title: The MAP kinase-interacting kinases regulate cell migration, vimentin expression and eIF4E/CYFIP1 binding.
abstract: The MAP kinase-interacting kinases (Mnk1 and Mnk2) are activated by ERK and are best known for phosphorylating the translation initiation factor eIF4E. Genetic knockout of the Mnks impaired the migration of embryonic fibroblasts both in two-dimensional wound-healing experiments and in three-dimensional migration assays. Furthermore, a novel and selective Mnk inhibitor, Mnk-I1, which potently blocks eIF4E phosphorylation, blocked the migration of fibroblasts and cancer cells, without exerting 'off-target' effects on other signalling pathways such as Erk. Mnk-I1 or genetic knockout of the Mnks decreased the expression of vimentin, a marker of mesenchymal cells, without affecting vimentin mRNA levels. Vimentin protein levels were much lower in Mnk1/2-knockout cells than in controls, although mRNA levels were similar. Our data suggest that the Mnks regulate the translation of the vimentin mRNA and the stability of the vimentin protein. Inhibition or genetic knockout of the Mnks increased the binding of eIF4E to the cytoplasmic FMRP-interacting protein 1 (CYFIP1), which binds the fragile-X mental retardation protein, FMRP, a translational repressor. Since FMRP binds mRNAs for proteins involved in metastasis, the Mnk-dependent release of CYFIP1 from eIF4E is expected to release the repression of translation of FMRP-bound mRNAs, potentially providing a molecular mechanism for the control of cell migration by the Mnks. As Mnk1/2 are not essential for viability, inhibition of the Mnks may be a useful approach to tackling cancer metastasis, a key process contributing to mortality in cancer patients.
authors.affiliation: *Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, U.K.
authors.forename: James E
authors.initials: JE
authors.lastname: Beggs
authors.affiliation: *Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, U.K.
authors.forename: Shuye
authors.initials: S
authors.lastname: Tian
authors.affiliation: *Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, U.K.
authors.forename: Greg G
authors.initials: GG
authors.lastname: Jones
authors.affiliation: *Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, U.K.
authors.forename: Jianling
authors.initials: J
authors.lastname: Xie
authors.affiliation: *Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, U.K.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iadevaia
authors.affiliation: †Cancer Sciences Unit, Somers Building, University of Southampton School of Medicine, Southampton, SO16 6YD, U.K.
authors.forename: Veronika
authors.initials: V
authors.lastname: Jenei
authors.affiliation: †Cancer Sciences Unit, Somers Building, University of Southampton School of Medicine, Southampton, SO16 6YD, U.K.
authors.forename: Gareth
authors.initials: G
authors.lastname: Thomas
authors.affiliation: *Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, U.K.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D034622:RNA Interference; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C115472:Cyfip1 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D050505:Mutant Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D014746:Vimentin; C106281:Mknk1 protein, mouse; C106282:Mknk2 protein, mouse; D017346:Protein Serine-Threonine Kinases