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Updated April 28, 2023.
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 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.
What to expect
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.