti-tumor agent everolimus (RAD0019) has been shown to occur as a results of mTORC1 (rapamycin-sensitive kinase complex containing raptor) inhibition in a rictor-dependent manner [46]. Further supporting this, a negative feedback loop has been described, where mTOR/S6K1 activation results in PI3K signaling inhibition by suppressing the insulin receptor-dependent cascade [47] [48] [49]. Hence, it remains to be determined whether the anti-proliferative response in cells incubated with PCP is accompanied by mTORC1 inhibition and whether suppression of AKT phosphorylation at S473 can be induced by rictor down-regulation. "
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