FIGURE 1.

Mechanism of activation of ERK5 and its relationship to the canonical ERK1/pathway. The ERK5 signalling pathway is a three-tiered mitogen-activated protein kinase (MAPK) signalling cascade comprising the kinases MEKK2 and MEKK3 that phosphorylate and activate dual specificity kinase MEK5, which in turn phosphorylates the activation-loop T-E-Y motif in the ERK5 kinase domain, thereby activating it. Unlike ERK1/2, ERK5 has a large C-terminal extension that contains a nuclear localization signal (N) and a transcriptional transactivation domain (TAD). Upon kinase domain activation, ERK5 auto-phosphorylates multiple residues within its C-terminus, promoting nuclear localization of ERK5. This drives gene expression by direct phosphorylation of MEF2 transcription factors and by activation of the ERK5 TAD. Whilst MEK5 and MEK1/2 exhibit high sequence similarity MEK5 does not activate ERK1/2 and MEK1/2 do not activate ERK5; indeed, any effect of RAF-MEK1/2-ERK1/2 signalling on ERK5 activity is indirect and represents feed forward signalling or pathway cross talk. Indeed, some phosphorylation sites within the ERK5 C-terminus can also be phosphorylated by ERK1/2 and by CDK1 in mitosis. The C-terminal TAD can therefore integrate signals from both the ERK5 kinase domain and non-ERK5 kinases, including ERK1/2, to direct nuclear entry of ERK5.