Regulation of a nutrient-dependent cell growth

Origin of eukaryotes is a fundamental breakthrough in evolution. By enhancing aerobic gain of energy, eukaryotic cells transformed a complexity of biological systems marked by a substantial increase in cell size and emergence of multicellular organisms. If quantified, an average mammalian cell is at least one thousand times larger than a bacterial E. coli. A substantial increase of eukaryotic cell size obligates a coordination of cell growth with metabolic input. This coordination is installed in every eukaryotic cell by a stringent signaling pathway controlling accumulation of cellular mass according to nutrients available to cell. It is known as a target of rapamycin (TOR) pathway and is referred as mTOR in mammalian cells. A central component of this pathway is a TOR protein that is an essential and large serine/threonine kinase conserved in all eukaryotes. It has been named after a natural compound rapamycin known as a highly specific allosteric inhibitor of TOR that was selected originally for its growth suppressing activity in yeast. Rapamycin is secreted by bacteria Streptomycin hygroscopicus and is likely an advantageous trait in territorial competition with yeast.

The biochemical studies determined that mTOR exists in two distinct complexes distinguished not only functionally but also by their sensitivity to rapamycin. mTOR in a complex with raptor forms the mTOR Complex 1 (mTORC1). It has been defined as a nutrient-dependent complex controlling cell growth (accumulation of cellular mass) by regulating a rate of protein synthesis through phosphorylation of its substrates 4EBP1 and the kinases of S6 ribosomal protein S6K1 and S6K2 (the members of AGC kinase family). Nutrients and growth factors promote protein synthesis by regulating a kinase activity of mTORC1. Interestingly, lysosomes were identified as the amino acid sensing organelle. Amino acids control a basal activity of mTORC1 by its translocation on a lysosomal surface mediated by Rag GTPase proteins. Growth factors enhance a basal kinase activity of mTORC1 by regulating Rheb GTPase. Deprivation of amino acids inhibits activity of mTORC1 leading to decline of protein synthesis, activation of autophagy (an intracellular “self-eating” survival process induced by starvation) and decrease of cell size. A lipophilic macrolide rapamycin mimics a nutrient deprivation effect by targeting mTORC1. Rapamycin in a complex with its small protein receptor FKBP12 inhibits mTORC1 by binding with a high specificity to the FKBP12 and rapamycin binding (FRB) domain of mTOR. FRB represents a stretch of 100 amino acids adjacent to the kinase domain which is located at the C-terminus of mTOR. A single mutation within FRB domain prevents binding of the rapamycin/FRB drug complex on mTOR and renders cells insensitive to rapamycin.

A binding of rictor and SIN1 proteins to mTOR forms a distinct complex without raptor known as mTORC2. The kinase activity of mTORC2 depends on a growth factor signaling and it regulates cell proliferation, metabolism and migration by functioning as a regulatory kinase of other AGC kinases (Akt, PKC and SGK) by phosphorylating their hydrophobic motifs. A basal activity of mTORC2 is growth factor independent and maintains a constitutive phosphorylation of the turn motifs of its kinase substrates. A basal activity of mTORC2 is sensitive to ATP depletion and observed under glucose deprivation. In a contrary to mTORC1, mTORC2 is not targeted by rapamycin suggesting that the FRB domain is hidden by rictor and SIN1 bound to mTOR. Besides, mTORC2 is less conserved compare to mTORC1 because it exists in yeast and animals but it has not been found in plants. Thus, two distinct mTOR complexes defining the fundamental roles of mTOR signaling in regulation of cell growth and proliferation indicate that mTOR determines growth of organism in development and maintains its body size according to a nutrient consumption and environmental factors. Deregulation of mTOR signaling is common in human diseases.