The first clue for a potential crosstalk between ERK1/2 and ERK5 signaling in tumor cells dates back to the late 90s of the last century, when Melanie Cobb’s group reported the activation of ERK1/2 as well as of a C-terminally truncated kinase-proficient ERK5 mutant upon overexpression of oncogenic H-RAS V12 in HEK293 cells [28]. Here, MAPK3 is linked to neoplasm.