Differential regulation and properties of MAPK

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


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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    • "Thus, there are central roles for JNKs in diabetes , but their roles in diabetes-induced male reproductive dysfunction are not clearly known. The upstream proteins such as ASK1 (apoptosis signal-regulating kinase 1) and MKK4/7 (MAPK kinase4/7) upon receiving varieties of stimuli activate the JNKs (Raman et al., 2007; Dhanasekaran and Reddy, 2008; Koch et al., 2015), which in turn activate a growing list of downstream proteins of the JNKs namely, c-Jun, c-Fos, ATF2 (activating transcription factor 2), ELK1 (ETS domaincontaining protein-1), SMAD4 (mothers against decapentaplegic homolog 4) and p53 (Koch et al., 2015). Differential regulation of these downstream target proteins of the JNKs, especially the c-Jun, decides whether or not the stimuli are pro-cell survival or pro-cell death (Sabapathy and Wagner, 2004). "
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    ABSTRACT: Diabetes adversely affects reproductive functions in humans and animals. The present study investigated the effects of Resveratrol on diabetes-induced alterations in oxidative stress, c-Jun N-terminal kinase (JNK) signaling and apoptosis in the testis. Adult male Wistar rats (13–15 weeks; n = 6/group) were segregated into 1) normal control, 2) Resveratrol-treated (5 mg/kg; ip; given during last 3 weeks), 3) Streptozotocin-induced diabetic and, 4) Resveratrol-treated diabetic groups, and euthanized on day 42 after the confirmation of diabetes. Resveratrol did not normalize blood glucose levels in diabetic rats. Resveratrol supplementation recovered diabetes-induced decreases in reproductive organ weights, sperm count and motility, intra-testicular levels of superoxide dismut-ase, catalase, and glutathione peroxidase and an increase in 4-hydroxynonenal activities (P b 0.05). Resveratrol also recovered diabetes-induced increases in JNK signaling pathway proteins, namely, ASK1 (apoptosis signal-regulating kinase 1), JNKs (46 and 54 kDa isoforms) and p-JNK to normal control levels (P b 0.05). Interestingly, the expression of a downstream target of ASK1, MKK4 (mitogen-activated protein kinase kinase 4) and its phos-phorylated form (p-MKK4) did not change in experimental groups. Resveratrol inhibited diabetes-induced increases in AP-1 (activator protein-1) components, c-Jun and ATF2 (activating transcription factor 2), but not their phosphorylated forms, to normal control levels (P b 0.05). Further, Resveratrol inhibited diabetes-induced increase in cleaved-caspase-3 to normal control levels. In conclusion, Resveratrol alleviates diabetes-induced apoptosis in testis by modulating oxidative stress, JNK signaling pathway and caspase-3 activities, but not by inhibiting hyperglycemia, in rats. These results suggest that Resveratrol supplementation may be a useful strategy to treat diabetes-induced testicular dysfunction.
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    • "Variation in these conditions can result in suboptimal growth, and therefore, cells use complex response pathways that sense environmental changes and promote the appropriate response resulting in adapted cellular states. MAPK (mitogen-activated protein kinase) pathways are widely used through evolution to perform this essential function (Raman et al, 2007). Changes in environmental conditions are commonly detected by sensors located at the cell surface, and the signal is transduced by GTPase nodes to MAPK phosphorylation cascades. "
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    Molecular Systems Biology 04/2015; 11(4). DOI:10.15252/msb.20145606 · 10.87 Impact Factor
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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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