Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We tested the hypothesis that activation Jak2, which is prominently involved in the up-regulation of the renin-angiotensin system (RAS), constitutes a focal point in relaying signals triggered by a Angiotensin II (Ang II) and hypoxia/reoxygenation separately to cause an enhanced susceptibility of cardiac myocyte to apoptotic cell death. Ang II-treated adult cardiomyocytes in culture exhibited an increased level of apoptosis that accompanied activation of pro-apoptotic as well as anti-apoptotic signaling pathways. We observed increased phosphorylation of Jak2 kinase, Stat1, JNK, with increased expression of Bax protein, followed by an increase in caspase-1 and caspase-3 activity. Activation of these pro-apoptotic pathways was blocked by the Jak2 pharmacological inhibitor, Tyrphostin AG490. We also observed an increase in phosphorylation of cardioprotective pathway components, namely S6 ribosomal protein, and heat shock protein 27 (HSP27). Likewise, the oxidative stress, via the hypoxia/reoxygenation treatment of rat adult cardiomyocytes, produced apoptosis that was dependent upon activation of Jak2. The apoptotic response was not only reduced by Losartan, an inverse agonist of the AT1, receptor, but by treatment with AG490 as well. Taken together, these observations provide clear evidence in favor of Jak2 signaling as mediator of the apoptotic response in cardiomyocytes. However, there was a concomitant induction of cytoprotective signaling that presumably provides a negative feed-back to the deleterious effects of the agonist.
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PMID:Janus kinase-2 signaling mediates apoptosis in rat cardiomyocytes. 1626 69

Cell migration is critical for many processes, such as angiogenesis, inflammation, development and wound healing, and is also involved in tumour progression and metastasis. Here we show that CXCL12, complement factor 5a (C5a), hepatocyte growth factor (HGF) and platelet-derived growth factor (PDGF)-BB, which stimulate cell migration, also activate p38alpha MAPK. Pharmacological inhibition of this protein kinase with SB 203580 or BIRB 0796, or the genetic ablation of p38alpha MAPK, blocked cell migration induced by the aforementioned chemo-attractants. Macrophages from mice lacking one or more of the other p38 MAPK isoforms showed normal cell migration in response to C5a. We also show that the activation of p38alpha MAPK in response to CXCL12 requires the p21-activated protein kinases (PAK)-1 and PAK-2. MAPKAP-K2 is a protein kinase that is activated by p38alpha MAPK. Reducing its expression using RNA interference blocked CXCL12-induced HeLa cell migration, while macrophages from mice that do not express MAPKAP-K2 failed to migrate in response to C5a. Moreover, RNA interference against the small heat shock protein 27 (HSP27), a physiological substrate of MAPKAP-K2, blocked the CXCL12-induced cell migration. These results demonstrate a general and essential role of the PAK-p38alpha MAPK-MAPKAP-K2-HSP27 signalling pathway in mediating the effects of chemotactic stimuli on cell migration.
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PMID:CXCL12 and C5a trigger cell migration via a PAK1/2-p38alpha MAPK-MAPKAP-K2-HSP27 pathway. 1657 78

The expression of heat shock proteins (HSPs) is known to be increased via activation of heat shock factor 1 (HSF1), and excess expression of HSPs exerts feedback inhibition of HSF1. However, the molecular mechanism to modulate such relationships between HSPs and HSF1 is not clear. In the present study, we show that stable transfection of either Hsp25 or inducible Hsp70 (Hsp70i) increased expression of endogenous HSPs such as HSP25 and HSP70i through HSF1 activation. However, these phenomena were abolished when the dominant negative Hsf1 mutant was transfected to HSP25 or HSP70i overexpressed cells. Moreover, the increased HSF1 activity by either HSP25 or HSP70i was found to result from dephosphorylation of HSF1 on serine 307 that increased the stability of HSF1. Either HSP25 or HSP70i inhibited ERK1/2 phosphorylation because of increased MKP1 phosphorylation by direct interaction of these HSPs with MKP1. Treatment of HOS and NCI-H358 cells, which showed high expressions of endogenous HSF1, with small interfering RNA (siRNA) of either HSP27 (siHSP27)or HSP70i (siHSP70i) inhibited both HSP27 and HSP70i proteins; this was because of increased ERK1/2 phosphorylation and serine phosphorylation of HSF1. The results, therefore, suggested that when the HSF1 protein level was high in cancer cells, excess expression of HSP27 or HSP70i strongly facilitates the expression of HSP proteins through HSF1 activation, resulting in severe radio- or chemoresistance.
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PMID:Heat shock protein 25 or inducible heat shock protein 70 activates heat shock factor 1: dephosphorylation on serine 307 through inhibition of ERK1/2 phosphorylation. 1662 16

