期刊
BIOCHEMICAL JOURNAL
卷 467, 期 -, 页码 63-76出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20141066
关键词
CYFIP1; eIF4E; EMT; Mnk; translation
资金
- UK Medical Research Council
- AstraZeneca UK
- Cancer Research UK [C17397/A13576]
- Biotechnology & Biological Sciences Research Council [BB/J007714/1]
- Biotechnology and Biological Sciences Research Council [BB/J007714/1] Funding Source: researchfish
- Cancer Research UK [13576] Funding Source: researchfish
- BBSRC [BB/J007714/1] Funding Source: UKRI
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 inMnk1/2-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 fragileX 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.
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