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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    • "Mitogen-activated protein kinase (MAPK) kinase (MAP2K) kinases (MAP3Ks) are important regulators of IkB kinases (IKKs) and MAP2Ks (Dong et al., 2002; Ghosh and Karin, 2002; Kyriakis and Avruch, 2001; Raman et al., 2007; Suddason and Gallagher, 2015). Nineteen MAP3Ks are present in mammals, though their precise roles in regulating the immune system are not fully understood (Karin and Gallagher, 2005; Suddason and Gallagher, 2015). "
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    ABSTRACT: MAPK signaling is important for T lymphocyte development, homeostasis, and effector responses. To better understand the role of Mekk1 (encoded by Map3k1) in T cells, we conditionally deleted Map3k1 in Lck Cre/+ Map3k1 f/f mice, and these display larger iNKT cell populations within the liver, spleen, and bone marrow. Mekk1 signaling controls splenic and liver iNKT cell expansion in response to glycolipid antigen. Lck Cre/+ Map3k1 f/f mice have enhanced liver damage in response to glycolipid antigen. Mekk1 regulates Jnk activation in iNKT cells and binds and transfers Lys63-linked poly-ubiquitin onto Carma1. Map3k1 is critical for the regulation of p27Kip1 (encoded by Cdkn1b). Suddason et al. use a T-cell-specific deletion of Map3k1 to show that Mekk1 regulates TCR-dependent Jnk activation and Cdkn1b expression to drive proliferation in response to antigen.
    Full-text · Article · Jan 2016 · Cell Reports
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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.
    Full-text · Article · Oct 2015 · Toxicology and Applied Pharmacology
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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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    ABSTRACT: Genetic interaction screens have been applied with great success in several organisms to study gene function and the genetic architecture of the cell. However, most studies have been performed under optimal growth conditions even though many functional interactions are known to occur under specific cellular conditions. In this study, we have performed a large-scale genetic interaction analysis in Saccharomyces cerevisiae involving approximately 49 × 1,200 double mutants in the presence of five different stress conditions, including osmotic, oxidative and cell wall-altering stresses. This resulted in the generation of a differential E-MAP (or dE-MAP) comprising over 250,000 measurements of conditional interactions. We found an extensive number of conditional genetic interactions that recapitulate known stress-specific functional associations. Furthermore, we have also uncovered previously unrecognized roles involving the phosphatase regulator Bud14, the histone methylation complex COMPASS and membrane trafficking complexes in modulating the cell wall integrity pathway. Finally, the osmotic stress differential genetic interactions showed enrichment for genes coding for proteins with conditional changes in phosphorylation but not for genes with conditional changes in gene expression. This suggests that conditional genetic interactions are a powerful tool to dissect the functional importance of the different response mechanisms of the cell.
    Full-text · Article · Apr 2015 · Molecular Systems Biology
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