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…
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CYFIP1 interacts with FMRP and with the translation initiation factor eIF4E.
“CYFIP1 interacts with the Fragile X mental retardation protein (FMRP, encoded by the FMR1 gene), whose absence causes Fragile X syndrome, and with the translation initiation factor eIF4E.”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Beggs et al., 2015
Cites
FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism
Darnell, J. C., Van Driesche, S. J., Zhang, C., Hung, K. Y. S., Mele, A., Fraser, C. E., Stone, E. F., Chen, C., Fak, J. J., Chi, S. W., et al. (2011) · Cell · doi:10.1016/j.cell.2011.06.013 · Cited by 2,072 · see citing works
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Abekhoukh, S., Sahin, H. B., Grossi, M., Zongaro, S., Maurin, T., Madrigal, I., Kazue-Sugioka, D., Raas-Rothschild, A., Doulazmi, M., Carrera, P., et al. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.025809 · Cited by 59 · see citing works
“CYFIP1 is involved in translational regulation by interacting not only with FMRP (Schenck et al., 2001), but also with the translation initiation factor 4E (Napoli et al., 2008; Beggs et al., 2015).”
- Authors
- Beggs, J. E., Tian, S., Jones, G. G., Xie, J., Iadevaia, V., Jenei, V., Thomas, G., & Proud, C. G.
- Affiliations
- University of Southampton (GB)
- Corresponding author
- Tian, Shuye
- Xie, Jianling
- Iadevaia, Valentina
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2015-03-20
- Volume
- 467
- Issue
- 1
- Pages
- 63-76
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2324098421
- Cited by
- 65
- References
- 1
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 9 · 2019: 7 · 2018: 8 · 2017: 6 · 2016: 8 · 2015: 3
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Open Research (University of Surrey) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- Funders
- Cancer Research UK (13576, C17397/A13576)
- Biotechnology and Biological Sciences Research Council (BB/J007714/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- MNK1, MNK2, eIF4E phosphorylation, CYFIP1, FMRP, vimentin expression, cell migration, ERK signaling, protein stability, metastasis, fragile X syndrome
- MeSH terms
- Animals, Cell Movement, Cells, Cultured, Embryo, Mammalian, Gene Expression Regulation, Humans, Neoplasm Proteins, Nerve Tissue Proteins, Phosphorylation, Protein Processing, Post-Translational, Recombinant Proteins, Vimentin, Wound Healing, Protein Serine-Threonine Kinases, RNA Interference, Eukaryotic Initiation Factor-4E, Cell Line, Tumor, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, Mutant Proteins, Mice, Protein Stability
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