mTOR SIGNALING PATHWAY
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, mTOR has been shown to directly
phosphorylate the ribosomal protein S6 kinase p70 (S6k), the translational
inhibitors 4E-BP1 and 4E-BP2, 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 identification 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.
A diagram of the mTOR signaling pathway can be found at www.genome.jp/kegg/pathway/hsa/hsa04150.html.
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Detection of Human eIF4B by
Western Blot and Immunoprecipitation.
Samples: Whole cell lysate (5, 15 and 50 mcg for WB; 1 mg
for IP, 20% of IP loaded) from HeLa cells.
Antibodies: Affinity purified rabbit anti-eIF4B antibody
A301-767A used for WB at 0.04 mcg/ml (A) and 1 mcg/ml (B) and used for IP
at 3 mcg/mg lysate. eIF4B was also immunoprecipitated by rabbit
anti-eIF4B antibody A301-766A,
which recognizes an upstream epitope. For blotting immunoprecipitated eIF4B,
the ReliaBLOT® Reagents and Procedures
(Cat. No.
WB120) were used.
Detection: Chemiluminescence with exposure times of 10
seconds (A) and 3 seconds (B).
ReliaBLOT is a registered trademark of
Bethyl Laboratories, Inc. |
Detection of Human AMPK by
Immunocytochemistry.
Sample: FFPE section of human skeletal muscle.
Antibody: Affinity purified rabbit anti-AMPK alpha 1 (Cat. No.
IHC-00002) used at a dilution of 1:250.
Detection: DAB. |
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