The complexes of mammalian target of rapamycin

Abstract

The mammalian target of rapamycin (mTOR) has attracted substantial attention because of its involvement in a variety of diseases, such as cancer, cardiac hypertrophy, diabetes and obesity. Current knowledge indicates that mTOR functions as two distinct multiprotein complexes, mTORC1 and mTORC2. mTORC1 phosphorylates p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), and regulates cell growth, proliferation, and survival by integrating hormones, growth factors, nutrients, stressors and energy signals. In contrast, mTORC2 is insensitive to nutrients or energy conditions. However, in response to hormones or growth factors, mTORC2 phosphorylates Akt, and regulates actin cytoskeleton and cell survival. These findings not only reveal the crucial role of mTOR in physiology and pathology, but also reflect the complexity of the mTOR signaling network. In this review, we discuss the advances in studies of the mTOR complexes, including the interacting proteins, the upstream regulators and the downstream effectors of mTOR complexes, as well as their implication in certain human diseases.

Fig. (1)

Domain structures of selected PIKKs. mTOR shown is of rat origin, and Mec1 and Tor1 are S. cerevisiae proteins. Other five proteins shown are of human origin. The number of residues for each protein is indicated in parentheses.

Fig. (2)

mTOR complexes and their known substrates. mTOR functions as two distinct complexes, mTORC1 and mTORC2. Besides mTOR, mTORC1 contains a positive regulatory subunit, raptor, two negative regulators, PRAS40 and DEPTOR, and a protein of unknown function called mLST8. mTORC2 also contains mTOR, mLST8 and DEPTOR, as well as other unique subunits, rictor, mSin1 and PROTOR.

Fig. (3)

Schematic structure of mTOR. N-terminus of mTOR contains two tandemly repeated HEAT motifs. Following the HEAT repeat region, there exist a FAT domain, an FRB domain, a catalytic kinase domain, an auto-inhibitory (repressor domain or RD domain), and a FATC domain that is located at the C-terminus of the protein.

Fig. (4)

mTOR signaling network. mTOR regulates multiple cellular processes by sensing energy and nutrient signals, and growth factors. Arrows represent activation, whereas bars represent inhibition.