mTOR (mechanistic Target Of Rapamycin, mammalian Target Of Rapamycin aka FRAP, FK506 binding protein 12 (FKBP12)-rapamycin associated protein 1) plays a key role in coordinating the signals for a number of pathways, including insulin signaling, nutrient sensing and mitogenic signaling. mTOR is a large (>280kD), multidomain protein that includes a kinase domain and a FKBP12 binding domain. Rapamycin binds to FKBP12 and then complexes with mTOR to inhibit the enzyme.
The PI 3-K pathway regulates mTOR via the tuberous sclerosis proteins, TSC1 and TSC2. These proteins activate the small GTPase Rheb, that in turn binds and activates the kinase domain of mTOR. In cells, mTOR exists as two large complexes: mTORC1 and mTORC2. mTORC1 includes several proteins, including the regulatory protein Raptor and mTORC2 includes the regulatory protein Rictor. Only mTORC1 is rapamycin sensitive. Upstream signals regulating mTORC1 include growth factors, and glucose and oxygen levels. The most widely known phosphorylation targets of mTORC1 are the key components of the protein translation machinery, 4E-BP and p70 S6 kinase 1(S6K1). A key role of mTORC2 is actin organization, although mTORC2 can phosphorylate and activate Akt. Serum glucocorticoid-induced protein kinase 1 (SGK1) has been recently identified as an mTORC2 substrate. mTORC2 is not as sensitive to nutrient levels as mTORC1, and is insensitive to rapamycin.
mTORC1 is a sensor of nutrient and growth factor levels. Consequently, it has been linked to autophagy and other metabolic pathways. mTORC1 inhibits autophagy in the presence of nutrients; under conditions such as those resulting from starvation, infection, or oxidative stress, mTORC1 is inhibited and autophagy is triggered. AMPK also inhibits mTORC1 in response to glucose deprivation. mTORC1 has also been associated with glycolysis, and sterol and lipid biosynthesis. Its regulation of SREBP-1 (sterol regulatory element binding protein 1) and HIF (hypoxia-inducible factor) is suggestive of a role for mTORC1 in cellular mechanisms balancing nutrient sensing with carbohydrate and lipid metabolism.View all products for mTOR »
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Literature for mTOR
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