Rapamycin enhances eIF4E phosphorylation by activating MAP kinase-interacting kinase 2a (Mnk2a)

•Rapamycin increases the phosphorylation of eukaryotic initiation factor eIF4E.•This effect requires the eIF4E kinase Mnk2.•Treating cells with rapamycin increases Mnk2 activity.•Rapamycin affects the phosphorylation of Mnk2 at Ser437.•Mutating Ser437 to alanine eliminates the effect of rapamycin on Mnk2 activity. Eukaryotic initiation factor eIF4E and its phosphorylation play key roles in cell transformation and tumorigenesis. eIF4E is phosphorylated by the Mnks (MAP (mitogen-activated protein) kinase-interacting kinases). Rapamycin increases eIF4E phosphorylation in cancer cells, potentially limiting their anti-cancer effects. Here we show that the rapamycin-induced increase in eIF4E phosphorylation reflects increased activity of Mnk2 but not Mnk1. This activation requires a novel phosphorylation site in Mnk2a, Ser437. Our findings have potentially important implications for the use of rapamycin and its analogues in cancer therapy, suggesting that inhibitors of mTOR and Mnk (or Mnk2) may be more efficacious than rapalogs alone.