China
Africa
Explore chapters and articles related to this topic
Molecular adaptation to resistance exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
The mechanistic target of rapamycin complex 1, abbreviated mTORC1, is a complex that contains a serine/threonine protein kinase (mTOR), an intermediary protein (raptor) and two kinase inhibitors (DEPTOR and PRAS40). In brief, mTOR phosphorylates proteins, that are identified by raptor, following activation by the small G-protein Rheb (Ras homologue enriched in brain). mTOR can also form a second complex (mTORC2), in which raptor is replaced by rictor (rapamycin insensitive companion of TOR) resulting in the targeting of a different subset of proteins for phosphorylation by mTOR.
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.
Roles of mTOR signaling in spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
The mechanistic target of rapamycin (mTOR) (TOR1/TOR2 in yeast) was originally identified in budding yeast through a genetic screen in 1991,1,2 and it is the target of a small molecule called rapamycin. mTOR is a large conserved serine/threonine protein kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family, and it forms two complexes in mammals called mTORC1 and mTORC2.3–6 mTORC1 consists of mTOR, Raptor, mLST8/GβL, PRAS40, and DEPTOR, and mTORC2 consists of mTOR, Rictor, mLST8/GβL, mSIN1, Protor1/2, and DEPTOR. Raptor and PRAS40 are specific components of mTORC1 complex that regulates ribosomal biogenesis, translation of mRNAs containing pyrimidine-rich 5’TOP or TOP-like motifs, and autophagy through downstream targets including ribosomal protein S6 kinase (S6K), eukaryotic initiation factor 4E binding protein-1 (4E-BP1), and ULK1/Atg13/FIP200 complex (unc-51-like kinase-1/mammalian autophagy-related gene 13/focal adhesion kinase-interacting protein of 200 kDα).7–11 In skeletal muscle tissues and cells, Raptor is required for maintaining mitochondrial respiration.3,12,13 In contrast, Rictor, mSIN1, and Protor1/2 are specific components of mTORC2 complex, which is involved in metabolism through AKT and serum/glucocorticoid induced kinase (SGK).14,15 It also sustains cytoskeleton through protein kinase C (PKC-α).16
Targeting signaling pathways involved in primordial follicle growth or dormancy: potential application in prevention of follicular loss and infertility
Published in Expert Opinion on Biological Therapy, 2022
Sara Ali Farhat, Forouq Jabbari, Parnian Jabbari, Nima Rezaei
The mTORC1 is expressed in primordial follicles granulosa cells (pfGCs) and is responsible for their differentiation. This is demonstrated by the failure of the flattened pfGCs to develop into cuboidal granulosa cells in the absence of Rptor (regulatory associated protein of mTOR) that forms an important element in the mTORC1 pathway [26,66]. The expression of mTORC1 in granulosa cells enhances the expression of KitL, which will ultimately lead to a promoted oocyte growth after KitL binds to its receptor on dormant oocytes via the PI3K pathway [26]. Kit signaling inactivation via the PI3K pathway in KitY719F mice through mutation of Kit tyrosine residue 719, involved in binding Kit to the regulatory subunit of PI3K [59], caused a decline of primordial follicle survival along with follicles arrest in the early phases of development. This is additionally in favor of the evident relation between these signaling factors [59].
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.
Icariin improves brain function decline in aging rats by enhancing neuronal autophagy through the AMPK/mTOR/ULK1 pathway
Published in Pharmaceutical Biology, 2021
Jie Zheng, Shanshan Hu, Jinxin Wang, Xulan Zhang, Ding Yuan, Changcheng Zhang, Chaoqi Liu, Ting Wang, Zhiyong Zhou
AMP-activated protein kinase (AMPK), an energy regulator of eukaryotic cells, also plays an important role in regulating autophagy. On the one hand, AMPK can promote autophagy by inhibiting the activation of mTORC1 through phosphorylating tuberous sclerosis complex 2 (TSC2) and Raptor. On the other hand, AMPK can directly phosphorylate multiple sites in the autophagy initiating factor Uncoordinated-51 like kinase 1 (ULK1), such as S317, S467, S555, T575, S637 and S777 etc., activate autophagy (Zang et al. 2006; Gwinn et al. 2008; Kalender et al. 2010; Wong et al. 2013). AMPKα1 deficiency impairs autophagy which leads to monocyte differentiation and decrease monocyte/macro-phage survival (Zhang et al. 2017). Furthermore, increasing p-AMPK can activate autophagy and rescue SHSY-5Y cells degeneration in PD model (Gong et al. 2016). Previous studies showed that the activation of AMPK was significantly decreased during aging (Cai et al. 2020; Lin et al. 2020). This evidence confirms that AMPK mediated autophagy is thought to be an important target to maintain neurons homeostasis during aging.