mTOR: a protein kinase switching between life and death

Abstract

The mammalian target of rapamycin (mTOR) is a central regulator of ribosome biogenesis, protein synthesis, cell growth and neurite plasticity. The mTOR kinase controls the translation machinery, in response to amino acids and growth factors, via activation of p70 ribosomal S6 kinase (p70S6K) and inhibition of eIF-4E binding protein (4E-BP1). The mTOR protein belongs to the PI3K pathway activated by insulin, nutrients and growth factors. The PI3K pathway involves the Akt kinase, an upstream regulator of mTOR. Rapamycin is a potent immunosuppressant and investigational anticancer drug, which inhibits mTOR, blocking protein synthesis and arresting the cell cycle in G1 phase. A wide body of evidence supports the role of mTOR in cell signaling related to cell growth and proliferation. Nevertheless, our recent findings have revealed that mTOR may be also involved in a signaling pathway activated by microtubule-damaging drugs, including taxol and nocodazole. It is known that agents affecting the integrity of microtubules activate apoptotic program by inducing phosphorylation and inactivation of the antiapoptotic Bcl-2 protein in G2-M phase. We have some evidence that mTOR is involved in the enzymatic cascade that, starting from damaged microtubules, induces downstream phosphorylation of the Bcl-2 protein. We also found that the level of activity of Akt can regulate Bcl-2 phosphorylation, through the mTOR kinase. Since mTOR activation by survival signals occurs in G1 phase and damaged microtubules activate proapoptotic signals in G2-M phase, we suggest that mTOR might mediate these two different pathways in two different phases of the cell cycle.