Doxorubicin (DOX) and its derivatives are used as chemotherapeutic drugs to treat cancer patients. However, production of DOX-mediated reactive oxygen species (ROS) by prolonged use of these drugs has been found to cause dilative cardiomyopathy and congestive heart failure. Thus various preventive modalities have been developed to avoid this side effect. We have found that the DOX-mediated oxidant-induced toxicity in cardiac cells could be minimized by hyperthermia-induced small heat shock protein 27 (HSP27); that is, this protein acts as an endogenous antioxidant against DOX-derived oxidants such as H(2)O(2). Heat shock-induced HSP27 was found to act as an antiapoptotic protein (reducing ROS and Bax-to-Bcl2 ratio) against DOX, and its phosphorylated isoforms stabilized F-actin remodeling in DOX-treated cardiac cells and, hence, attenuated the toxicity. Protein kinase assays and proteomic analyses suggested that higher expression of HSP27 and its phosphorylation are responsible for the protection in heat-shocked cells. Two-dimensional gel electrophoresis showed six isoforms (nonphosphorylated and phosphorylated) of HSP27. Matrix-assisted laser desorption/ionization time of flight analyses showed alpha- and beta-isoforms of HSP27, which are phosphorylated by various protein kinases. Ser(15) and Ser(85) phosphorylation of HSP27 by MAPK-assisted protein kinase 2 was found to be the key mechanism in reduction of apoptosis and facilitation of F-actin remodeling. The present study illustrates that hyperthermia protects cells from DOX-induced death through induction and phosphorylation of HSP27 and its antiapoptotic and actin-remodeling activities.
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PMID:Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27. 1678 45

We previously reported that prostaglandin D(2) (PGD(2)) stimulates the induction of heat shock protein 27 (HSP27) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether PGD(2) stimulates the phosphorylation of HSP27 in MC3T3-E1 cells exposed to heat shock. In the cultured MC3T3-E1 cells, PGD(2) markedly stimulated the phosphorylation of HSP27 at Ser-15 and Ser-85 in a time-dependent manner. Among the mitogen-activated protein (MAP) kinase superfamily, p44/p42 MAP kinase and p38 MAP kinase were phosphorylated by PGD(2) which had little effect on the phosphorylation of stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). The PGD(2)-induced phosphorylation of HSP27 was attenuated by PD169316, an inhibitor of p38 MAP kinase or PD98059, a MEK inhibitor. SP600125, a SAPK/JNK inhibitor did not affect the HSP27 phosphorylation. In addition, PD169316 suppressed the PGD(2)-induced phosphorylation of MAPKAP kinase 2. These results strongly suggest that PGD(2) stimulates HSP27 phosphorylation via p44/p42 MAP kinase and p38 MAP kinase but not SAPK/JNK in osteoblasts.
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PMID:Prostaglandin D2 induces the phosphorylation of HSP27 in osteoblasts: function of the MAP kinase superfamily. 1687 88

The expression of GPR41 and 43, which have recently been identified as G-protein-coupled cell-surface receptors for short-chain fatty acids (SCFAs), was detected in a human breast cancer cell line (MCF-7) by RT-PCR. Acetate, propionate and butyrate induced an increase in intracellular Ca2+ in these cells that was not blocked by treatment with pertussis toxin (PTX). SCFAs significantly reduced forskolin-induced cAMP levels in these cells. The phosphorylation of mitogen-activated protein kinase (MAPK) p38 was selectively increased by SCFAs. The downstream substrate heat shock protein 27 (HSP27) was also phosphorylated by SCFAs at Ser-78 and-82, but not-15. Propionate induced elevations in intracellular Ca2+ and the phosphorylation of p38 were inhibited by the silencing of GPR43 using a specific siRNA. These results suggest that GPR41 and 43 mediate SCFA signaling in mammary epithelial cells and thereby play an important role in their stress management.
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PMID:Short-chain fatty acids induce acute phosphorylation of the p38 mitogen-activated protein kinase/heat shock protein 27 pathway via GPR43 in the MCF-7 human breast cancer cell line. 1688 31

