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To grow and multiply, a living cell must take a variety of factors into account, such as its own energy levels and the availability of nutrients. A protein called mTOR sits at the core of a signaling pathway that integrates these and other sources information. Problems with the mTOR pathway contribute to several diseases including diab...
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The Target of rapamycin (TOR) protein kinase forms part of TOR complex 1 (TORC1) and TOR complex 2 (TORC2), two multi-subunit protein complexes that regulate growth, proliferation, survival and developmental processes by phosphorylation and activation of AGC-family kinases. In the fission yeast, Schizosaccharomyces pombe , TORC2 and its target, the...
Gene variants that hyperactivate PI3K-mTOR signaling in the brain lead to epilepsy and cortical malformations in humans. Some gene variants associated with these pathologies only hyperactivate mTORC1, but others, such as PTEN, PIC3CA, and AKT, hyperactivate both mTORC1- and mTORC2-dependent signaling. Previous work has established a key role for mT...
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Significance
The mechanistic target of rapamycin (mTOR) plays a central role in growth, metabolism, and aging. It is assembled into two multiprotein complexes, namely, mTORC1 and mTORC2. We previously demonstrated the efficacy of sirolimus in ARHL in mice by decreasing mTORC1. However, the aspect of mTORC2 regulation in the cochlea is poorly charac...
Background
Although 5-Flourouracil(5-FU) is used as the first-choice treatment for advanced hepatocellular carcinoma (HCC), it is associated with acquired and intrinsic resistance. Hyperactivation of mTOR signaling has been linked to tumorigenesis and chemoresistance in HCC. The aim of this study was to evaluate and compare the antitumor effects of...
Citations
... mTORC2 is largely insensitive to rapamycin [17], and includes as specific components Rictor and SIN1. Additionally, Protor-1/2 and Deptor can bind to mTORC2 [18]. mTORC2 participate of chaperone-mediated autophagy [19] and may have a role in autophagy via FoxO3 [11]. ...
In recent years, progress in nanotechnology provided new tools to treat cancer more effectively. Advances in biomaterials tailored for drug delivery have the potential to overcome the limited selectivity and side effects frequently associated with traditional therapeutic agents. While autophagy is pivotal in determining cell fate and adaptation to different challenges, and despite the fact that it is frequently dysregulated in cancer, antitumor therapeutic strategies leveraging on or targeting this process are scarce. This is due to many reasons, including the very contextual effects of autophagy in cancer, low bioavailability and non-targeted delivery of existing autophagy modulatory compounds. Conjugating the versatile characteristics of nanoparticles with autophagy modulators may render these drugs safer and more effective for cancer treatment. Here, we review current standing questions on the biology of autophagy in tumor progression, and precursory studies and the state-of-the-art in harnessing nanomaterials science to enhance the specificity and therapeutic potential of autophagy modulators.
... mTORC2 phosphorylates the kinase complex, thereby regulating cell survival, metabolism, apoptosis, growth, and proliferation [102]. The downstream complex contains PKA, PKG, and PKC, which are a part of the AGC-kinase family [103,104]. In addition to controlling organismal growth and homeostasis, the mTOR signaling pathway has been linked to an increasing variety of clinical diseases, including obesity. ...
Dietary polyphenols can be utilized to treat obesity and chronic disorders linked to it. Dietary polyphenols can inhibit pre-adipocyte proliferation, adipocyte differentiation, and triglyceride accumulation; meanwhile, polyphenols can also stimulate lipolysis and fatty acid β-oxidation, but the molecular mechanisms of anti-obesity are still unclear. The mechanistic target of rapamycin (mTOR) is a protein kinase that regulates cell growth, survival, metabolism, and immunity. mTOR signaling is also thought to play a key role in the development of metabolic diseases such as obesity. Recent studies showed that dietary polyphenols could target mTOR to reduce obesity. In this review, we systematically summarized the research progress of polyphenols in preventing obesity through the mTOR signaling pathway. Mechanistically, polyphenols can target multiple signaling pathways and gut microbiota to regulate the mTOR signaling pathway to exert anti-obesity effects. The main mechanisms include: modulating lipid metabolism, adipogenesis, inflammation, etc. Dietary polyphenols exerting an anti-obesity effect by targeting mTOR signaling will broaden our understanding of the anti-obesity mechanisms of polyphenols and provide valuable insights for researchers in this novel field.
