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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).
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.
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
PAR is degraded by Poly (ADP-ribose) glycohydrolase and possibly ADP-ribose hydrolase 3, into ADP-ribose molecules, which are metabolized further to AMP. The increased AMP: ATP ratio catalyzes the metabolic sensor AMP-activated protein kinase (AMPKs). Mammalian target of rapamycin complex 1 (MTORC1) is thereby inhibited, inducing autophagy [50]. Thus, cellular energy homeostasis is regulated. In the process of making PAR, NAD+ is converted to nicotinamide. To replenish the NAD+ from nicotinamide, phosphoribosyl pyrophosphate and ATP are converted to AMP and pyrophosphate (Fig. 15.1). In the case of extreme DNA damage, as with ischemia, PARP 1 hyperactivation results in depletion of NAD+ and ATP, resulting in cell death by necrosis or apoptosis [108].
Evaluating everolimus for the treatment of breast cancer
Published in Expert Opinion on Pharmacotherapy, 2023
Camille Moreau-Bachelard, Marie Robert, Carole Gourmelon, Emmanuelle Bourbouloux, Anne Patsouris, Jean-Sébastien Frenel, Mario Campone
mTOR is a kinase, which is dysregulated in many cancers. Everolimus links to the FKBP-12 intracellular protein and forms a complex inhibiting mTORC1. The inhibition of the mTORC1 signaling pathway leads to reduced activity of ribosomal protein kinase S6 (S6K1) and eukaryotic elongation factor-binding protein 4 (4EBP–1). These two proteins are implicated in the cell cycle, angiogenesis, and glycolysis [10]. The S6K1 protein activates the functional domain of the estrogen receptor by phosphorylation. This leads to a permanent activation of the receptor. Everolimus reduces the levels of vascular endothelial growth factor (VEGF) responsible for tumoral neo-angiogenesis. Everolimus reduces glycolysis and is an inhibitor of the proliferation of tumor cells, endothelial cells, vascular smooth muscle cells, and fibroblasts. It blocks the hypoxia-inducible factor 1 (HIF-1) expression [10].
New insights into the metabolism of Th17 cells
Published in Immunological Medicine, 2023
The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is an essential regulator of cell growth and metabolism. Th1 and Th17 cells depend on mTORC1, which enhances glycolysis, fatty acid synthesis and mevalonate pathway [39,61,62]. Inhibition of mTOR reduces glycolysis and Th1 and Th17 differentiation [39,62]. Mechanistically, mTORC1 induces HIF-1α, which sustains glycolysis [39]. mTOR activity is enhanced in CD4 T cells in many autoimmune diseases, including SLE, multiple sclerosis and giant cell arteritis [13,28,63]. Several studies have revealed that mTOR inhibitors ameliorate animal models of lupus and EAE [63,64]. Sirolimus, one of the mTOR inhibitors, improved disease activity in patients with refractory SLE in a single-arm, open-label, phase I/II trial [65]. Other non-randomized controlled studies have reported that sirolimus is beneficial for patients with SLE [66]. Sirolimus normalized Th17/Treg balance and TCR-induced Ca2+ flux in patients with SLE [67,68]. Additional randomized controlled trials are needed to prove the efficacy and to document the possible side effects of sirolimus in patients with SLE [69].
Glycometabolic rearrangements–aerobic glycolysis in pancreatic ductal adenocarcinoma (PDAC): roles, regulatory networks, and therapeutic potential
Published in Expert Opinion on Therapeutic Targets, 2021
The mTOR protein exists intracellularly in two distinct complexes, mTORC1 and mTORC2, both of which are involved in regulation of cell proliferation and energy metabolism [34,148]. The mTORC1 complex, which is extensively involved in metabolism, can enhance protein translation and adipogenesis, as well as regulating glucose metabolism by converting OXPHOS of glucose to glycolysis in tumor cells. Experimental studies have shown that the activities of GLUT1 and HK2 are regulated by activated mTORC1 signaling, which directly affects cellular glucose uptake and glycolytic rate. In addition, mTORC1 promotes the upregulation of transcription factor HIF-1α, which further upregulates glycolysis-related genes including GLUT1, HK2, LDHA, and PFK [149,150]. The mTORC2 complex is involved in regulating downstream targets of the AGC kinase family and promotes glycolysis by upregulating Akt signaling, which can activate HK2 and PFK1 [151–153]. Therefore, the mTOR signaling pathway has an indispensable role in the regulation of glycolysis in tumor cells, and further exploration of its regulatory network is expected to contribute to the development of new approaches for targeted therapy with glucose metabolism.