TI - Activation of the p70 S6 kinase and phosphorylation of the 4E-BP1 repressor of mRNA translation by type I interferons . AB - The Type I IFN receptor -generated signals required for initiation of mRNA translation and , ultimately , induction of protein products that mediate IFN responses , remain unknown . We have previously shown that IFNalpha and IFNbeta induce phosphorylation of insulin receptor substrate proteins and downstream engagement of the phosphatidylinositol ( PI ) 3'-kinase pathway . In the present study we provide evidence for the existence of a Type I IFN -dependent signaling cascade activated downstream of PI 3'-kinase , involving p70 S6 kinase . Our data demonstrate that p70 S6K is rapidly phosphorylated on threonine 421 and serine 424 and is activated during treatment of cells with IFNalpha or IFNbeta . Such activation of p70 S6K is blocked by pharmacological inhibitors of the PI 3'-kinase or the FKBP 12-rapamycin-associated protein/mammalian target of rapamycin ( FRAP/mTOR ) . Consistent with this , the Type I IFN -dependent phosphorylation/activation of p70 S6K is defective in embryonic fibroblasts from mice with targeted disruption of the p85alpha and p85beta subunits of the PI 3'-kinase ( p85alpha-/-beta-/- ) . Treatment of sensitive cell lines with IFNalpha or IFNbeta also results in phosphorylation/inactivation of the 4E-BP-1 repressor of mRNA translation . Such 4E-BP1 phosphorylation is also PI3'-kinase -dependent and rapamycin-sensitive , indicating that the Type I IFN-inducible activation of PI3'-kinase and FRAP/mTOR results in dissociation of 4E-BP1 from the eukaryotic initiation factor-4E ( eIF4E ) complex . Altogether , our data establish that the Type I IFN receptor -activated PI 3'-kinase pathway mediates activation of the p70 S6 kinase and inactivation of 4E-BP1 , to regulate mRNA translation and induction of Type I IFN responses .