RT Journal Article SR Electronic T1 The signaling pathway leading to ERK5 activation via G-proteins and ERK5-dependent neurotrophic effects JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.109.060236 DO 10.1124/mol.109.060236 A1 Yutaro Obara A1 Norimichi Nakahata YR 2009 UL http://molpharm.aspetjournals.org/content/early/2009/10/26/mol.109.060236.abstract AB 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 N-terminus kinase 1/2/3, p38MAPK ϵ/ϵ/ϵ/ϵ and ERK5 as classical 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 as compared to the other classical MAPKs. For example, the pharmacological reagents that induce second messengers cAMP and Ca2+ downstream of GPCRs do not activate ERK5 in neuronal cells. Also, 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, were reported last year. Another reason is that the use of interfering mutants is limited in neuronal cells since 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.The American Society for Pharmacology and Experimental Therapeutics