title: Rapamycin enhances eIF4E phosphorylation by activating MAP kinase-interacting kinase 2a (Mnk2a).
abstract: 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.
authors.affiliation: Centre for Biological Sciences, Building 85, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stead
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
mesh_terms: D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012694:Serine / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D012694:Serine; D006160:Guanosine Triphosphate; C491395:MKNK1 protein, human; C106281:Mknk1 protein, mouse; C106282:Mknk2 protein, mouse; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases; D000409:Alanine; D020123:Sirolimus
keywords: Mnk; Rapamycin; eIF4E; mTORC1