... As a core component of mTORC1 (mTOR-mLST8-RAPTOR), RAPTOR plays an essential role in recruiting substrates and in the subcellular localization of mTORC1, while mLST8 stabilizes the kinase domain of mTOR. In contrast to the structural assembly of mTORC1, mTORC2 comprises the following subunits: mTOR, rapamycin-insensitive companion of mTOR (RICTOR), DEPTOR, mLST8, and target of rapamycin complex 2 subunit mapkap1 (MAPKAP1), with mTOR, mLST8, and RICTOR as the core of the complex (mTOR-mLST8-RICTOR) [36,37]. mTORC1 is found in multiple subcellular locations, including the nucleus, cytoplasm, and endoplasmic reticulum (ER). ...
Antipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.
... Little is known about the upstream regulators of mTORC2 but it is shown that its regulation and activity depend on its subcellular localization and it is found in multiple pools in the cytosol, plasma membrane, early and late endosomes, and mitochondria (Ebner et al., 2017;Fu and Hall, 2020). The activity of the mTORC2 complex specifically depends on its components Stuttfeld et al., 2018;Scaiola et al., 2020;Tafur, Kefauver and Loewith, 2020). MLST8 functions as a scaffold to maintain mTORC2 integrity and kinase activity (Hwang et al., 2019), whereas RICTOR acts as an essential core for mTORC2 complex formation (Gao et al., 2021). ...
... SIN1-ΔaRBD lacks amino acids 364-390, and isoform 6 (Iso6) is missing the whole PH domain and contains an alternative exon 9a instead of the aRBD. Because endogenous SIN1 could interfere with the effect of transfected SIN1 variants, which could be caused by the formation of heterodimers (Stuttfeld et al., 2018;Scaiola et al., 2020), we performed a CRISPR/Cas9 knock-out of SIN1 in HEK293 cells and selected a single clone (clone 2A) for further overexpression experiments. The single clone showed no signal for either SIN1 antibody or phosphorylated AKT at S473 (Supplementary Figure S11). ...
Stress-activated MAP kinase-interacting protein 1 (SIN1) is a central member of the mTORC2 complex that contains an N-terminal domain (NTD), a conserved region in the middle (CRIM), a RAS-binding domain (RBD), and a pleckstrin homology domain. Recent studies provided valuable structural and functional insights into the interactions of SIN1 and the RAS-binding domain of RAS proteins. However, the mechanism for a reciprocal interaction of the RBD-PH tandem with RAS proteins and the membrane as an upstream event to spatiotemporal mTORC2 regulation is not clear. The biochemical assays in this study led to the following results: 1) all classical RAS paralogs, including HRAS, KRAS4A, KRAS4B, and NRAS, can bind to SIN1-RBD in biophysical and SIN1 full length (FL) in cell biology experiments; 2) the SIN1-PH domain modulates interactions with various types of membrane phosphoinositides and constantly maintains a pool of SIN1 at the membrane; and 3) a KRAS4A-dependent decrease in membrane binding of the SIN1-RBD-PH tandem was observed, suggesting for the first time a mechanistic influence of KRAS4A on SIN1 membrane association. Our study strengthens the current mechanistic understanding of SIN1-RAS interaction and suggests membrane interaction as a key event in the control of mTORC2-dependent and mTORC2-independent SIN1 function.
