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Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
Furthermore, mTOR is a serine/threonine kinase known to exist in the form of two complexes, mTORC1 and mTORC2, although more is known about the mTORC1 signaling pathway. Upon AKT activation, mTORC1 inhibits autophagy and promotes protein synthesis in neurons (54). In addition, activated hypothalamic mTOR signaling reduces food intake (55). Furthermore, in neurons, it has been established that both insulin and IGF-1 are able to increase mRNA translation which is thought to occur via mTORC1 phosphorylation (56).
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].
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].
Preventive Effect of Combined Zingiber officinale and Terminalia chebula against DMBA-Induced Breast Cancer Rats via mTOR Inhibition
Published in Nutrition and Cancer, 2022
Jayasindu Mathiyazhagan, Ramamoorthy Siva, Rama Jayaraj, Harishkumar Madhyastha, Gothandam Kodiveri Muthukaliannan
mTOR, a serine/threonine kinase composed of two conserved complexes, mTORC1 and mTORC2, is involved in signaling key information for cell metabolism and proliferation. mTOR is one of the most commonly altered pathways in cancer biology (10) and plays a central role in tumor initiation and progression (11). Elevated mTOR expression activates ribosome biogenesis, which provides a system to maintain cancer cell metabolism and growth (12). Therefore, developing therapeutic strategies based on the inhibition of mTOR signaling appears as a promising avenue for the cure of cancer. Rapamycin is a potent inhibitor of mTOR but has adverse side effects (13). Hence, there is a need to develop natural mTOR inhibitors with fewer side effects. Here, we provide evidence of preventive action of ZOTC against DMBA-induced breast cancer rats occurs via mTOR inhibition.
Insulin regulates Nedd4-2 via a PKB-dependent mechanism in HEI-OC1 auditory cells-crosstalks with sphingolipid and cAMP signaling
Published in Acta Oto-Laryngologica, 2022
Ann-Ki Pålbrink, Björn Morén, Karin G. Stenkula, Måns Magnusson, Eva Degerman
Regarding the insulin sensitive kinase mediating the effect on Nedd4-2, our data support a main role for PKB in HEI-OC1 cells which is in agreement with some previous studies in other cell types, for examples in alveolar cells [15], however, most studies give support for SGK1 as a major Nedd4-2 upstream kinase, for example [11–14]. Thus, in HEI-OC1 cells, GSK650394 prevented insulin-induced phosphorylation of the SGK1 substrate NDRG1, but not of PKB and Nedd4-2. One should stress that PKB and SGK1 appear to display a high level of overlapping substrate specificity, which complicates the attribution of specific biological functions to either of them. For example, PKB and SGK1 share the same optimal target motif, Arg-X-Arg-X-X-Ser/Thr, for example see [13] and references therein, and also share the essential features of their activation mechanism involving mTOR Complex 2, PDK1 and PI3K [11,14] which is in agreement with our result that the PKB inhibitor MK2206 also prevented the phosphorylation of the SGK1 substrate NDRG1. However, it has been demonstrated that activation of SGK1 and PKB occurs at distinct subcellular compartments which provides a mechanism for the selective activation of these functionally distinct mTORC2 targets [19].