ERK5, the last MAP kinase family member discovered, is activated by the upstream 
kinase MEK5 in response to growth factors and stress stimulation. MEK5-ERK5 
pathway has been associated to different cellular processes, playing a crucial 
role in cell proliferation in normal and cancer cells by mechanisms that are 
both dependent and independent of its kinase activity. Thus, nuclear ERK5 
activates transcription factors by either direct phosphorylation or acting as 
co-activator thanks to a unique transcriptional activation TAD domain located at 
its C-terminal tail. Consequently, ERK5 has been proposed as an interesting 
target to tackle different cancers, and either inhibitors of ERK5 activity or 
silencing the protein have shown antiproliferative activity in cancer cells and 
to block tumor growth in animal models. Here, we review the different mechanisms 
involved in ERK5 nuclear translocation and their consequences. Inactive ERK5 
resides in the cytosol, forming a complex with Hsp90-Cdc37 superchaperone. In a 
canonical mechanism, MEK5-dependent activation results in ERK5 C-terminal 
autophosphorylation, Hsp90 dissociation, and nuclear translocation. This 
mechanism integrates signals such as growth factors and stresses that activate 
the MEK5-ERK5 pathway. Importantly, two other mechanisms, MEK5-independent, have 
been recently described. These mechanisms allow nuclear shuttling of 
kinase-inactive forms of ERK5. Although lacking kinase activity, these forms 
activate transcription by interacting with transcription factors through the TAD 
domain. Both mechanisms also require Hsp90 dissociation previous to nuclear 
translocation. One mechanism involves phosphorylation of the C-terminal tail of 
ERK5 by kinases that are activated during mitosis, such as Cyclin-dependent 
kinase-1. The second mechanism involves overexpression of chaperone Cdc37, an 
oncogene that is overexpressed in cancers such as prostate adenocarcinoma, where 
it collaborates with ERK5 to promote cell proliferation. Although some ERK5 
kinase inhibitors have shown antiproliferative activity it is likely that those 
tumors expressing kinase-inactive nuclear ERK5 will not respond to these 
inhibitors.