mTOR Signaling Pathway
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 (see AKT pathway). 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 (see also the Regulation of eIF4e and p70 S6 Kinase pathway).
Contributor:
REFERENCES: Aoki, M., Blazek, E., Vogt, P.K. A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc. Natl. Acad. Sci. U. S. A. 2001, 98(1), 136-41 Brown, E., et al. Control of p70 S6 Kinase by Kinase Activity of FRAP in vivo. Nature 1995, 377, 441-446. Dennis, P.B. et al. Mammalian TOR: a homeostatic ATP sensor. Science 2001, 294(5544), 1102-5. Gingras, A.C., Raught, B., Sonenberg, N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001, 15(7), 807-26 Jungwon, C., Chen J., Schreiber,S., Clardy, J. Structure of the FKBP12-Rapamycin Complex Interacting with the Binding Domain of FRAP. Science 1996, 273, 239-242 Neshat M., et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP / mTOR. PNAS 2001 Vol 28(18): pp 10314-10319 Neuhaus P. et al. mTOR inhibitors: an overview. Liver Transpl. 2001, (6), 473-84 Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice. Proc. Natl. Acad. Sci. U. S. A. 2001, 98(18), 10320-5
