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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Structurally, mTOR is the catalytic subunit of two molecular complexes, mTORC1 and mTORC2. mTORC1 (mTOR Complex 1) is composed of mTOR itself, Raptor (the Regulatory-Associated Protein of mTOR), mLST8/GβL (Mammalian Lst8/G-Protein Β-Subunit-Like Protein), and the partner proteins PRAS40 and DEPTOR. This whole complex functions as the nutrient/energy/redox sensor and controls protein synthesis. The activity of the mTORC1complex is stimulated by nutrients including glucose and amino acids (particularly leucine), insulin, growth factors, serum, phosphatidic acid, and oxidative stress. It is inhibited by low nutrient levels, growth factor deprivation, and reductive stress, and also by certain compounds such as rapamycin and farnesylthiosalicylic acid (FTS). The mTOR pathway can become dysregulated in some human diseases, especially some cancers, and so inhibition of the pathway can lead to a beneficial therapeutic effect. This works because inhibition of mTOR delivers the false signal that the cell is starved of nutrients and lacks growth factor stimulation. This initiates a cellular starvation response which includes metabolic reprogramming, prevention of cell growth and arrest of cell division. mTORC2 appears to be insensitive to nutrients and energy signals. Also, mTOR is a crucial component of the transmission of signals mediated by the phosphatidylinositol 3-kinase (PI3K) pathway, a signaling cascade that is aberrant in more than 70% of tumors. Activation of PI3K by growth factors signals through AKT (PKB) to stimulate growth and proliferation.
Tuberous Sclerosis Complex
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Joana Jesus Ribeiro, Filipe Palavra, Flávio Reis
mTOR is a serine/threonine protein kinase, member of the phosphoinositide 3-kinase-(PI3K)-related kinase family and of cell survival pathways [58,61]. mTOR functions in two separate pathways, with two distinct protein complexes: mTORC1 and mTORC2 [61–63]. Both mTOR complexes are large, with mTORC1 having six and mTORC2 seven known protein components [62]. The common proteins are the catalytic mTOR subunit; mammalian lethal with sec-13 protein 8 (mLST8, also known as GβL), which works as a positive regulator; DEP domain containing mTOR-interacting protein (DEPTOR), negative regulator and the tti1/tel2 complex [62,64]. mTORC1 is inhibited by the action of rapamycin and consists of regulatory-associated protein of mTOR (Raptor), a positive regulator involved in substrate recruitment; and proline-rich AKT substrate of 40 kDa (PRAS40), responsible for mTORC1 inhibition [56,61,63]. The second pathway, involving mTORC2, requires binding mTOR to rapamycin-insensitive companion of mTOR (Rictor), essential for the interaction between mTORC2 and TSC2; mammalian stress-activated protein kinase interacting protein (mSIN-1), important for complex construction; and the protein observed with rictor 1 and 2 (PROTOR 1/2), which seems to have a role in enabling mTORC2 to activate serum-and glucocorticoid−induced kinase 1 (SGK1) [58,61–63]. mTORC2 is rapamycin-insensitive and functions upstream of Rho GTPases to regulate the actin cytoskeleton [56,61,64]. TSC1-TSC2 complex negatively regulates mTORC1 [28,62].
mTOR signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
The subunits of the mTORC2 are mTOR, Rictor (Rapamycin-insensitive companion of mammalian target of rapamycin), mLST8/GβL, DEPTOR and mSIN1 (Stress-activated MAP kinase-interacting protein 1) (10). Rictor and SIN1 subunits maintain the stability and integrity of mTORC2 and are supposed to carry the regulatory functions of this complex. DEPTOR interacts specifically with mTOR in both mTORC1 and mTORC2 and is believed to be an endogenous inhibitor of both the complexes (11). The mTORC2 assembles by forming a complex between the heterodimers rictor/SIN1 and mTOR/mLST8, which is the first step in the assembly of mTORC2 (Figure 14.1). The core subunits Rictor and Sin1 determine the integrity and stability of the mTORC2 complex. The mLST8 is a small adaptor protein, which is essential for maintaining the interaction between rictor-mTOR but not between raptor-mTOR. It regulates the kinase activity of mTOR by binding to the kinase domain of mTOR. A study reported that mTOR without mLST8 failed to bind to the rictor/SIN1 heterodimer, and knockout of mLST8 only disrupted the mTORC2 assembly (12). The two mTOR complexes show different sensitivity toward rapamycin (or Sirolimus, a macrocyclic lactone produced by Streptomyces hygroscopicus): mTORC1 is highly sensitive to rapamycin, whereas mTORC2 is relatively less sensitive (13,14).
