mTOR pathway

Introduction to mTOR signaling

The mammalian target of rapamycin (mTOR) is a master regulator that controls a wide variety of cellular processes, including cell growth, metabolism, proliferation, motility, survival, transcription, and protein synthesis1. The serine/threonine-protein kinase mTOR is found in two complexes, mTORC1 and mTORC2. 

mTORC1 complex is sensitive to rapamycin and contains mTOR, the regulatory-associated protein of mTOR (Raptor), and mammalian LST8 homolog (mLST8), a target of the rapamycin complex subunit. The complex also includes Deptor, which is an mTOR inhibitor, and PRAS40, an inhibitor of mTORC1. mTORC1 mediates cell growth by regulating translation, transcription, ribosome biogenesis, nutrient transport, and autophagy¹.

mTORC2 complex is less sensitive to rapamycin and contains mTOR, the rapamycin-insensitive companion of mTOR (Rictor), mammalian stress-activated protein-kinase-interacting protein (mSIN1), proline-rich protein 5 (PRR5), and mLST8. The complex also includes Deptor and a Rictor-binding subunit Protor. This second complex controls cell growth by regulating the actin cytoskeleton. 

mTOR has attracted broad interest because of its involvement in several human diseases, including type II diabetes and multiple cancer types. As a central controller of cell growth and metabolism, mTOR plays a significant role in development and aging and has been implicated in many major diseases, including cancer, cardiovascular disease, and metabolic disorders. It is estimated to be upregulated in 70% of all tumors².

mTOR activation

mTOR is activated during various processes, such as angiogenesis, adipogenesis, and T-lymphocyte activation, but it is dysregulated in many human diseases, including cancer and type 2 diabetes. Many processes crucial to cellular growth are controlled through the mTOR integration of four important signals: growth factors, glucose, amino acids, and oxygen. 

One of the most critical sensors regulating the activity of mTORC1 is the tuberous sclerosis complex (TSC). The TSC1/2 heterodimer acts as a GTPase-activating protein (GAP) for the small Ras-related GTPase Rheb ( RAS homolog enriched in brain)³.  Rheb interacts directly with mTOR through its active GTP-associated form. Both mTORC1 and mTORC2 respond to growth factors, whereas mTORC1 is also controlled by nutrients, such as glucose and amino acids.

mTORC activity is stimulated by the insulin and Ras signaling pathways. The stimulation of these pathways increases the phosphorylation of TSC2 by AKT (protein kinase B), extracellular signal-regulated kinase 1/2 (ERK1/2), and p90 ribosomal s6 kinase 1 (RSK1). TSC1/2 are subsequently inactivated, resulting in mTORC1 activation.

AMP-activated protein kinase (AMPK) can directly detect glucose and energy level fluctuations and relay them to mTOR. In response to low energy status, AMPK phosphorylates RAPTOR, providing binding sites for the regulatory protein 14-3-3, which diminishes mTORC1 signaling⁴. 

Amino acids act as a strong signal that regulates mTORC1 and are an absolute requirement for mTORC1 activation. Growth factors and other stimuli cannot activate mTOR if the cell is deficient in amino acids. A high level of amino acids can compensate for an absence of other mTORC1 inputs, but not the reverse⁵. 

mTOR response

mTORC1 positively regulates cell growth and proliferation by regulating various anabolic processes, including the biosynthesis of proteins, lipids, and organelles. At the same time, mTORC1 limits catabolic processes, such as autophagy. mTORC1 promotes protein synthesis through phosphorylation of the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and p70 ribosomal S6 kinase 1 (S6K1). 

mTOR also plays an essential role in insulin signaling and nutrient sensing by controlling downstream pathway components. The binding of insulin to its cell-surface receptor promotes the tyrosine kinase activity of the insulin receptor, the recruitment of insulin receptor substrate 1 (IRS1), the production of phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3] through the activation of phosphoinositol 3-kinase (PI3K), and the recruitment and activation AKT at the plasma membrane. A PI3K-AKT pathway upstream of PI3K is strongly repressed by the activation of mTORC1 in many cell types. S6K1 is activated by mTORC, which promotes its phosphorylation and reduces its stability.

Cell survival, metabolism, and proliferation are all highly dependent upon the activation status of AKT, which positively regulates these processes through the phosphorylation of multiple effectors. mTORC2 is required to fully activate AKT by phosphorylating it at two sites.

mTOR effects

mTORC1 positively controls protein synthesis, which is required for cell growth, through various downstream effectors. The stimulation of S6K1 activity by mTORC promotes mRNA biogenesis, cap-dependent translation, and ribosomal protein translation. Additionally, mTORC1 promotes ribosome biogenesis.

Metabolism and biogenesis of mitochondria are also regulated by mTOR. mTORC1 controls the transcriptional activity of peroxisome proliferation-activated receptor gamma (PPAR-gamma) coactivator 1 (PGC1-alpha), a nuclear co-factor. PGC1-alpha plays a key role in mitochondrial biogenesis and oxidative metabolism by directly altering its physical interaction with yin-yang 1 (YY1), another transcription factor.

Numerous cellular stressors inhibit mTORC1 signaling, reducing biosynthesis rates and promoting autophagy. In contrast,  mTORC inhibits autophagy by phosphorylating and thereby repressing unc-51 like autophagy activating kinase 1 (ULK1) and autophagy-related protein 13 (ATG13).

mTORC2 regulates cytoskeletal organization. It affects the actin cytoskeleton by promoting the phosphorylation of protein kinase C-alpha (PKC-alpha), phosphorylation of paxillin, and relocalization of paxillin to focal adhesions. 

mTOR in hypoxia

mTORC1 activity is sensitive to oxygen deprivation. This is mediated by a mechanism involving activation of the TSC1-TSC2 complex by REDD1 (regulated in development and DNA damage response 1).

REDD1 is a hypoxia-inducible protein that inhibits mTORC1 in a TSC-dependent manner⁶.  By releasing TSC2 from its growth-factor-induced association with 14-3-3 proteins, REDD1 inhibits mTORC1 signaling. This ability may have evolved to limit energy-consuming processes when oxygen, but not growth factors, is scarce.

Our poster includes mTOR signaling in response to calcium, glucose, and amino acid uptake into the cell. It also features the downstream activation of mTOR signaling after hypoxia. You will find how mTOR signaling can regulate cytoskeleton organization, ribosome biogenesis, and cap-dependent translation.