The ERK Cascade: A Prototype of MAPK Signaling

Rubinfeld, Hadara; Seger, Rony

doi:10.1385/mb:31:2:151

Cited by 400 publications

(308 citation statements)

References 251 publications

Supporting

Mentioning

302

Contrasting

Unclassified

Order By: Relevance

“…Fourteen MAPK isoforms have been identified in mammalian cells, which can broadly be divided into four groups, the classical MAPK (ERK1 and ERK2), p38 MAPK, JNK and atypical MAPK, which include ERK5, ERK3 and ERK8 [1][2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

ERK5 regulation in naïve T‐cell activation and survival

et al. 2008

View full text Add to dashboard Cite

ERK5 has been implicated in regulating the MEF2-dependent genes Klf2 and nur77 downstream of the TCR and the maintenance of expression of CD62L on peripheral T cells. Based on this data, knockout of ERK5 would be predicted to compromise T-cell development and the maintenance of T cells in the periphery. Using an ERK5 conditional knockout, driven by CD4-CRE or Vav-CRE transgenes resulting in the loss of ERK5 in T cells, we have found that ERK5 is not required for T-cell development. In addition, normal numbers of T cells were found in the spleens and lymph nodes of these mice. We also find that TCR stimulation is not a strong signal for ERK5 activation in primary murine T cells. ERK5 was found to contribute to the induction of Klf2 but not nur77 mRNA following TCR activation. Despite the reduction in Klf2 mRNA, no effect was seen in ERK5 knockouts on either the mRNA levels for the Klf2 target genes CD62L, CCR7 and S1P, or the cell surface expression of CD62L. These results suggest that while ERK5 does contribute to Klf2 regulation in T cells, it is not essential for the expression of CD62L or T-cell survival. IntroductionMitogen-activated protein kinase (MAPK) cascades are important mediators of cellular responses to a variety of signals, including growth factors, cytokines and cellular stresses. Fourteen MAPK isoforms have been identified in mammalian cells, which can broadly be divided into four groups, the classical MAPK (ERK1 and ERK2), p38 MAPK, JNK and atypical MAPK, which include ERK5, ERK3 and ERK8 [1][2][3][4][5].ERK5 is an unusual MAPK, as it contains a large C-terminal domain in addition to the MAPK domain [2,6,7]. The precise role of the C-terminal domain is unclear; however, it has been shown to be involved in the regulation of ERK5 sub-cellular localisation [8]. The C-terminal domain has also been suggested to act as a transcriptional co-activator for the MEF2 transcription factors [9]. In cells, ERK5 is activated in response to specific growth factors including EGF, as well as by some stresses, such as sorbitol and hydrogen peroxide [10,11]. Like other MAPK, ERK5 is activated by phosphorylation on its TXY motif downstream of a MAPK kinase. MEK5 was originally proposed as the kinase responsible for ERK5 activation, based on its interaction with ERK5 in a yeast two-hybrid assay [12]. This finding was later confirmed by the observation that embryonic fibroblasts isolated from MEK5 knockout mice were unable to activate ERK5 [13]. MEK5 is activated downstream of a MAPK kinase kinase Ã These authors contributed equally to this study. 2534(MAP3 K), most probably MEKK2. ERK5 signalling has been reported to be deficient in EGF and FGF stimulated embryonic fibroblast cells from MEKK2 knockout mice suggesting that MEKK2 is the predominant MAP3 K for MEK5, downstream of these signals [14,15]. It is not clear, however, if MEKK2 is the only MAP3 K able to activate the ERK5 pathway. Mouse knockouts of either ERK5 or MEK5 are embryonic lethal, however knockouts of MEKK2 are viable and do not exhibit obvious phen...

show abstract

Section: Introductionmentioning

confidence: 99%

ERK5 regulation in naïve T‐cell activation and survival

et al. 2008

View full text Add to dashboard Cite

show abstract

“…In particular, we investigated the impact of blocking the extracellular signal-regulated kinase (ERK1/2) MAPK signaling pathway on Mcl-1 protein expression. Although ERK1/2 MAPK have been frequently associated with cellular proliferation, their role in promoting survival in different cellular models became recently evident (Rubinfeld and Seger, 2005;Sridhar et al, 2005;Yoon and Seger, 2006). Phospho-ERK1/2 were previously shown to be overexpressed in LNCaP-IL-6 þ (Gioeli et al, 1999;Steiner et al, 2003) and Du145 prostate cancer cells (Shimada et al, 2002) and clinical specimens (Gioeli et al, 1999;Royuela et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

et al. 2006

View full text Add to dashboard Cite

“…ERK including ERK1 and ERK2 belongs to the MAPKs family, and accumulating evidences suggest that ERK signal path way may take part in pathogenesis of depression and the mechanism of antidepressant-like action (Gourley et al, 2008). ERK is one of the most-studied intracellular signaling pathways and it is highly sensitive to stress and closely associated with mood processing (Gerrits et al, 2006;Rubinfeld and Seger, 2005). Moreover, recent studies have demonstrated a positive modulation of ERK1/2 by antidepressant drugs such as fluoxetine (Kuo et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Piper sarmentosum Roxb. produces antidepressant-like effects in rodents, associated with activation of the CREB-BDNF-ERK signaling pathway and reversal of HPA axis hyperactivity

Gao

et al. 2017

Journal of Ethnopharmacology

View full text Add to dashboard Cite

Ethnopharmacological relevance: There are many plants of genus Piper which have been reported to induce antidepressant-like effects, Piper sarmentosum (PS) is one of them. PS is a Chinese herbal medicine and a traditional edible vegetable. Materials and Methods:In the present study, the antidepressant-like effects of PS extracts and the ethyl acetate fraction of PS extracts (PSY) were assessed using the open field test (OFT), forced swimming test (FST), and tail suspension test (TST) in mice. Furthermore, we applied a 4 consecutive weeks of chronic unpredictable mild stress (CUMS) as a model of depression in rats, followed by a sucrose preference test. Then we examined the possible mechanisms of this action.The activity of the hypothalamic-pituitary-adrenal (HPA) axis was evaluated by detecting the serum corticosterone (CORT) concentrations, and the protein expression levels of brain-derived neurotrophic factor (BDNF), the phosphorylated form CREB and ERK1/2 were detected by qRT-PCR or Western blot. Results:The results showed that PS extracts (100, 200 mg/kg) and PSY (12.5, 25, 50 mg/kg) treatment produced antidepressant-like effects in mice similar to fluoxetine (20 mg/kg), indicated by the reduced immobility time in the FST and TST, while both had no influence on the locomotor activity in the OFT. PSY treatment significantly increased sucrose preference and reduced serum CORT levels in CUMS rats. Moreover, PSY up-regulated BDNF protein levels, and increased CREB and ERK phosphorylation levels in the hippocampus on CUMS rats. Conclusions:These findings suggest that the antidepressant-like effects of PS extracts and PSY are mediated, at least in part, by modulating HPA axis, BDNF, CREB and ERK phosphorylation and expression in the hippocampus.

show abstract

The ERK Cascade: A Prototype of MAPK Signaling

Cited by 400 publications

References 251 publications

ERK5 regulation in naïve T‐cell activation and survival

ERK5 regulation in naïve T‐cell activation and survival

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

Piper sarmentosum Roxb. produces antidepressant-like effects in rodents, associated with activation of the CREB-BDNF-ERK signaling pathway and reversal of HPA axis hyperactivity

Contact Info

Product

Resources

About