scholarly journals Sustained activation of p42/p44 mitogen-activated protein kinase during recovery from simulated ischaemia mediates adaptive cytoprotection in cardiomyocytes

2000 ◽  
Vol 350 (3) ◽  
pp. 891-899 ◽  
Author(s):  
Anu PUNN ◽  
James W. MOCKRIDGE ◽  
Saleha FAROOQUI ◽  
Michael S. MARBER ◽  
Richard J. HEADS
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
P38 Mapk ◽  
Cell Injury ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Neonatal Rat ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Sustained Activation

Delayed cytoprotection (preconditioning) occurs 24h after sublethal simulated ischaemia and reperfusion (SI/R) in neonatal rat ventricular cardiomyocytes. SI/R was used to investigate the role of activation of mitogen-activated protein kinases (MAPKs), stress-activated protein kinases (SAPKs) and phosphoinositide 3-kinase-dependent protein kinase B (PKB)/Akt in cytoprotection. SI resulted in transient dual (Thr/Tyr) phosphorylation of p42/p44-MAPK and p38-MAPK, weak phosphorylation of p46/p54-SAPK, but no phosphorylation of PKB. ‘Reperfusion’ caused further transient phosphorylation of p38-MAPK, but sustained phosphorylation of p42/p44-MAPK (lasting 4h) and of Ser473 of PKB (lasting 2h). Furthermore, SI/R (24h) induced delayed protection against lethal SI, as determined by an increase in cell viability {bioreduction of MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide]} and a decrease in cell injury (release of creatine kinase). Both protection and phosphorylation of p42/p44-MAPK were blocked by the MEK-1/2 (MAPK/Erk kinase-1/2) inhibitor PD98059 (50µM) when given during SI/R, but not when given during SI alone. The p38-MAPK inhibitor SB203580 (10µM) blocked the p38-MAPK-dependent phosphorylation of activating transcription factor 2 in vitro, and the phosphoinositide 3-kinase inhibitor wortmannin (100nM) blocked PKB phosphorylation on Ser473. However, neither SB203580 nor wortmannin had any effect on delayed protection. Therefore sustained activation of p42/p44-MAPK during simulated ‘reperfusion’ following sublethal SI mediates preconditioning in cardiomyocytes independently of transient activation of p38-MAPK or sustained activation of PKB.

Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies

2008 ◽  
Vol 413 (3) ◽  
pp. 429-436 ◽  
Author(s):  
Yan Zeng ◽  
Heidi Sankala ◽  
Xiaoxiao Zhang ◽  
Paul R. Graves
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Processing Bodies ◽  
Mitogen Activated Protein

Ago (Argonaute) proteins are essential effectors of RNA-mediated gene silencing. To explore potential regulatory mechanisms for Ago proteins, we examined the phosphorylation of human Ago2. We identified serine-387 as the major Ago2 phosphorylation site in vivo. Phosphorylation of Ago2 at serine-387 was significantly induced by treatment with sodium arsenite or anisomycin, and arsenite-induced phosphorylation was inhibited by a p38 MAPK (mitogen-activated protein kinase) inhibitor, but not by inhibitors of JNK (c-Jun N-terminal kinase) or MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]. MAPKAPK2 (MAPK-activated protein kinase-2) phosphorylated bacterially expressed full-length human Ago2 at serine-387 in vitro, but not the S387A mutant. Finally, mutation of serine-387 to an alanine residue or treatment of cells with a p38 MAPK inhibitor reduced the localization of Ago2 to processing bodies. These results suggest a potential regulatory mechanism for RNA silencing acting through Ago2 serine-387 phosphorylation mediated by the p38 MAPK pathway.

scholarly journals Interleukin-13 Induction of 15-Lipoxygenase Gene Expression Requires p38 Mitogen-Activated Protein Kinase-Mediated Serine 727 Phosphorylation of Stat1 and Stat3

2003 ◽  
Vol 23 (11) ◽  
pp. 3918-3928 ◽  
Author(s):  
Bo Xu ◽  
Ashish Bhattacharjee ◽  
Biswajit Roy ◽  
Hong-Min Xu ◽  
David Anthony ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Kinase Inhibitor ◽  
Specific Inhibitor ◽  
Serine Phosphorylation ◽  
Time Dependent ◽  
Mitogen Activated Protein Kinase ◽  
Human Monocytes ◽  
Interleukin 13 ◽  
Mitogen Activated Protein

