Mtor

mTOR is the acronym for "mechanistic Target of Rapamycin", a regulatory protein found in all mammals that indirectly binds the immunosuppressant rapamycin. The mTOR gene is located on chromosome 1p36.22 and codes for the mTOR protein.

The MTOR protein belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stress factors such as DNA damage and nutrient deprivation.

The MTOR kinase is part of two different complexes (mTOR complex1/2):

• mTORC1, which controls protein synthesis, cell growth and cell proliferation and
• mTORC2, which regulates the actin cytoskeleton and promotes cell survival and cell cycle progression.

The mechanistic target of mTOR is a PI3K-related kinase (PIKK) represented by the two catalytic protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which have distinct activation and signal transduction mechanisms. In particular, mTORC1 can be activated by TCR and CD28 co-stimulation, environmental stimuli such as growth factors and stressors, and nutrients such as amino acids. It is crucial for regulating the growth and proliferation of T cells and for the differentiation of T helper cells 1(Th1) and Th17.

mTORC1 is sensitive to rapamycin. mTORC2 is not directly inhibited by this drug. Rapamycin has facilitated the discovery of the different functions of mTORC1 in metabolism (Szwed A et al. 2021). For example, activation of mTORC1 leads to phosphorylation of two key proteins that regulate protein translation: 4E-BP1 (eukaryotic initiation factor 4E (eIF-4E) binding protein-1) and S6K1 (protein S6 kinase 1).

Dysregulation of the mTOR signaling pathway promotes the development of metabolic diseases such as diabetes, obesity and tumors. Increased mTORC1 activity has been detected in the skin of acne patients(Melnik B 2018).

One of the key signaling molecules linking growth and metabolism is the protein kinase mTOR, which responds to nutrient levels and growth signals.The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process in which growth signals and metabolic pathways are intertwined. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. mTORC1 responds to growth signals. mTORC2 is also activated by anabolic signals, but is additionally activated by stress. mTORC2 mediates signals from growth factor receptors and G-protein-coupled receptors.

A variety of downstream effectors of mTORC2 have been identified, but among the best characterized mTORC2 substrates are Akt, PKC and SGK, which are members of the AGC protein kinase family (Ragupathi A et al. 2024).

As mTOR is an important target for cancer, aging and other metabolic diseases, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is critical for the development of more effective therapeutic strategies.

T cells, cells of blood and lymph vessels, smooth muscle cells and tumor cells are particularly sensitive to mTOR inhibition. In hereditary cystic kidney disease, mTOR is upregulated in the epithelial cells of renal cysts. In animal models, rapamycin leads to apoptosis of the cyst wall cells and thus inhibits the growth of the cysts. An overactivation of mTORC1 leads to a degradation of the amino acid glutamine as a result of which the level of the stress hormone FGF21 increases. The administration of glutamine can reduce FGF21 levels and thus prevent pathological impairments.

Dysregulation of the mTOR signaling pathway promotes the development of metabolic diseases such as diabetes, obesity and tumors. Numerous tumours are characterized by a dysregulated mTORC1 signalling network and glutamine dependence.

mTOR downregulation has been observed in many cancers. As part of the PI3K/Akt signaling pathway, there is broad interest in the biology of mTOR in all cancers. Inhibition of mTOR has been studied for nearly a decade. Everolimus, temsirolimus and zotarolimus are three of the most commonly used mTOR inhibitors used in clinical treatment today.

1. Melnik B et al. (2018) Acne and rosacea. In: G Plewig G et al. (Eds.) Braun-Falco's Dermatology, Venereology and Allergology. Springer Reference Medicine S 1306

2. Ragupathi A et al. (2024) The mTORC2 signaling network: targets and cross-talks. Biochem J 481:45-91.

3. Szwed A et al. (2021) Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev 101:1371-1426.