Regulation of the rapamycin and FKBP-target 1/mammalian target of rapamycin and cap-dependent initiation of translation by the c-Abl protein-tyrosinekinase

The c-Abl protein-tyrosine kinase is activated by ionizing radiation and ce rtain other DNA-damaging agents. The rapamycin and FKBP-target 1 (RAFT1), a lso known as FKBP12-rapamycin-associated protein (FRAP, mTOR), regulates th e p70S6 kinase (p70(S6k)) and the eukaryotic initiation factor 4E (eIF4E)-b inding protein 1 (4E-BP1), The present results demonstrate that c-Abl binds directly to RAFT1 and phosphorylates RAFT1 in vitro and in vivo. c-Abl inh ibits autophosphorylation of RAFT1 and RAFT1-mediated phosphorylation p70S6 k. The functional significance of the c-Abl-RAFT1 interaction is further su pported by the finding that eIF4E-dependent translation in mouse embryo fib roblasts from Abl(-/-) mice is significantly higher than that compared in w ildtype cells. The results also demonstrate that exposure of cells to ioniz ing radiation is associated with c-Abl-mediated binding of 4E-BP1 to eIF4E and inhibition of translation. These findings with the c-Abl tyrosine kinas e represent the first demonstration of a negative physiologic regulator of RAFT1-mediated 5' cap-dependent translation.