... The molecular basis of the preference for incorporation of Tor2 into (and exclusion of Tor1 from) yeast TORC2 has been illuminated, first, by the determination of near-atomic resolution cryo-EM structures for TORC2 from both yeast [16,17] and mammalian cells [18][19][20]. Second, the construction and analysis of an extensive set of chimeric Tor1-Tor2 proteins [21,22] indicates that Tor2 makes multiple non-contiguous contacts with other constituent subunits of TORC2, but that a handful of single-residue differences between Tor2 and Tor1 within an ∼500-residue segment of their N-terminal HEAT repeat region (425-930 in Tor2), dubbed the 'major assembly specificity' (MAS) domain (corresponding, in the main, to the so-called Spiral and Bridge structural elements formed by the HEAT repeats in this region [16]), are sufficient to dictate its TORC2-specific assembly. ...
As first demonstrated in budding yeast (Saccharomyces cerevisiae), all eukaryotic cells contain two, distinct multi-component protein kinase complexes that each harbor the TOR (Target Of Rapamycin) polypeptide as the catalytic subunit. These ensembles, dubbed TORC1 and TORC2, function as universal, centrally important sensors, integrators, and controllers of eukaryotic cell growth and homeostasis. TORC1, activated on the cytosolic surface of the lysosome (or, in yeast, on the cytosolic surface of the vacuole), has emerged as a primary nutrient sensor that promotes cellular biosynthesis and suppresses autophagy. TORC2, located primarily at the plasma membrane, plays a major role in maintaining the proper levels and bilayer distribution of all plasma membrane components (sphingolipids, glycerophospholipids, sterols, and integral membrane proteins). This article surveys what we have learned about signaling via the TORC2 complex, largely through studies conducted in S. cerevisiae. In this yeast, conditions that challenge plasma membrane integrity can, depending on the nature of the stress, stimulate or inhibit TORC2, resulting in, respectively, up-regulation or down-regulation of the phosphorylation and thus the activity of its essential downstream effector the AGC family protein kinase Ypk1. Through the ensuing effect on the efficiency with which Ypk1 phosphorylates multiple substrates that control diverse processes, membrane homeostasis is maintained. Thus, the major focus here is on TORC2, Ypk1, and the multifarious targets of Ypk1 and how the functions of these substrates are regulated by their Ypk1-mediated phosphorylation, with emphasis on recent advances in our understanding of these processes.
... The mTORC2, a symmetric dimer of heterotetramer (mTOR-RIC-TOR-mLST8-mSIN1) also adopts hollow rhombohedral shape, however mTORC2 shows more compact conformation than mTORC1 [27]. The architecture of mTORC2 revealed that RICTOR binds to common binding site as RAPTOR in mTORC1 [28]. Moreover, C-regions of RICTOR also interacts with FRB domain of mTOR. ...
... a: IC 50 and pIC 50 values of selected rapalogs(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). b: Solubility and bioassays of selected rapalogs(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). ...
Mechanistic target of rapamycin (mTOR) is a highly conserved protein kinase acting as a central regulator of cell functions. The kinase forms two distinct mTOR complexes termed as mTORC1 and mTORC2. Dysregulation of mTOR activity is associated with various pathological conditions. Inhibition of overactivated mTOR represent a rational approach in the treatment of numerous human diseases. Rapamycin is a potent natural inhibitor of mTOR exhibiting significant antitumor and immunosuppressive activity. Derivatization of rapamycin provided rapalogs, the first generation of mTOR inhibitors that selectively inhibit mTORC1 activity. Further interest of research community resulted in creation of the second generation of mTOR inhibitors involving both, mTOR kinase inhibitors and dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitors. Recently, combining advances of first and second generation of mTOR inhibitors yielded in the third generation of inhibitors termed as rapalinks. Nowadays, novel inhibitors belonging to all of the three generations are still under development. These inhibitors help us better to understand role of mTOR in mTOR signaling pathway as well as in diverse human diseases. In this review, we summarize recent reported mTOR inhibitors or methods of use thereof in the treatment of various diseases.
