Regulation of Mnk1 by p38α MAPK in Stress Mediated Translation Initiation

Abstract

Multiple signaling pathways control protein synthesis by modulating translation initiation factors. Map Kinase Integrating Kinase 1 (Mnk1) relays signals to its major downstream target eIF4E. Activation of Mnk1 and subsequent phosphorylation of eIF4E results in changes in translation rates for subsets of mRNAs. Both the Erk1/2 and p38 MAPK pathways activate Mnk1 meaning that Mnk1 responds to growth signals through Erk1/2 and stress signals through p38 MAPK. However, it is not clear how Mnk1 mediates translational changes specific to each pathway. We investigated the activation of Mnk1 by stress and cytokines through the p38 MAPK pathway. We found that of the four different p38 MAPK isoforms, p38α alone controls acute stress and cytokine signaling to translation machinery. Furthermore, this regulatory axis is greatly diminished in neurons. We discovered that p38α expression is repressed in the brain due to two neuron-selective microRNAs, miR-124 and -128. Next, we investigated the mechanism of p38α mediated Mnk1 activation to see if it differed from Erk1/2 mediated activation. Looking at the induced binding of Mnk1 to eIF4G, we found that the dissociation rate varies depending on the activating pathways. This shows that Mnk1 is not a true convergence point of p38 and Erk1/2 MAPK pathways resulting in identical downstream effects, but that Mnk1 mediates pathway specific effects on translation factors.