Differential regulation and properties of MAPKs

Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Oncogene (Impact Factor: 8.46). 06/2007; 26(22):3100-12. DOI: 10.1038/sj.onc.1210392
Source: PubMed

ABSTRACT Mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs including embryogenesis, proliferation, differentiation and apoptosis based on cues derived from the cell surface and the metabolic state and environment of the cell. In mammals, there are more than a dozen MAPK genes. The best known are the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK(1-3)) and p38(alpha, beta, gamma and delta) families. ERK3, ERK5 and ERK7 are other MAPKs that have distinct regulation and functions. MAPK cascades consist of a core of three protein kinases. Despite the apparently simple architecture of this pathway, these enzymes are capable of responding to a bewildering number of stimuli to produce exquisitely specific cellular outcomes. These responses depend on the kinetics of their activation and inactivation, the subcellular localization of the kinases, the complexes in which they act, and the availability of substrates. Fine-tuning of cascade activity can occur through modulatory inputs to cascade component from the primary kinases to the scaffolding accessory proteins. Here, we describe some of the properties of the three major MAPK pathways and discuss how these properties govern pathway regulation and activity.

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    • "Indeed, several molecular pathways have been reported to be involved in the neurological damage caused by exposure to an electromagnetic field, such as the caspase3-dependent pathway (Liu et al., 2012), cAMP/PKA pathway (He et al., 2013), ATM-Chk2-p21 Pathway (Huang et al., 2014) and ERK pathway (Caraglia et al., 2005). Among these pathways, ERK1/2, a member of the mitogenactivated protein kinase (MAPK) family, plays a crucial role in signal transduction pathways related to cell growth, differentiation and albumin extravasations (Gorostizaga et al., 2013; Raman et al., 2007). The activity and expression of ERK1/2 is dependent on the phosphorylation process, which is modulated by MAP kinase phosphatase-1 (mkp-1) a short-lived nuclear enzyme (Gorostizaga et al., 2013). "
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    ABSTRACT: With the rapid increase in the number of mobile phone users, the potential adverse effects of the electromagnetic field radiation emitted by a mobile phone has become a serious concern. This study demonstrated, for the first time, the blood-brain barrier and cognitive changes in rats exposed to 900 MHz electromagnetic field (EMF) and aims to elucidate the potential molecular pathway underlying these changes. A total of 108 male Sprague-Dawley rats were exposed to a 900 MHz, 1 mW/cm2 EMF or sham (unexposed) for 14 or 28 days (3 h per day). The specific energy absorption rate (SAR) varied between 0.016 (whole body) and 2 W/kg (locally in the head). In addition, the Morris water maze test was used to examine spatial memory performance determination. Morphological changes were investigated by examining ultrastructural changes in the hippocampus and cortex, and the Evans Blue assay was used to assess blood brain barrier (BBB) damage. Immunostaining was performed to identify heme oxygenase-1 (HO-1)-positive neurons and albumin extravasation detection. Western blot was used to determine HO-1 expression, phosphorylated ERK expression and the upstream mediator, mkp-1 expression. We found that the frequency of crossing platforms and the percentage of time spent in the target quadrant were lower in rats exposed to EMF for 28 days than in rats exposed to EMF for 14 days and unexposed rats. Moreover, 28 days of EMF exposure induced cellular edema and neuronal cell organelle degeneration in the rat. In addition, damaged BBB permeability, which resulted in albumin and HO-1 extravasation were observed in the hippocampus and cortex. Thus, for the first time, we found that EMF exposure for 28 days induced the expression of mkp-1, resulting in ERK dephosphorylation. Taken together, these results demonstrated that exposure to 900 MHz EMF radiation for 28 days can significantly impair spatial memory and damage BBB permeability in rat by activating the mkp-1/ERK pathway.
    Brain Research 01/2015; 1601. DOI:10.1016/j.brainres.2015.01.019 · 2.84 Impact Factor
    • "The MAPK pathway occupies a central position in the signal transduction machinery, which links external signals to the various cellular processes (Kim et al., 2002; Le and Richardson, 2002). The c-Jun NH2- terminal protein kinase (JNK) and p38 MAPK are known to have anti-proliferative and pro-apoptotic function, while ERK1/2 MAPK is primarily known for its proliferative role (Dhillon et al., 2007; Raman et al., 2007). The p38 and JNK are known for cell cycle arrest by phosphorylating p53 and increasing the stabilization of the cdk inhibitor p21 WAF1/CIP1 (Yu and Richardson, 2011). "
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    ABSTRACT: Recently, we have described the use of Caerulomycin A (CaeA) as a potent novel immunosuppressive agent. Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation and treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. The objective of this study was to identify cellular target of CaeA and decipher its mechanism of action. Jurkat cells were treated with CaeA and cellular iron content, iron uptake/release, DNA content and dNTP pool determined. Activation of MAPKs; expression level of TFR1, ferritin and cell cycle control molecules; ROS level and cell viability were measured using Western blotting, qRT-PCR or flow cytometry. CaeA causes intracellular iron depletion by reduced uptake and increased release by cells. CaeA causes cell cycle arrest by (i) inhibiting ribonucleotide reductase (RNR) enzyme, which catalyses the rate-limiting step in the synthesis of DNA (ii) stimulating MAPKs signalling transduction pathways that play important role in cell growth, proliferation and differentiation and (iii) by targeting cell cycle control molecules such as cyclin D1, cdk4 and p21(CIP1/WAF1) . The effect of CaeA on cell proliferation is reversible. CaeA exerts its immunosuppressive effect by targeting iron. The effect is reversible which makes CaeA not only an attractive candidate for development as potent immunosuppressive drug, but also indicate that iron chelation can be used as a rationale approach to selectively suppress the immune system; because compared to normal cells, rapidly proliferating cells require higher utilization of iron. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 12/2014; 172(9). DOI:10.1111/bph.13051 · 4.84 Impact Factor
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    • "Differences in ERK activation have also been correlated with separation of the ab and gd T cell fates, although the importance of these differences in controlling the ab versus gd lineage separation process has never been investigated. Despite the central role that ERK signaling plays in essentially every lymphoid fate decision, the basis by which differences in ERK signaling promote the specification of alternative cell fates remains poorly understood (Raman et al., 2007). Consequently, we have investigated the basis by which differences in ERK signaling specify alternate developmental fates, using separation of the ab and gd lineages as a model. "
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    ABSTRACT: Gradations in extracellular regulated kinase (ERK) signaling have been implicated in essentially every developmental checkpoint or differentiation process encountered by lymphocytes. Yet, despite intensive effort, the molecular basis by which differences in ERK activation specify alternative cell fates remains poorly understood. We report here that differential ERK signaling controls lymphoid-fate specification through an alternative mode of action. While ERK phosphorylates most substrates, such as RSK, by targeting them through its D-domain, this well-studied mode of ERK action was dispensable for development of γδ T cells. Instead, development of γδ T cells was dependent upon an alternative mode of action mediated by the DEF-binding pocket (DBP) of ERK. This domain enabled ERK to bind a distinct and select set of proteins required for specification of the γδ fate. These data provide the first in vivo demonstration for the role of DBP-mediated interactions in orchestrating alternate ERK-dependent developmental outcomes. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 12/2014; 41(6):934-946. DOI:10.1016/j.immuni.2014.10.021 · 21.56 Impact Factor
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