... Both complexes contain LST8 (orthologue of mLST8/GβL) as a common subunit, as well as a number of nonconserved, complex-specific proteins, including AVO2 in TORC2 (Loewith et al., 2002;Wedaman et al., 2003;Reinke et al., 2004;Tafur et al., 2020). Models derived from biochemical and ultrastructural studies of both yeast and mammalian complexes indicate that they likely function as dimers and possess an overall rhomboid-like, symmetrical shape, determined primarily by the superhelical topology of the large N-terminal domain of TOR/mTOR (Wullschleger et al., 2005;Yang et al., 2013Yang et al., , 2016Yang et al., , 2017Gaubitz et al., 2015;Aylett et al., 2016;BaretiL et al., 2016;Karuppasamy et al., 2017;Chen et al., 2018;Stuttfeld et al., 2018;Scaiola et al., 2020). High-resolution (∼3.0 Å) Cryogenic electron microscopy (Cryo-EM) models have emerged recently for both mTORC1 and mTORC2 (Yang et al., 2017;Scaiola et al., 2020), revealing key architectural details as well as insights into their regulation, for example evidence for conformation changes within the mTORC1 active site following interaction with the upstream activator Rheb (Yang et al., 2017). ...
mTOR is a large protein kinase that assembles into two multi-subunit protein complexes, mTORC1 and mTORC2, to regulate cell growth in eukaryotic cells. While significant progress has been made in our understanding of the composition and structure of these complexes, important questions remain regarding the role of specific sequences within mTOR important for complex formation and activity. To address these issues, we have used a molecular genetic approach to explore TOR Complex assembly in budding yeast, where two closely related TOR paralogs, TOR1 and TOR2, partition preferentially into TORC1 versus TORC2, respectively. We previously identified a ∼500 amino acid segment within the N-terminal half of each protein, termed the Major Assembly Specificity (MAS) Domain, which can govern specificity in formation of each complex. In this study, we have extended the use of chimeric TOR1-TOR2 genes as a “sensitized” genetic system to identify specific subdomains rendered essential for TORC2 function, using synthetic lethal interaction analyses. Our findings reveal important design principles underlying the dimeric assembly of TORC2, as well as identify specific segments within the MAS domain critical for TORC2 function, to a level approaching single amino acid resolution. Together these findings highlight the complex and cooperative nature of TOR Complex assembly and function.
... Structural studies in both yeast and humans have determined that both mTORC1 and mTORC2 and their yeast homologues, TORC1 and TORC2, are dimers with the dimerization facilitated by the interlocking interactions of mTOR with RAPTOR/KOG1 or RICTOR/AVO3, respectively (Stuttfeld et al., 2018;Yip et al., 2010). This dimerization explains in part the complex specific inhibition by rapamycin, as the FKBP12-rapamycin complex directly blocks the formation of the interaction interface for RAPTOR but not the interface for RICTOR (Gaubitz et al., 2015;Stuttfeld et al., 2018). ...
... Structural studies in both yeast and humans have determined that both mTORC1 and mTORC2 and their yeast homologues, TORC1 and TORC2, are dimers with the dimerization facilitated by the interlocking interactions of mTOR with RAPTOR/KOG1 or RICTOR/AVO3, respectively (Stuttfeld et al., 2018;Yip et al., 2010). This dimerization explains in part the complex specific inhibition by rapamycin, as the FKBP12-rapamycin complex directly blocks the formation of the interaction interface for RAPTOR but not the interface for RICTOR (Gaubitz et al., 2015;Stuttfeld et al., 2018). FKBP12-rapamycin is unable to interact with mTORC2/TORC2, as RICTOR/AVO3 masks the rapamycin-interacting domain of TOR; the deletion of this masking domain of RICTOR/AVO3 sensitizes mTORC2/TORC2 to rapamycin (Gaubitz et al., 2015;Karuppasamy et al., 2017;Scaiola et al., 2020). ...
