mTOR (mammalian target of
rapamycin) is a member of the ATM (ataxia telangiectasia mutated)-related
family of kinases. Studies of mTOR have demonstrated that it performs an
essential role in integrating cellular signals received from growth factors
and from the detection of nutrient, stress, and energy levels in the cell. The
integration of signals by mTOR functions to control cell growth by
influencing cellular processes such as translation initiation, ribosome
biogenesis, and transcription factor localization. mTOR is an
evolutionarily conserved protein originally identified as the direct target
of the cell cycle arresting activity of the immunosuppressive drug,
rapamycin. Through its interaction with FKBP12, rapamycin is able to exert
its effects by binding the mTOR Complex1 (mTORC1) and inhibiting the mTOR
signaling pathway. In response to growth and survival signals, m TOR has
been shown to directly phosphorylate the ribosomal protein S6 kinase p70
(S6k), the translational inhibitors 4EBP1 and 4EBP2, and PHAS; therefore
mTOR exerts many of its effects via the control of protein translation.
Biochemical characterization of the mTORC1 complex has identified the mTOR
interacting proteins Raptor and Lst8p. A rapamycin-insensitive mTOR
complex, mTORC2 has also been identified. This complex does not possess
Raptor but another protein termed Rictor (rapamycin insensitive companion
of TOR). In addition to Rictor, the mTORC2 complex contains mLST8, mSin1,
and protor 1. This complex appears to play a role in the regulation of
cytoskeletal organization and has been shown to be the phosphoinositide-dependent
protein kinase-2 (PDK2) responsible for AKT activation. Two negative
regulators of mTOR have been identified. The TSC1-TSC2 complex is a
heterodimer of the TSC1 and TSC2 gene products responsible for the genetic
disorder tuberous sclerosis. The identifica tion of mTOR and the study of
its function in yeast, humans, and drosophila have defined the mTOR pathway
as a complex central regulator of cell growth. Future studies that focus on
the convergence of mTOR signaling with other growth and survival pathways
will provide a framework for targeting proteins in the mTOR and related
pathways as anti-cancer therapies.