mTOR is a highly conserved serine NSC-330507 threonine protein kinase that belongs to the PI3K related family and serves as a central regulator Inhibitors,Modulators,Libraries of cell metabolism, growth, proliferation Inhibitors,Modulators,Libraries and survival. Extensive knowledge about the function of this protein has come from the experi mental use of the natural bacterial Inhibitors,Modulators,Libraries antibiotic rapamycin, which inhibits the activity of mTOR. mTOR consists of two separate multi protein complexes, mTORC1 and mTORC2, that are both activated by growth factor sti mulation. The mTORC1 complex is rapamycin sensitive. rapamycin binds the FK506 binding protein which binds to and causes allosteric inhibition of the sig Inhibitors,Modulators,Libraries nalling complex mTORC1 which contains mTOR, the regulatory associated protein, mLST8, PRAS40 and DEPTOR proteins.
mTORC1 positively regulates protein Inhibitors,Modulators,Libraries translation and synthesis via its main substrates, p70 ribosomal S6 kinase and the eukaryotic initiation factor 4E binding protein 1. Upon phosphorylation, 4E BP1 dissociates from the mRNA cap binding protein eIF4E and allows it to interact with eIF4G to form a translation initiation com plex. In the less well defined rapamycin insensitive mTORC2 complex, mTOR is associated with the rapamycin insensitive companion, LST8, mSIN1, PROCTOR and DEPTOR and phosphorylation of 4E BP1 on t37 46 is also considered rapamycin insensitive. The mTORC2 complex is involved in cytoskeletal organisation via paxillin, rho rac and PKB, but it also plays a key role in cell proliferation and survival via activation of serum and glucocorticoid protein kinase 1 and direct activation of Akt.
However, the characterisation of mTORC1 and mTORC2 as rapamycin sensitive and insensitive complexes may not always be entirely accurate, as chronic rapamycin treatment has also been reported to inhibit mTORC2 activ ity by blocking its assembly. The mTOR inhibitor antiangiogenic rapamycin has been used clinically as an immunosuppressant drug in trans plant medicine. However, it has recently been rea lised that the increased activity of the mTOR pathway caused by upstream changes in regulators, such as phosphatidylinositol 3 phosphatase and PI3K, also makes mTORC1 an attractive anti cancer tar get and a number of rapamycin analogues have been produced RAD001, CCI 779 and AP23573. The first clinical cancer trials in metastatic breast cancer with temsirolimus as a monotherapy resulted in only partial responses.