The protein kinase mechanistic target of rapamycin (mTOR) functions as a central regulator of metabolism, integrating diverse nutritional and hormonal cues to control anabolic processes, organismal physiology, and even aging. This review discusses the current state of knowledge regarding the regulation of mTOR signaling and the metabolic regulation of the four macromolecular building blocks of the cell: carbohydrate, nucleic acid, lipid, and protein by mTOR. We review the role of mTOR in the control of organismal physiology and aging through its action in key tissues and discuss the potential for clinical translation of mTOR inhibition for the treatment and prevention of diseases of aging.
... mSIN1 is able to assemble mTORC2 on the plasma membrane through its phospholipidbinding pleckstrin homology domain (Yuan and Guan, 2015). Structural analyses reveal that mTORC2 also forms a mega-Dalton lozenge-like dimer but RICTOR-associated mSIN1 blocks the interaction sites of FKBP12-rapamycin binding on mTOR, thereby leading to the insensitivity of mTORC2 to acute rapamycin treatment Stuttfeld et al., 2018). ...
Target of rapamycin (TOR) is an evolutionarily conserved protein kinase that functions as a central signaling hub to integrate diverse internal and external cues to precisely orchestrate cellular and organismal physiology. During evolution, TOR both maintains the highly conserved TOR complex compositions, and cellular and molecular functions, but also evolves distinctive roles and strategies to modulate cell growth, proliferation, metabolism, survival, and stress responses in eukaryotes. Here, we review recent discoveries on the plant TOR signaling network. We present an overview of plant TOR complexes, analyze the signaling landscape of the plant TOR signaling network from the upstream signals that regulate plant TOR activation to the downstream effectors involved in various biological processes, and compare their conservation and specificities within different biological contexts. Finally, we summarize the impact of dysregulation of TOR signaling on every stage of plant growth and development, from embryogenesis and seedling growth, to flowering and senescence.
... mTOR, a serine/threonine-protein kinase acts as a master regulator of cell growth and shown to be altered in various types of cancers including CRC. The mTOR protein is part of two structurally distinct signalling complex mTORC1 and mTORC2 (Stuttfeld et al., 2018). Here, we investigated the ATP-binding kinase domain of mTOR by using crystal structure of mTOR available at RCSB protein data bank [PDB ID: 4JT5]. ...
Worldwide disease burden of colorectal cancer (CRC) increasing alarmingly, but a suitable therapeutic strategy is not available yet. Abnormal activation of the PI3K/Akt/mTOR signalling because of mutation in the PIK3CA gene is a driving force behind CRC development. Therefore, this study aimed to comprehensively characterise the potential of phenolic compounds from Olea europaea against the PI3K/Akt/mTOR axis by using in silico methodologies. Molecular docking was utilised to study key interactions between phenolic compounds of O. europaea and target proteins PI3K, Akt, mTOR with reference to known inhibitor of target. Drug likeness and ADME/T properties of selected phenols were explored by online tools. Dynamic properties and binding free energy of target-ligand interactions were studied by molecular dynamic simulation and MM-PBSA method respectively. Molecular docking revealed apigenin, luteolin, pinoresinol, oleuropein, and oleuropein aglycone as the top five phenolic compounds which showed comparable/better binding affinity than the known inhibitor of the respective target protein. Drug likeness and ADME/T properties were employed to select the top three phenols namely, apigenin, luteolin, and pinoresinol which shown to bind stably to the catalytic cleft of target proteins as confirmed by molecular dynamics simulations. Therefore, Apigenin, luteolin, and pinoresinol have the potential to be used as the non-toxic alternative to synthetic chemical inhibitors generally used in CRC treatment as they can target PI3K/Akt/mTOR axis. Particularly, pinoresinol showed great potential as dual PI3K/mTOR inhibitor. However, this study needs to be complemented with future in vitro and in vivo studies to provide an alternative way of CRC treatment.
Communicated by Ramaswamy H. Sarma
