The MAP kinase-interacting kinases regulate cell migration, vimentin expression and eIF4E/CYFIP1 binding
The MAP kinase-interacting kinases regulate cell migration, vimentin expression and eIF4E/CYFIP1 binding
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DOI：
10.1042/bj20141066
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发表时间：
2015-04-01
影响因子：
4.1
通讯作者：
Proud, Christopher G.
中科院分区：
文献类型：
--
作者：
Beggs, James E.;Tian, Shuye;Proud, Christopher G.
MAP激酶相互作用激酶（Mnk 1和Mnk 2）由ERK激活，最为人所知的是磷酸化翻译起始因子eIF 4 E。基因敲除Mnks在二维伤口愈合实验和三维迁移试验中均损害胚胎成纤维细胞的迁移。此外，一种新型的选择性Mnk抑制剂Mnk-I1可以有效地阻断eIF 4 E磷酸化，阻断成纤维细胞和癌细胞的迁移，而不会对其他信号通路（如Erk）产生“脱靶”效应。Mnk-I1或Mnks基因敲除降低了间充质细胞标志物波形蛋白的表达，而不影响波形蛋白mRNA水平。Mnk 1/2基因敲除细胞中波形蛋白的水平比对照组低得多，尽管mRNA水平相似。我们的数据表明，Mnks调节波形蛋白mRNA的翻译和波形蛋白的稳定性。Mnks的抑制或基因敲除增加了eIF 4 E与细胞质FMRP相互作用蛋白1（CYFIP 1）的结合，CYFIP 1结合fragileX精神发育迟滞蛋白FMRP，一种翻译阻遏物。由于FMRP结合参与转移的蛋白质的mRNA，因此预期CYFIP 1从eIF 4 E的Mnk依赖性释放将释放对FMRP结合的mRNA的翻译的抑制，从而潜在地提供Mnk控制细胞迁移的分子机制。由于Mnk 1/2对生存力不是必需的，因此抑制Mnk可能是解决癌症转移的有用方法，这是导致癌症患者死亡的关键过程。
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.