Abl-kinase-sensitive levels of ERK5 and its intrinsic basal activity contribute to leukaemia cell survival.

It is well established that the mitogen-activated protein kinase (MAPK) signal is regulated through phosphorylation-dependent activation by the three-tiered MAPK cascade. However, our studies on the interaction of the MAPK ERK5 with the tyrosine kinase c-Abl and its oncogenic variants v-Abl and Bcr/Abl disclosed an alternative aspect of regulation. Independent of the MAPK cascade, Abl kinases were able to regulate the cellular amount of ERK5, at least in part, by stabilizing the protein. The resulting level of ERK5 and its intrinsic basal activity, but not necessarily its activation, were essential and sufficient to increase transformation by v-Abl and to mediate survival of Bcr/Abl-expressing leukaemia cells. These results suggest that the ability to regulate the cellular abundance of ERK5 contributes to the oncogenic potential of Abl kinases.