ABSTRACT Interleukin-13 (IL-13) is a cytokine secreted by Th2 lymphocytes that is capable of inducing expression of 15-lipoxygenase (15-LO) in primary human monocytes. We recently demonstrated that induction of 15-LO requires the activation of Jak2 and Tyk2 kinases and Stats 1, 3, 5, and 6. Since IL-13-induced 15-LO expression was inhibited by H7 (a serine-threonine kinase inhibitor), we predicted that Stat serine phosphorylation may also be crucial for 15-LO expression. In this study, we present evidence indicating that IL-13-induced 15-LO mRNA expression was detectable as early as 1 h by real-time reverse transcription-PCR. We found that IL-13 induced a time-dependent serine phosphorylation of both Stat1 and Stat3, detectable at 15 min after IL-13 treatment. In addition, the activation of p38 mitogen-activated protein kinase (MAPK) was detected in a time-dependent fashion, with peak phosphorylation at 15 min after IL-13 treatment. SB202190, a p38 MAPK-specific inhibitor, markedly inhibited IL-13-induced Stat1 and Stat3 serine phosphorylation as well as DNA binding. Furthermore, treatment of cells with Stat1 or Stat3 decoys significantly impaired IL-13-induced 15-LO expression. Taken together, our results provide the first evidence that IL-13 induces p38 MAPK phosphorylation/activation, which regulates Stat1 and Stat3 serine 727 phosphorylation. Both of these events are important steps in IL-13-induced 15-LO expression in human monocytes.

scholarly journals Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by the G-protein-coupled receptor agonist phenylephrine in the perfused rat heart

1998 ◽  
Vol 332 (2) ◽  
pp. 459-465 ◽  
Author(s):  
Antigone LAZOU ◽  
Peter H. SUGDEN ◽  
Angela CLERK
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Hypertrophic Growth ◽  
Mitogen Activated Protein ◽  
Powerful Activator ◽  
P38 Mapk Inhibitor ◽  
Cellular Stresses ◽  
P38 Mapks

We investigated the ability of phenylephrine (PE), an α-adrenergic agonist and promoter of hypertrophic growth in the ventricular myocyte, to activate the three best-characterized mitogen-activated protein kinase (MAPK) subfamilies, namely p38-MAPKs, SAPKs/JNKs (i.e. stress-activated protein kinases/c-Jun N-terminal kinases) and ERKs (extracellularly responsive kinases), in perfused contracting rat hearts. Perfusion of hearts with 100 µM PE caused a rapid (maximal at 10 min) 12-fold activation of two p38-MAPK isoforms, as measured by subsequent phosphorylation of a p38-MAPK substrate, recombinant MAPK-activated protein kinase 2 (MAPKAPK2). This activation coincided with phosphorylation of p38-MAPK. Endogenous MAPKAPK2 was activated 4–5-fold in these perfusions and this was inhibited completely by the p38-MAPK inhibitor, SB203580 (10 µM). Activation of p38-MAPK and MAPKAPK2 was also detected in non-contracting hearts perfused with PE, indicating that the effects were not dependent on the positive inotropic/chronotropic properties of the agonist. Although SAPKs/JNKs were also rapidly activated, the activation (2–3-fold) was less than that of p38-MAPK. The ERKs were activated by perfusion with PE and the activation was at least 50% of that seen with 1 µM PMA, the most powerful activator of the ERKs yet identified in cardiac myocytes. These results indicate that, in addition to the ERKs, two MAPK subfamilies, whose activation is more usually associated with cellular stresses, are activated by the Gq/11-protein-coupled receptor (Gq/11PCR) agonist, PE, in whole hearts. These data indicate that Gq/11PCR agonists activate multiple MAPK signalling pathways in the heart, all of which may contribute to the overall response (e.g. the development of the hypertrophic phenotype).

scholarly journals Correlations between Insulin Receptor Substrate-1 with Phosphoinositide 3-Kinase and P38 Mitogen-Activated Protein Kinase Levels after Treatment of Diabetic Rats with Puguntano (Curanga Fel-Terrae [Merr.]) Leaf Extract

