The Signaling Pathway Leading to Extracellular Signal-Regulated Kinase 5 (ERK5) Activation via G-Proteins and ERK5-Dependent Neurotrophic Effects

Abstract

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 ␣, ␤, ␥, and -␦, 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 2ϩ 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.Extracellular signal-regulated kinases (ERKs) or mitogenactivated protein kinases (MAPKs) are involved in cellular proliferation, differentiation, migration, and gene expression. The MAPK family includes ERK1/2, c-Jun N-terminal kinases 1, 2, and 3, p38MAPK ␣, ␤, ␥, and ␦, and ERK5 as conventional MAPKs, and ERK3, ERK4 NLK, and ERK7 as atypical MAPKs (Coulombe and Meloche, 2007). Threonine and tyrosine activation motifs (T-X-Y) are conserved among conventional MAPKs and ERK7, whereas the atypical MAPKs lack these motifs. The most well studied MAPK family member, ERK1/2, is activated by a variety of stimuli, and the signaling pathway leading to ERK1/2 activation has been better characterized than that to ERK5 activation (Goldsmith and Dhanasekaran, 2007). ERK5 is approximately twice the molecular size of ERK1/2. The kinase domain is encoded by its amino-terminal half and shares approximately 50% of homology with ERK1/2, whereas its unique carboxyl terminus encodes two proline-rich regions and a nuclear localization signal (Nishimoto and Nishida, 2006;Wang and Tournier, 2006). It has been reported that the autophosphorylated carboxyl terminus of ERK5 plays a critical role in activating transcription (Morimoto et al., 2007). The threonine and tyrosine residues on ERK5 are Article, publ...

Molecular Pathways: Mitogen-Activated Protein Kinase Pathway Mutations and Drug Resistance

“…Oncogenically mutated RAS has been reported to activate the ERK5 pathway in certain cell types (52); however, this finding has not been confirmed by other studies (53). The wild-type forms of RAS do not seem to stimulate this cascade (54).…”

Extracellular Signal-regulated Kinase 5 (ERK5) Mediates Prolactin-stimulated Adult Neurogenesis in the Subventricular Zone and Olfactory Bulb

“…MEK5 is an upstream kinase that phosphorylates and activates ERK5 (30,31), and BIX02188 is a selective MEK5/ERK5 inhibitor (22,23). Prolactin-induced phosphorylation of STAT5 was inhibited by this STAT5 inhibitor but not by the MEK5 inhibitor (Fig.…”

Protein Kinase C (PKC)ζ-mediated Gαq Stimulation of ERK5 Protein Pathway in Cardiomyocytes and Cardiac Fibroblasts

“…More recently, we have reported a novel role for G␣ q as a scaffold protein capable of recruiting both PKC and the kinase MEK5 into an active complex, leading to the activation of the ERK5 pathway in epithelial cells (18). ERK5 is a member of the MAPK family that is activated by the upstream MEK5 kinase in response to different growth factors and cellular stressors (19). Activation of G␣ q is a potent inducer of MAPK signaling in cardiac myocytes.…”