ReviewRegulation of cellular functions by the ERK5 signalling pathway
Introduction
The mitogen-activated protein kinases (MAPKs) are crucial components of signalling cascades that regulate numerous physiological processes during development and pathogenesis [1], [2]. At least four subfamilies have been identified: extracellular-regulated protein kinases 1 and 2 (ERK1/2), ERK5, c-Jun NH2-terminal protein kinases (JNKs), and p38 MAPKs. They belong to an evolutionary conserved family of proline-directed protein kinases that phosphorylate Ser and Thr residues preceding a Pro residue. The specificity is determined by docking domains within substrates [3]. These include the D domain that consists of a conserved cluster of positively charged amino acids surrounded by hydrophobic amino acids. The D domain is recognised by amino acid sequences in the C-termini of the MAPKs identified as the common docking (CD) domain. By tethering the substrate to the MAPK, docking interactions contribute to the efficiency of the kinase reaction. MAPKs control by phosphorylation the activity of numerous transcription factors and enzymes, through regulating binding partners, conformational changes, subcellular localisation, and protein stability [1], [4].
MAPK activity is increased following phosphorylation at Thr and Tyr residues within a Thr-X-Tyr (T-X-Y) motif in the activation loop by a MAPK/ERK kinase (MEK or MKK) [1]. X corresponds to a Glu residue in ERK, a Pro residue in JNK and a Gly residue in p38 MAPK subfamilies. MAPK activators include MEK1 and MEK2 for ERK1/2, MEK5 for ERK5, MKK4 and MKK7 for JNKs, and MKK3 and MKK6 for p38 MAPKs. MEKs are activated by phosphorylation at Ser and Thr residues by a MEK kinase (MEKK). Two main mechanisms have been proposed to ensure specific transmission of the signals from upstream kinases to MAPKs [5], [6]: (i) adaptor/scaffold proteins that assemble the different components of a cascade, and (ii) direct physical interactions between the components of a cascade. Both mechanisms may operate in parallel and allow distinct responses of the same MAPK signalling pathways to different stimuli. Gene targeting experiments in mice have provided evidence that MAPK modules are associated with different biological responses [7]. For example, the ERK subfamilies are mostly associated with cell proliferation and survival, while JNKs and p38 MAPKs are mainly activated in response to cytokines and extracellular stresses and can mediate apoptosis.
Section snippets
Cloning
Two groups cloned ERK5 in 1995. Dixon and co-workers [8] first identified the ERK5 activator, MEK5. Based on the assumption that MEKs interact with MAPKs, they used MEK5 as bait in a yeast two-hybrid screen and identified ERK5 as a binding partner. Further studies confirmed the binding of ERK5 with MEK5 but not with MEK1 or MEK2 supporting the highly specific nature of the MEK/MAPK interaction. At the same time Lee et al. [9] identified a protein identical to ERK5 that they called big MAPK 1
Dual phosphorylation of ERK5 by MEK5
ERK5 activity is increased in response to growth factors, oxidative stress and hyperosmolarity via the dual phosphorylation of its TEY motif by MEK5 [27] (Fig. 1). The phosphorylation of ERK5 by MEK5 may contribute to stabilising ERK5 in an active conformation promoted by the auto-phosphorylation of its C-terminal tail [14], [24], [27]. The physiological significance of MEK5 was demonstrated by the analysis of mek5 gene ablation in mice [22]. Similar to the erk5−/− embryos [28], [29], [30], the
ERK5 regulation of neuronal survival
Suzaki et al. were the first to implicate ERK5 in the survival response of PC12 cells to oxidative stress [43]. The physiological significance of these results was provided by the demonstration that ERK5 contributes to the survival response of dorsal root ganglion (DRG) neurones to neuronal growth factor (NGF) [44]. TrkA receptors present at the surface of the extending axon auto-phosphorylate following the binding of NGF. Phosphorylated TrkA receptors are internalised into a “signalling
ERK5 and cell proliferation
The discovery that serum was a potent inducer of c-jun gene transcription via ERK5-induced MEF2C transcriptional activation provided the first evidence that the ERK5 signalling pathway was involved in regulating cell proliferation [15]. Consistent with this study, mitogens including EGF and granulocyte colony-stimulating factor (G-CSF), were subsequently found to transmit their growth promoting signals via ERK5 [55], [56]. However, no marked difference was observed in the ability of erk5−/−,
Activation of ERK5 by oncogenes
Mutant ras has been identified in cancers of many different origins, including pancreas (90%), colon (50%), lung (30%), thyroid (50%), bladder (6%), ovarian (15%), breast, skin, liver, kidney, and some leukemias. Among the signalling pathways suspected to be involved in mediating the oncogenic effect of Ras is the ERK5 cascade. In certain cell types, including PC12, C2C12, and COS7 cells, ERK5 is activated by Ras [10], [24], [62]. Furthermore, foci induced by a dominant active mutant of Raf
Role of ERK5 during cardiovascular development
The targeted deletion of the erk5 and mek5 genes in mice has provided genetic evidence for an essential role of the ERK5 signalling pathway during heart development [22], [28], [29], [30]. The phenotypes observed in these mice are almost identical. They die around embryonic day 10 (E10) due to cardiovascular defects that include disorganisation of the trabeculae and underdevelopment of the myocardium. Vasculogenesis and angiogenesis are impaired in both the embryo itself and the extraembryonic
Conclusion
Efforts of many scientists in recent years has led to major progress in understanding the regulation of ERK5 and its function in vivo. In particular, genetically modified mice in which the mek5 or erk5 genes have been mutated have provided important information regarding the physiological relevance of the ERK5 signalling pathway during cardiovascular development. The potentially crucial role of ERK5 in cancers and heart diseases make this cascade highly attractive for the development of new
Acknowledgments
We thank A. Whitmarsh for critically reviewing the manuscript. The work in the authors' laboratory is supported by grants from the BBSRC and the MRC, and a Lister Institute of Preventive Medicine Research Fellowship to CT.
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