A Network of Mitogen-Activated Protein Kinases Links G Protein-Coupled Receptors to the c-jun Promoter: a Role for c-Jun NH₂-Terminal Kinase, p38s, and Extracellular Signal-Regulated Kinase 5

Abstract

The expression of the c-jun proto-oncogene is rapidly induced in response to mitogens acting on a large variety of cell surface receptors. The resulting functional activity of c-Jun proteins appears to be critical for cell proliferation. Recently, we have shown that a large family of G protein-coupled receptors (GPCRs), represented by the m1 muscarinic receptor, can initiate intracellular signaling cascades that result in the activation of mitogen-activated protein kinases (MAPK) and c-Jun NH2-terminal kinases (JNK) and that the activation of JNK but not of MAPK correlated with a remarkable increase in the expression of c-jun mRNA. Subsequently, however, we obtained evidence that GPCRs can potently stimulate the activity of the c-jun promoter through MEF2 transcription factors, which do not act downstream from JNK. In view of these observations, we set out to investigate further the nature of the signaling pathway linking GPCRs to the c-jun promoter. Utilizing NIH 3T3 cells, we found that GPCRs can activate the c-jun promoter in a JNK-independent manner. Additionally, we demonstrated that these GPCRs can elevate the activity of novel members of the MAPK family, including ERK5, p38alpha, p38gamma, and p38delta, and that the activation of certain kinases acting downstream from MEK5 (ERK5) and MKK6 (p38alpha and p38gamma) is necessary to fully activate the c-jun promoter. Moreover, in addition to JNK, ERK5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. Taken together, these results suggest that the pathway linking GPCRs to the c-jun promoter involves the integration of numerous signals transduced by a highly complex network of MAPK, rather than resulting from the stimulation of a single linear protein kinase cascade. Furthermore, our findings suggest that each signaling pathway affects one or more regulatory elements on the c-jun promoter and that the transcriptional response most likely results from the temporal integration of each of these biochemical routes.

Aberrant Extracellular Signal-Regulated Kinase (ERK) 5 Signaling in Hippocampus of Suicide Subjects

“…MEF2C is a member of the family of transcription factor MEF2 (Kato et al, 1997;Marinissen et al, 1999) and is highly expressed in developing and adult brain (Leifer et al, , 1994McDermott et al, 1993;Lyons et al, 1995). Activation of ERK5 leads to phosphorylation and therefore enhanced transactivation capacity of MEF2C (Yang et al, 1998).…”

“…In neurons, ERK5 is activated by neurotrophins, including brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4 (Cavanaugh et al, 2001;Watson et al, 2001;Liu et al, 2003;Shalizi et al, 2003). A number of other extracellular stimuli, such as epidermal growth factor and G-protein-coupled receptors, also activate ERK5 (Kato et al, 1998;Marinissen et al, 1999). Activation of ERK5 requires phosphorylation of Thr-219 and Tyr-221 residues by upstream MAPK kinase5 (MEK5), which in turn is activated by MEKK2, MEKK3, and Cot (Chao et al, 1999;Chiariello et al, 2000;Sun et al, 2001).…”

“…This suggests that the regulation and function of this kinase may be different from that of other MAPKs (Lee et al, 1995;Zhou et al, 1995). ERK5 directly or indirectly phosphorylates many transcription factors, such as myocyte enhancer factor (MEF)2, c-Myc, c-Fos, c-Jun, Sap1a, p90 ribosomal S6 kinase (RSK), CREB, and NF-kB (Kato et al, 1997;English et al, 1998;Kamakura et al, 1999;Marinissen et al, 1999;Chiariello et al, 2000;Pearson et al, 2001b). ERK5 also regulates transcription, through a kinaseindependent mechanism that involves its unique C-terminal half (Kasler et al, 2000;Terasawa et al, 2003).…”

ERK5 regulation in naïve T‐cell activation and survival

“…In agreement with the low level of TCRinduced ERK5 activation in our studies, we also found that ERK5 was not rate limiting for the upregulation of the MEF2 target gene nur77 downstream of the TCR in primary T cells. The initial studies linking ERK5 to nur77 expression made use of overexpression experiments [9,46], and thus may have given rise to some artefacts. Another possible explanation for this difference is that the transcription of IE genes is wired slightly differently in T lymphoblasts.…”

Up-regulation of c-jun mRNA in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-Jun N-terminal kinases are required for efficient up-regulation of c-Jun protein

“…However, in NIH-3T3 cells overexpressing the muscarinic m1 acetylcholine receptor, stimulation of c-jun expression is mediated through JNKs, p38-MAPKs (α and γ isoforms) and an additional member of the ERK family, ERK5 [22]. Whereas JNKs and p38-MAPKα act primarily on the proximal AP-1\CRE-like site [22], ERK5 activates the myocyte-specific enhancer-binding factor 2 (MEF2) transcription factor(s) [23] that, in the c-jun promoter, acts at a site immediately 3h to the proximal AP-1\CRE-like site [8,[22][23][24]. Here we have examined the regulation of c-jun expression at the mRNA and protein level in cardiac myocytes exposed to hypertrophic stimuli or PMA.…”