mTOR (mammalian target of rapamycin) appears to play a central role in signaling caused by nutrients and mitogens such as growth factors to regulate translation. The drug rapamycin acts on mammalian cells through the mTOR protein kinase, also known as FRAP. When bound to the immunophilin binding protein FKBP12, rapamycin inhibits mTOR kinase activity and has immunosuppressant activity. Rapamycin and the mTOR inhibitor CCI-779 are being tested as anti-cancer agents, acting to block mitogenic signaling. Recently, mTOR was also found to act as an ATP sensor to regulate cell growth. Upstream activation of PI 3 kinase activity that leads to oncogenic transformation can be blocked by inhibition of mTOR by rapamycin. Growth factor receptors first stimulate PI 3 kinase, and through inositol phosphates activate PDK-1 and AKT (protein kinase B). AKT phosphorylates mTOR. The phosphorylation of p70S6K and 4EBP by mTOR and the phosphorylation downstream of RPS6 and EIF-4B stimulate translational initiation and contribute to cell growth.
