Extracellular signal-regulated kinases (ERKs) or mitogen-activated protein kinases (MAPKs) are involved in cellular proliferation, differentiation, migration, and gene expression. The MAPK family includes ERK1/2, c-Jun NH(2)-terminal kinases 1, 2, and 3, p38MAPK alpha, beta, gamma, and -delta, and ERK5 as conventional MAPKs and ERK3, ERK4 NLK, and ERK7 as atypical MAPKs. Like other MAPKs, ERK5 is activated by variety of stimuli, including growth factors, G-protein-coupled receptor (GPCR) agonists, cytokines, and stress. However, the signaling pathway leading to ERK5 activation is not well understood compared with the other conventional MAPKs. For example, the pharmacological reagents that induce second messenger cAMP and Ca(2+) downstream of GPCRs do not activate ERK5 in neuronal cells. In addition, conflicting results have come from studies examining the involvement of small G-proteins in ERK5 activation by growth factors, and the details of the signaling pathway remain controversial. In addition, the physiological roles of ERK5 in neuronal cells have not been clarified. One reason was the lack of a selective ERK5 pharmacological inhibitor until the novel selective MEK5/ERK5 inhibitors BIX02188 and BIX02189 (Biochem Biophys Res Commun 377:120-125, 2008) reported last year. Another reason is that the use of interfering mutants is limited in neuronal cells because the transfection efficiency is low. Despite these difficulties, recent studies suggest that ERK5 mediates the promotion of neuronal survival and neuronal differentiation in vitro and in vivo. In this review, the signaling pathway leading to ERK5 activation through heterotrimeric and small G-proteins and the physiological roles of ERK5 in neuronal cells are summarized and discussed.
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