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.

Fig. 1

History of research on the discovery and development of mTOR signaling. The figure describes the journey of mTOR signaling from its origin to the most advanced scientific discoveries including the identification, isolation, development of inhibitors, and their application as therapeutics in human health and diseases. Created with BioRender.com. FDA Food and Drug Administration, TOR target of rapamycin, mTOR mammalian target of rapamycin, mTORC1 mTOR complex 1, mTORC2 mTOR complex 2, MCL mental cell lymphoma, Nab-sirolimus nanoparticle albumin-bound sirolimus, PEComa perivascular epithelioid cell tumor, PNET pancreatic neuroendocrine tumor, RCC renal cell carcinoma, SEGA subependymal giant-cell astrocytoma

Fig. 2

The domain structures of mTORC1 and mTORC2, their downstream signaling targets and functional role. N-terminal domain of mTOR possesses tandem HEAT repeats and C-terminal domains composed of FATC, kinase, FRB, and FAT. The mTOR signaling pathway is majorly constituted of two distinctive mTOR complexes named mTORC1 and mTORC2. The mTORC1 is a complex of DEPTOR, Raptor, PRAS40, mLST8, mTOR, and phosphorylate downstream targets to regulate protein synthesis or mRNA translation, lipid synthesis, nucleotide synthesis, lysosomal biogenesis, and autophagy. The mTORC2 is a complex of mTOR, DEPTOR, mSIN1, Rictor, Protor, and mLST8 to regulate cell survival, proliferation, migration, and cytoskeleton remodeling. Created with BioRender.com

Fig. 3

The major upstream regulators of mTORC1 and mTORC2. Growth factors, amino acids like arginine and leucine, energy from glucose or other sources, cell stresses including DNA damage, and ROS stimulate mTORC1 to modulate various biological processes like mitochondrial biogenesis, nucleotide synthesis, mRNA translation (protein synthesis), lipid synthesis, and autophagy. The growth factors are the main regulators of the mTORC2 to control cell proliferation, migration, cytoskeleton remodeling, ion transport, and glucose metabolism. Created with BioRender.com

Fig. 4

The association of long noncoding RNAs in mTOR signaling. The lncRNAs act as a sponge for miRNA that controls the expression of the upstream or downstream protein coding gene involved in the mTOR signaling cascade. DLEU1 and HAGLROS can directly bind with mTOR whereas FA2H-2 and NBR2 lncRNA regulate mTOR signaling through AMPK. LINC-ROR, CRNDE, DANCR, and LINC01133, regulate mTORC2-mediated signaling. HULC, ZNNT1 activate elF4E, H19 inhibit 4E-BP1, and CRNDE, DLEU1, TUG1, UCA1, and MALAT1 activate P70S6K1 to modulate mTOR signaling. Created with BioRender.com

Fig. 5

Key events involved in mTOR-mediated autophagy. The mTORC1 suppressed the ULK1 complex activity via phosphorylation of ULK1/ATG13. The mTORC1 can help in the translocation of TFEB in the nuclear compartment to regulate the process of autophagy. The mTORC1 has an important role in the induction of autophagy, nucleation, phagosome elongation, autolysosome formation, and finally degradation through lysosomes. Created with BioRender.com

Fig. 6

The mTOR signaling is crucial for modulating the key immune responses. The activated dendritic cells can present the antigen through T-cell receptors that initiate activation, proliferation, and differentiation of invariant natural killer T cells, CD4⁺, and CD8⁺ T cells through stimulation of mTOR. The higher levels of mTOR determine the metabolic active state while lower levels of mTOR define the quiescent state of the T- and B cells. The absence of mTOR signaling during differentiation of naive CD4⁺ T cells generates T-regulatory cell and T-follicular helper cell. The high mTOR activity during activation of naive CD4⁺ T cells supports the expression of the crucial transcription factors needed for their differentiation into Th1, Th2, and Th17 cells. T-follicular helper cells activate the germinal center to generate antibodies. Created with BioRender.com

Fig. 7

Pharmacological targeting of the mTOR signaling cascade in human malignancies. The mTOR pathway can be targeted at different levels in human malignancies using Rapalogs or mTOR inhibitors, PI3K small molecule inhibitors, dual mTOR/PI3K inhibitors, compounds targeting AKT, and ATP-competitive inhibitors against mTOR. Created with BioRender.com