ERK5 and Cell Proliferation: Nuclear Localization Is What Matters

Abstract

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.

Keywords: Cdc37; ERK5; Hsp90; MAP kinase; cancer; cell proliferation; nuclear translocation; transcriptional co-activator.

Figure 1

Molecular mechanisms controlling nucleocytoplasmatic transport of ERK5. Different mechanisms have been proposed for ERK5 shuttling to the nucleus, depending or not of C-terminal phosphorylation. Once in the nucleus, ERK5 enhances gene transcription by either phosphorylating transcription factors, or by interacting with these factors through the transactivation TAD domain located at the C-terminal. ERK5 does not require kinase activity to interact with and activate transcription factors and therefore, forms of nuclear ERK5 devoid of kinase activity are able to activate transcription. Inactive ERK5 binds the cytoplasmatic chaperone Hsp90 and co-chaperone Cdc37, which helps Hsp90 in the stabilization of ERK5 (Erazo et al., 2013). In basal conditions, Hsp90 serves as a cytosolic anchor for ERK5, and inactive ERK5 adopts a closed conformation where the NLS motif is hidden and not available for the nuclear transport. Nuclear shuttling of ERK5 requires both a conformational change to allow exposure of the NLS motif and the release of Hsp90 (Erazo et al., 2013). In response to growth factors stimulation or different stresses, activated MEK5 phosphorylates and activates ERK5. Then, active ERK5 phosphorylates its C-terminal tail resulting in dissociation of the cytosolic anchor Hsp90 from ERK5-Cdc37 complex, adoption of an open conformation in which the NLS motif is exposed, and nuclear translocation. ERK5 C-terminal tail can also be phosphorylated by other kinases, such as Cyclin-dependent kinase-1 (CDK1) during mitosis. This phosphorylation is not MEK5-dependent but induce the release of Hsp90 and nuclear translocation of a kinase-inactive form of ERK5 which retains its transcriptional activity (Diaz-Rodriguez and Pandiella, ; Inesta-Vaquera et al., 2010). Finally, overexpression of Cdc37 (reported to happen in some cancers) induces the release of Hsp90 and nuclear shuttling of a kinase-inactive but transcriptionally active form of ERK5 (Erazo et al., 2013).