Features of the Catalytic Domains and C Termini of the MAPK Signal-integrating Kinases Mnk1 and Mnk2 Determine Their Differing Activities and Regulatory Properties

Josep Lluis Parra, Maria Buxadé, Christopher G. Proud
2005 Journal of Biological Chemistry  
The MAPK signal-integrating kinases Mnk1 and Mnk2 are closely related but show marked differences in their basal activities and regulation. Both possess, within their C termini, motifs for binding to MAPKs, although these differ between Mnk1 and Mnk2. Mnk2 shows much higher activity in unstimulated cells than Mnk1, whose activity is greatly increased, e.g. by stimulation of the MEK/ ERK pathway. Such increases are sensitive to blockade of that pathway, whereas the activation state of Mnk2 is
more » ... state of Mnk2 is relatively insensitive to inhibition of upstream signaling. Here we have studied the roles of features in their catalytic domains and C termini in determining their regulatory properties and basal activities. Mnk2 can bind to phosphorylated, active ERK, whereas Mnk1 cannot. Such binding apparently protects ERK against dephosphorylation and inactivation. The high basal activity of Mnk2 and its binding to (phospho)ERK requires features both of the catalytic domain and of the C terminus. For example, within the catalytic region an aspartate in Mnk2 plays a key role. Mutation to alanine inactivates Mnk2. In the C terminus, features within the MAPK-binding motif and to either side of it, including potential phosphorylation sites, affect MAPK binding and activity. The association of Mnks with the scaffold protein eukaryotic initiation factor 4G is negatively modulated by Mnk activity. These data indicate that multiple features determine the activities of the Mnks and thus impact on their ability to phosphorylate physiological substrates such as eukaryotic initiation factor 4E. The MAPK 2 -interacting kinases (Mnks) were first discovered by virtue of their ability to interact with or to be phosphorylated by MAPKs (1, 2). MAPKs phosphorylate two threonine residues within the activation or T-loop of the Mnks leading to their activation. However, the regulatory properties of the various Mnk isoforms differ (3-6). The best known substrate for the Mnks is the translation initiation factor eIF4E (2). This protein binds the 5Ј-terminal cap structure found on cytoplasmic mRNA and recruits other translation factors, and the 40 S ribosomal subunit, to the mRNA. Phosphorylation of eIF4E alters its affinity
doi:10.1074/jbc.m508356200 pmid:16162500 fatcat:y43mxyuyd5acleh4dimnuqxs2q