Mnk kinase pathway: Cellular functions and biological outcomes

Abstract

The mitogen-activated protein kinase (MAPK) interacting protein kinases 1 and 2 (Mnk1 and Mnk2) play important roles in controlling signals involved in mRNA translation. In addition to the MAPKs (p38 or Erk), multiple studies suggest that the Mnk kinases can be regulated by other known kinases such as Pak2 and/or other unidentified kinases by phosphorylation of residues distinct from the sites phosphorylated by the MAPKs. Several studies have established multiple Mnk protein targets, including PSF, heterogenous nuclear ribonucleoprotein A1, Sprouty 2 and have lead to the identification of distinct biological functions and substrate specificity for the Mnk kinases. In this review we discuss the pathways regulating the Mnk kinases, their known substrates as well as the functional consequences of engagement of pathways controlled by Mnk kinases. These kinases play an important role in mRNA translation via their regulation of eukaryotic initiation factor 4E (eIF4E) and their functions have important implications in tumor biology as well as the regulation of drug resistance to anti-oncogenic therapies. Other studies have identified a role for the Mnk kinases in cap-independent mRNA translation, suggesting that the Mnk kinases can exert important functional effects independently of the phosphorylation of eIF4E. The role of Mnk kinases in inflammation and inflammation-induced malignancies is also discussed.

Keywords: Mnk kinases, mRNA translation, Mitogen-activated protein kinase signaling, eIF4E phosphorylation, Drug resistance, Cytokine production, Cytokine signaling

Core tip: The Mnk kinases are important downstream targets of the Erk and p38 mitogen-activated protein kinase (MAPK) pathways and their activity can also be modulated by MAPK independent signals. The Mnk kinases play important roles in regulating mRNA translation and, because of this, are key mediators of oncogenic progression, drug resistance, production of pro-inflammatory cytokines and cytokine signaling. This review focuses on the pathways regulating the Mnk kinases, the substrates on the Mnk kinases as well as the biological functions of the Mnk kinases.