mTOR that is an evolutionarily conserved serine-threonine kinase of a 289-kDa in length belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family. mTOR is composed of an N-term; 20 tandem repeats-HEAT which are implicated in protein-protein interactions; and a C-term which includes a FAT domain, a FBR domain, a kinase CYT387 clinical trial domain, a NDR INCB28060 domain and a FATC domain. The FATC domain is essential to mTOR activity and the deletion of a single amino acid from this domain abrogates the activity. mTOR can be autophosphorylated
via its intrinsic serine/threonine kinase activity. mTOR exerts its multiple functions in the context of two different multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is composed of mTOR, Raptor, mLST8, and PRAS40, and importantly activates p70 ribosomal protein S6 kinase and inactivates eIF4E binding protein 1, which promotes protein translation and cell growth. Conversely, mTORC2 is composed of mTOR, Rictor, Sin1, and mLST8, phosphorylates
and activates another member of the AGC kinase family, Akt. Current research indicates that mTOR integrates the input from multiple upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and mitogens. mTOR also functions as a sensor of cellular nutrient and pheromone energy levels and redox status [2–5]. P70 S6 kinase (p70S6K) is activated in a signaling pathway that includes mTOR. P70S6K is a mitogen-activated Ser/Thr
CB-839 molecular weight protein kinase that is required for cell growth and G1 cell cycle progression. This kinase is controlled by multiple phosphorylation events located within the catalytic, linker and pseudosubstrate domains and subsequently phosphorylates specifically ribosomal protein S6. Activation occurs via phosphorylation at ser411, Thr421 and Ser424 within the pseudosubstrate region. Phosphorylation of Thr229 in the catalytic domain and Thr389 in the linker domain are most critical for kinase function. Stimulation of mammalian cells by a variety of mitogenic stimuli results in a rapid, biphasic activation of p70S6K. Inhibition of p70 activity inhibits the entry into S phase of the cell cycle and exhibits cell cycle arrest at G0/G1 phase, suggesting that the activation of p70S6k plays an obligatory role in mediating mitogenic signals during cell activation [6–8]. mTOR signaling pathway and its downstream serine/threonine kinase p70S6k were frequently activated in human cancers and the dysregulation of the mTOR pathway is implicated as a contributing factor to various human disease processes, especially various types of cancer[5, 6, 8–11].