Mnk kinases in cytokine signaling and regulation of cytokine responses

Abstract

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.

Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo

“…eIF4E is a key component of the cap-binding complex required for mRNA translation of mitogenic proteins, including cyclins, c-Myc, and Bcl-xl, and its activity has been linked to leukemogenesis and malignant cell proliferation. [7][8][9] The phosphorylation and activation of eIF4E by Mnk1/2 on serine 209 (Ser209) is critical for its oncogenic activity. 10,11 As Mnk1/2 double knockout mice have a normal phenotype, 12 Mnk1/2 are attractive targets for cancer therapy as their inhibition could conceivably target selectively malignant cells.…”

An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis

“…Mnk1 is activated by Erk and p38 kinases in response to mitogens and stress, respectively, but Mnk2 is only phosphorylated via the Erk pathway. Mnk2 does not respond to the stimuli-induced p38 activation, and therefore may have a different role in inducing cytokine production and regulating cytokine responses in comparison with Mnk1 [25]. As no specific Mnk1 or Mnk2 inhibitors exists, our first-in-class selective inhibitors of Mnk1/2 will be powerful pharmacological tools in distinguishing Mnk1/2-related biology, pharmacology and drug discovery.…”

Interferon γ (IFNγ) Signaling via Mechanistic Target of Rapamycin Complex 2 (mTORC2) and Regulatory Effects in the Generation of Type II Interferon Biological Responses

“…Beyond the classical JakStat pathways, several other signaling pathways have been shown to be activated by the type II IFN receptor, and their function appears to be critical for IFN␥ responses. These include PKC (17), MAP kinase (18,19), and Mnk kinase cascades (20). There is evidence that the AKT/mTOR pathway is engaged in IFN␥ signaling, controlling the initiation of mRNA translation for ISGs (21,22).…”