1. The MAP kinase-interacting kinases regulate cell migration, vimentin expression and eIF4E/CYFIP1 binding.
- Author
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Beggs JE, Tian S, Jones GG, Xie J, Iadevaia V, Jenei V, Thomas G, and Proud CG
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Cell Line, Tumor, Cell Movement drug effects, Cells, Cultured, Embryo, Mammalian cytology, Eukaryotic Initiation Factor-4E genetics, Humans, Mice, Mutant Proteins metabolism, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Nerve Tissue Proteins genetics, Phosphorylation drug effects, Protein Kinase Inhibitors pharmacology, Protein Processing, Post-Translational drug effects, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases genetics, Protein Stability drug effects, RNA Interference, Recombinant Proteins genetics, Recombinant Proteins metabolism, Vimentin chemistry, Vimentin genetics, Eukaryotic Initiation Factor-4E metabolism, Gene Expression Regulation drug effects, Nerve Tissue Proteins metabolism, Protein Serine-Threonine Kinases metabolism, Vimentin metabolism, Wound Healing drug effects
- 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.
- Published
- 2015
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