MEK5/ERK5 pathway: the first fifteen years

Abstract

While conventional MAP kinase pathways are one of the most highly studied signal transduction molecules, less is known about the MEK5 signaling pathway. This pathway has been shown to play a role in normal cell growth cycles, survival and differentiation. The MEK5 pathway is also believed to mediate the effects of a number of oncogenes. MEK5 is the upstream activator of ERK5 in many epithelial cells. Activation of the MEK-MAPK pathway is a frequent event in malignant tumor formation and contributes to chemoresistance and anti-apoptotic signaling. This pathway may be involved in a number of more aggressive, metastatic varieties of cancer due to its role in cell survival, proliferation and EMT transitioning. Further study of this pathway may lead to new prognostic factors and new drug targets to combat more aggressive forms of cancer.

Fig. 1

Mitogen-activated protein kinase (MAPK) pathways are a family of related and sometimes interconnected pathways. Signals are transduced through a three-tiered kinase cascade; MAPKKK through MAPKK to MAPK (5). Conventional members of the MAPK family have known activators. For example, MEK1 and MEK2 activate ERK1/2; MKK4 and MKK7 for JNKs; MEK3 and MEK6 for p38; and MEK5 for ERK5 (–6). However, the activators of the atypical MAPKs such as ERK3/4, ERK7 and ERK8 are still not fully understood (–9).

Fig. 2

MEK5 regulation and downstream targets. MEK5/ERK5 pathway activation can occur through extracellular stressors, mitogens or cytokine activation. Activation of this pathway may lead to epithelial mesenchymal transitions (EMT), cell survival, anti-apoptotic signaling and an increase in cell proliferation.

Fig. 3

MEK5/ERK5 pathway is activated by cell stressors, mitogens or cytokines. Once stimulated, MEKK2 or MEKK3 will phosphorylate MEK5 on its serine 311 and threonine 315 residues(51). MEK5 then phosphorylates the threonine 218 and tyrosine 220 residues of ERK5(2). Upon activation, ERK5 can phosphorylate downstream target molecules such as Sap1, cFOS, c-Myc and MEF2 or autophosphorylate its carboxyl-terminal region which contains a NLS region (nuclear localization signal) allowing ERK5 to shuttle from the cytosol to the nucleus. This gives ERK5 two possible mechanisms for signaling; either by activating downstream molecules or potentially acting directly as a transcription factor (2, 21).

Fig. 4

Pathway for MEK5/ERK5- mediated cell survival: When cell stress occurs, a nonphosphorylated form of Bad translocates to the mitochondria to induce cytochrome c release and a nonphosphorylated Foxo3a translocates to the nucleus to induces transcription of FasL receptor. Both processes initiate apoptosis. Activated ERK5 phosphorylates Bad and Foxo3a either directly or through a PKB dependent mechanism. Phosphorylation sequesters Bad and Foxo3a in the cytoplasm thereby blocking their apoptotic effects. In neurons, ERK5 also mediates cell survival in response to growth factors by activation of the transcriptional factors CREB and MEF2 (3).

Fig. 5

Proposed MEK5 regulation in breast cancer: Similarly to MEK5/ERK5 pathway activation in physiologically healthy tissue, activation may occur through extracellular stressors, mitogens or cytokine activation to promote survival, anti-apoptotic signaling and proliferation of cancer cells. Some of the microarray analysis of breast cancer tissue samples as well as experiments completed by our laboratory suggests that activation of this pathway may lead to epithelial mesenchymal transitions (EMT), metastasis and invasion especially in more aggressive phenotypes of breast cancer.