2019 ◽  
Vol 7 (8) ◽  
pp. 1247-1251 ◽  
Author(s):  
Santi Syafril ◽  
Dharma Lindarto ◽  
Aznan Lelo ◽  
Rosita Juwita Sembiring ◽  
Awaluddin Saragih
Keyword(s):  
Treatment Group ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Leaf Extract ◽  
Mitogen Activated Protein Kinase ◽  
Control Group ◽  
Insulin Receptor Substrate ◽  
Mitogen Activated Protein ◽  
Positive Correlations ◽  
Phosphoinositide 3 Kinase

BACKGROUND: Defects in post-receptor insulin signalling are the major cause of insulin resistance in type 2 diabetes mellitus (T2DM). AIM: This study aimed to investigate the correlations between insulin receptor substrate (IRS)-1 with phosphoinositide 3-kinase (PI3K) and p38 mitogen-activated protein kinase (MAPK) levels after puguntano (Curanga fel-terrae [Merr.]) leaf extract treatment in a rat model of T2DM. METHODS: A combination of high-fat diet-feeding (HFD) and multiple low dose intraperitoneal injections of streptozotocin was used to induced T2DM in 48 Wistar rats, which were then randomly divided into control and treatment groups (n = 24 per group). Puguntano leaf extract was administered to the treatment group once daily (200 mg/kg.bw) for 10 days. IRS-1, PI3K and p38 MAPK levels were measured in skeletal muscle using sandwich ELISAs in control group after becoming T2DM and in the treatment group after 10 days of puguntano treatment. Data were analysed using the Wilcoxon test and Spearman’s correlation. RESULTS: IRS-1, PI3K and p38 MAPK levels were significantly higher in the treatment group than in the control group. There were also significant positive correlations between IRS-1 with PI3K and p38 MAPK levels (r = 0.375, p = 0.035; r = 0.552, p = 0.003; respectively) after the treatment. CONCLUSION: This study demonstrated significant positive correlations between IRS-1 with PI3K and p38 MAPK levels after puguntano leaf extract treatment of T2DM rats.

scholarly journals Bax translocates to mitochondria of heart cells during simulated ischaemia: involvement of AMP-activated and p38 mitogen-activated protein kinases

2006 ◽  
Vol 395 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Michela Capano ◽  
Martin Crompton
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
P38 Mapk ◽  
Fluorescent Protein ◽  
Mitogen Activated Protein Kinase ◽  
Heart Cells ◽  
Intermembrane Space ◽  
Neonatal Cardiomyocytes ◽  
Mitogen Activated Protein ◽  
Green Fluorescent

The cytosolic protein Bax plays a key role in apoptosis by migrating to mitochondria and releasing proapoptotic proteins from the mitochondrial intermembrane space. The present study investigates the movement of Bax in isolated rat neonatal cardiomyocytes subjected to simulated ischaemia (minus glucose, plus cyanide), using green fluorescent protein-tagged Bax as a means of imaging Bax movements. Simulated ischaemia induced Bax translocation from the cytosol to mitochondria, commencing within 20 min of simulated ischaemia and progressing for several hours. Under the same conditions, there was an increase in the active, phosphorylated forms of p38 MAPK (mitogen-activated protein kinase) and AMPK (AMP-activated protein kinase). The AMPK activators AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) and metformin also stimulated Bax translocation. Inhibition of p38 MAPK with SB203580 attenuated the phosphorylation of the downstream substrates, MAPK-activated protein kinases 2 and 3, but not that of the upstream MAPK kinase 3, nor of AMPK. Under all conditions (ischaemia, AICAR and metformin), SB203580 blocked Bax translocation completely. It is concluded that Bax translocation to mitochondria is an early step in ischaemia and that it occurs in response to activation of p38 MAPK downstream of AMPK.

scholarly journals PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

2012 ◽  
Vol 14 ◽  
Author(s):  
Simon M. Schultze ◽  
Brian A. Hemmings ◽  
Markus Niessen ◽  
Oliver Tschopp
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Glucose Homeostasis ◽  
Inflammatory Diseases ◽  
Mitogen Activated Protein Kinase ◽  
New Therapeutic Approaches ◽  
The Metabolic Syndrome ◽  
Obesity And Diabetes ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications.

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