Apositive regulator of growth called mTOR (mammalian Target of Rapamycin) is a direct detector of ATP levels, according to George Thomas (Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland) and colleagues. This connection from ATP to growth may explain why certain oxygen- and ATP-starved tumor cells are particularly sensitive to the mTOR- inhibitor rapamycin, as such tumors, through increased glycolysis and ATP production, may use the mTOR signaling pathway to proliferate.Dennis et al. began their studies with mTOR kinase assays. Results in several labs had been spotty, to the extent that mTOR's qualifications as a kinase were in question. “We were about ready to toss it out,” says Thomas.
Figure .
All roads lead to TOR.
Thomas/AAAS
But, by chance, the authors discovered that higher ATP concentrations converted mTOR into a robust kinase. Dropping ATP levels in vitro, or adding glycolytic inhibitors in vivo resulted in a drop in mTOR-specific phosphorylations of target proteins.
Apparently mTOR can act as a cellular ATP sensor because it has a weak, millimolar affinity for ATP. When both ATP and amino acids are available, mTOR upregulates translation and ribosome biogenesis, and downregulates autophagy. The remaining question is whether cancer cells that have gained a selective growth advantage by boosting mTOR activity do so through raising intracellular ATP levels. ▪
Reference:
Dennis, P.B., et al. 2001. Science. 294:1102–1105.