Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease

Abstract

The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain cellular homeostasis. The mTOR signaling cascade consists of two distinct multi-subunit complexes named mTOR complex 1/2 (mTORC1/2). mTOR catalyzes the phosphorylation of several critical proteins like AKT, protein kinase C, insulin growth factor receptor (IGF-1R), 4E binding protein 1 (4E-BP1), ribosomal protein S6 kinase (S6K), transcription factor EB (TFEB), sterol-responsive element-binding proteins (SREBPs), Lipin-1, and Unc-51-like autophagy-activating kinases. mTOR signaling plays a central role in regulating translation, lipid synthesis, nucleotide synthesis, biogenesis of lysosomes, nutrient sensing, and growth factor signaling. The emerging pieces of evidence have revealed that the constitutive activation of the mTOR pathway due to mutations/amplification/deletion in either mTOR and its complexes (mTORC1 and mTORC2) or upstream targets is responsible for aging, neurological diseases, and human malignancies. Here, we provide the detailed structure of mTOR, its complexes, and the comprehensive role of upstream regulators, as well as downstream effectors of mTOR signaling cascades in the metabolism, biogenesis of biomolecules, immune responses, and autophagy. Additionally, we summarize the potential of long noncoding RNAs (lncRNAs) as an important modulator of mTOR signaling. Importantly, we have highlighted the potential of mTOR signaling in aging, neurological disorders, human cancers, cancer stem cells, and drug resistance. Here, we discuss the developments for the therapeutic targeting of mTOR signaling with improved anticancer efficacy for the benefit of cancer patients in clinics.

Senolytics enhance longevity inCaenorhabditis elegansby altering betaine metabolism

“…Onken B et al indicated that metformin could increase the expression of akk-2 and extend lifespan through the AMPK/ akk-2 pathway [51]. In addition, as previously reported, the AMPK/mTOR signaling pathway protects the expected initiation of autophagy and delays the organism’s ageing [22]. However, there is no clear understanding of how autophagy promotes lifespan extension.…”

“…Among them, several of the pathways are longevity-related, such as MAPK signaling pathway and longevity regulating pathway, which have been proposed to be related to lifespan [19,20]. At the same time, we identified critical metabolic pathways, such as autophagy, the forkhead box transcription factor (FoxO) signaling pathway, and the target of rapamycin (mTOR) signaling pathway, which are closely related to physiological activities, including autophagy and oxidative stress [21,22] (Figure S3a, S3b). To further identify the metabolites related to aging, correlation analysis was conducted.…”

Herbs and Spices: Modulation of Gut Microbiota for Healthy Aging

“…By integrating intra-and extracellular signals, mTOR can profoundly impact disease development. The GM and its metabolites regulate various host functions, including autophagy, fatty acid metabolism, oxidative phosphorylation, and immune response [60,61]. Dysregulation of these pathways is associated with various age-related health disorders involving the mTOR signaling pathway.…”

From Genes to Therapy: Pituitary Adenomas in the Era of Precision Medicine

“…Recent studies have shown that the constitutive activation of the mTOR pathway, due to genetic changes like mutations, amplifications, or deletions in mTOR itself, its complexes (mTORC1 and mTORC2), or its upstream targets, plays a role in aging, neurological disorders, and various human cancers. Progress in targeting mTOR signaling could significantly improve anti-cancer treatments and benefit patients in clinical settings [105].…”

“…[41] AMIGO2, ZFP36, BTG1, DLG5 (in gonadotroph tumors) Identified as novel tumor-related genes [42] HSPB1 Associated with reduced overall survival in tumors, potential therapeutic target in invasive pituitary adenoma [46] Immune Checkpoint Blockers Explored as a new therapeutic option for aggressive pituitary adenomas/PitNETs and pituitary carcinomas [47,59] IL-6, TNF-α Play significant roles in the development and progression of invasive pituitary adenoma [56,57] VEGF/VEGFR Signaling Associated with an immunosuppressive microenvironment in non-functioning PitNETs with CS invasion, potential target for therapy [58] Tumor-Associated Fibroblasts (TAFs) Impact tumor invasiveness, angiogenesis, and epithelial-to-mesenchymal pathways in PAs, target of SSAs [60] mTOR Inhibitors Target the constitutive activation of the mTOR pathway in various human cancers, including pituitary tumors [104,105] Mismatch Repair Deficiency (MMRd) and PD-L1 Expression Correlated with responsiveness to anti-PD-1 therapies; PD-L1 prevalent in functional pituitary adenomas [50,109] Tyrosine Kinase Inhibitors (targeting EGFR)…”