The C-terminal domain of Mnk1a plays a dual role in tightly regulating its activity

The human family of MAP kinase signal-integrating kinases (Mnks) comprises four related proteins derived from two genes by alternative splicing. The Mnk1 gene gives rise to two proteins, Mnk1a and Mnk1b, which possess distinct C-termini and properties. Despite lacking the C-terminal MAP kinase-binding site, Mnk1b shows higher basal activity than Mnk1a. In contrast, the activity of Mnk1a is tightly regulated by signalling through ERK and p38 MAP kinase. We show that the short C-terminus of Mnk1b confers on it a 'default' behaviour of substantial, but unregulated, activity. In contrast, the longer C-terminus of Mnk1a represses the basal activity and T (activation)-loop phosphorylation of this isozyme while allowing both properties to be stimulated by upstream MAP kinase signalling. Two features of the C-terminus of Mnk1a appear to account for this behaviour: the known MAP kinase-binding site and a region (predicted to be alpha-helical) which occludes access to the catalytic domain and the T-loop. The activation of Mnk1a results in a marked conformational change leading to a more 'open' structure. We also identify a conserved phenylalanine in an Mnk-specific insert as playing a key role in governing the ease with which Mnk1a can be phosphorylated. These studies help to identify the features that give rise to the diverse properties of human Mnk isoform