Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses

Joshi, Sonali; Kaur, Surinder; Redig, Amanda J.; Goldsborough, Katy; David, Kevin A.; Ueda, Takeshi; Watanabe-Fukunaga, Rie; Baker, Darren P.; Fish, Eleanor N.; Fukunaga, Rikiro; Platanias, Leonidas C.

doi:10.1073/pnas.0900562106

Cited by 74 publications

(68 citation statements)

References 40 publications

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“…When U937 human myeloid leukemia cells or U266 human myeloma cells were treated with IFNα or IFNβ, we observed an increase in the phosphorylation of Mnk1 and its downstream target eIF4E [96]. Studies involving pharmacological inhibition of Mnk kinases or studies in mouse embryonic fibroblasts (MEFs) lacking both Mnk1 and Mnk2 demonstrated that the phosphorylation of eIF4E on Ser209 by type I IFNs is controlled by Mnk kinases [96]. In experiments employing pharmacological inhibition of p38 MAPK or p38α knockout MEFs we found that type I IFN- mediated engagement of Mnk1/eIF4E is p38 MAPK-independent [96].…”

Section: Rantesmentioning

confidence: 99%

“…Studies involving pharmacological inhibition of Mnk kinases or studies in mouse embryonic fibroblasts (MEFs) lacking both Mnk1 and Mnk2 demonstrated that the phosphorylation of eIF4E on Ser209 by type I IFNs is controlled by Mnk kinases [96]. In experiments employing pharmacological inhibition of p38 MAPK or p38α knockout MEFs we found that type I IFN- mediated engagement of Mnk1/eIF4E is p38 MAPK-independent [96]. On the other hand the engagement of Mnk1/eIF4E by type I IFNs was found to be MEK1/Erk dependent [96].…”

Section: Rantesmentioning

confidence: 99%

“…In experiments employing pharmacological inhibition of p38 MAPK or p38α knockout MEFs we found that type I IFN- mediated engagement of Mnk1/eIF4E is p38 MAPK-independent [96]. On the other hand the engagement of Mnk1/eIF4E by type I IFNs was found to be MEK1/Erk dependent [96]. In further studies, it was established that pharmacological inhibition of Mnk kinases attenuates IFNα stimulated expression of ISG15, an ISG known to play roles in mediating the biological effects of type I IFNs [97].…”

Section: Rantesmentioning

confidence: 99%

“…In further studies, it was established that pharmacological inhibition of Mnk kinases attenuates IFNα stimulated expression of ISG15, an ISG known to play roles in mediating the biological effects of type I IFNs [97]. IFNα-induced ISG15 expression was attenuated in MEFs with targeted disruption of either Mnk1 or Mnk2 or both Mnk1 and Mnk2 [96]. Transcriptional mRNA induction of ISG15 by IFNα was unaltered in MEFs with a targeted disruption of both Mnk1 and Mnk2; consistent with these results, Mnk kinases did not mediate IFNα induced phosphorylation of STAT1 [96].…”

Section: Rantesmentioning

confidence: 99%

“…IFNα-induced ISG15 expression was attenuated in MEFs with targeted disruption of either Mnk1 or Mnk2 or both Mnk1 and Mnk2 [96]. Transcriptional mRNA induction of ISG15 by IFNα was unaltered in MEFs with a targeted disruption of both Mnk1 and Mnk2; consistent with these results, Mnk kinases did not mediate IFNα induced phosphorylation of STAT1 [96]. Analysis of polysomal mRNA in the presence or absence of IFNα revealed that Mnk kinases are essential for the optimal translation of ISG15 as well as ISG54; and that such Mnk mediated translation of ISGs is essential for generation of the antiproliferative effects of IFNα on leukemic cell lines and primary hematopoietic progenitors derived from normal donors [96].…”

Section: Rantesmentioning

confidence: 99%

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Mnk kinases in cytokine signaling and regulation of cytokine responses

Joshi¹,

Platanias²

2012

Biomolecular Concepts

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The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed.

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Section: Rantesmentioning

confidence: 99%