Potential molecular mechanism of action of sodium-glucose co-transporter 2 inhibitors in the prevention and management of diabetic retinopathy
Published in Expert Review of Ophthalmology, 2022
Lia Meuthia Zaini, Arief S Kartasasmita, Tjahjono D Gondhowiardjo, Maimun Syukri, Ronny Lesmana
The mTOR plays a significant role in the pathophysiology of DR (Figure 3). It is a 289-kDa serine/threonine-protein kinase that is remarkably preserved both in function and formation [46]. In vivo, mTOR forms two distinct complexes called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC2 mainly regulates the insulin-signaling cascade, whereas mTORC1 controls various cellular processes [47]. Previous studies by Calton and Vollrath showed that mTOR inhibition leads to reduced migration of retinal pigment epithelial cells (RPE). In DR, the activation of mTOR produces the p-S6 protein to control the expression of VEGF and PDF. These growth factors alter the proliferation and migration of endothelial cells, indicating the hallmark of retinopathy disease [48]. Jacot et al. described that the inhibition of the PI3K/Akt/mTOR pathway provides several beneficial effects. It augments the apoptosis of endothelial cells and prevents vasculopathy progression, which inhibits neovascularization formation. Inhibiting PI3K/Akt/mTOR pathway can also preserve the function of photoreceptors and insulin signaling [49]. The inhibition of the PI3K/Akt/mTOR pathway is also appropriate during the late proliferative stage of DR, which is predominated by vasoproliferative processes because the mTOR pathway promotes hypoxia-induced vascular cell, smooth muscle, and endothelial cell proliferation as well as angiogenesis [46,49].
Advances in autophagy as a target in the treatment of tumours
Published in Journal of Drug Targeting, 2022
Yingying Li, Shan Gao, Xiyou Du, Jianbo Ji, Yanwei Xi, Guangxi Zhai
Mammalian rapamycin (mTOR) is a key regulatory centre in the initiation of autophagy which could be divided into two kinds of complexes with different structures and functions, mTORC1 and mTORC2 [156]. The former mainly includes mTOR, Raptor, G β L and Dintor, which controls cell growth and metabolism by receiving signals of amino acid, glucose, growth factor and ATP. The latter includes mTOR, Rictor, G β L, PRR5, DEPOR and SIN1 which could regulate the expression of mTORC1 and mainly involved in the regulation of cell proliferation. There are evidence suggesting that some molecules could directly control the expression of mTORC1 or mTORC2 to regulate autophagy flux. For example, PP2A protein phosphatase 2 A [157] (CIP2A) binds to mTORC1 to act as an allosteric inhibitor of PP2A, thus enhancing mTORC1 dependent growth signals and inhibiting autophagy. Also the expression level of peroxisome proliferator activated receptor gamma (PPAR γ) [158], is positively correlated with the level of mTORC2, thus regulating autophagy, and subsequently, it’s described that taurine (Tau) activate PPARγ‐mTORC2 signalling and inhibit autophagy. So this signalling pathway could be taken into account for therapeutic target.
pre-existing diabetes and PTDM in kidney transplant recipients: how to handle immunosuppression
Published in Expert Review of Clinical Pharmacology, 2021
Eloi Chevallier, Thomas Jouve, Lionel Rostaing, Paolo Malvezzi, Johan Noble
Different mechanisms of modification to glycemic metabolism have been suggested in patients that receive mTOR-Is [113]. Most in vitro and in vivo studies are consistent with both a detrimental effect of mTOR-Is on insulin secretion and on beta-cell survival and proliferation [114–118]. In a lean C57B/L6 mouse model, rapamycin-treated mice had lower plasmatic insulin secretion after glucose stimulation through interference in the leucine pathway and a reduction in beta-cell mass [119,120]. Moreover, animal and human studies also report a mechanism of insulin-resistance with mTOR-is through the reduction of mTOR signaling in the liver and inhibition of the phosphorylation of IRS-1 and IRS-2 mediated by mTORC2. Chronic rapamycin use is also associated with the lower ability to activate fatty acid beta-oxidation and ketogenesis [119,121,122]. Finally, chronic use of rapamycin is associated with increased gluconeogenesis in the liver [122,123].