A stress-responsive, mitogen-activated protein kinase, p38, is activated by phosphorylation in response to adverse environmental insults. In the present study, the effects of hyperosmolarity on p38 activation and protein synthesis in the brain were examined. Hyperosmotic stress of rat brain slices, produced by addition of sorbitol to the incubation buffer, produced prolonged phosphorylation and activation of p38, most prominently in the hippocampus as compared to the cortex or cerebellum. In comparison, the prototypic mitogen-activated protein kinase, extracellular signal-regulated kinase, was transiently phosphorylated and another stress-activated protein kinase, c-Jun NH(2)-terminal kinase, was not phosphorylated above basal levels. Examination of downstream p38 signaling events revealed phosphorylation of the small heat shock protein 27 (HSP27) that was abolished by incubation with SB202190 [4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole], a p38 inhibitor. Concomitantly, hyperosmolarity diminished total levels of protein synthesis within hippocampal slices, as determined by incorporation of (35)S-labeled methionine/cysteine into protein during tissue incubation. However, synthesis of a 30-kDa protein, identified as 14-3-3epsilon with mass spectrometry, increased in response to hyperosmolarity. The synthesis of 14-3-3epsilon was dose-dependently induced by increasingly hyperosmotic conditions in a p38-independent manner. We conclude from these results that 14-3-3epsilon synthesis and p38-mediated HSP27 phosphorylation in the hippocampus are parallel responses to the hyperosmotic environment.
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PMID:Phosphorylation of HSP27 and synthesis of 14-3-3epsilon are parallel responses to hyperosmotic stress in the hippocampus. 1695 Feb 35

The p38 MAPK and heat shock protein 27 (hsp27) form a signaling complex with serine/threonine kinase Akt and MAPK-activated protein kinase-2 (MK2), which plays an important role in controlling stress-induced apoptosis and reorganizing actin cytoskeleton. However, regulation of the complex is poorly understood. In this study, the interaction between p38 and hsp27 was visualized in single living L929 cells using fluorescence resonance energy transfer technology, while their association with Akt was examined by immunoprecipitation analysis. Under normal growth conditions, p38 kinase constitutively interacts with hsp27. When cells were exposed to H(2)O(2) or stimulated by arachidonic acid, this interaction was disrupted. However, inhibition of the activation of p38 and Akt by selective inhibitors or overexpression of the kinase-dead mutant of p38 diminished such effects. Furthermore, mutation of phosphorylation sites of hsp27 renders the interaction resistant to H(2)O(2) and arachidonic acid. It was interesting to find that the interaction disappeared in the cells from MK2-knock-out mice or the cells treated with lemptomycin B that blocks export of MK2 from nucleus to cytosol. However, MK2 is not required for the association of hsp27 with Akt. This study suggests that MK2 mediates the incorporation of p38 into the pre-existing complex of hsp27 with Akt. Phosphorylation of hsp27 finally breaks the signaling complex.
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PMID:MAPK-activated protein kinase-2 (MK2)-mediated formation and phosphorylation-regulated dissociation of the signal complex consisting of p38, MK2, Akt, and Hsp27. 1701 49

In the present study, we investigated the induction of the p38-MAPK signalling pathway by copper, as exemplified by CuCl(2), in the isolated perfused heart of the amphibian Rana ridibunda. We found that p38-MAPK phosphorylation by CuCl(2) occurs in a dose-dependent manner, with maximum activation (8.73+/-1.43-fold relative to control values) attained by perfusion with 500 micromol l(-1) CuCl(2) for 15 min, while this activation sustained even after 60 min of reperfusion with normal bicarbonate buffer. CuCl(2) also induced the phosphorylation of the small heat shock protein 27 (Hsp27) in a p38-MAPK dependent manner, as revealed by experiments using the p38-MAPK inhibitor SB203580. p38-MAPK and Hsp27 phosphorylations were also strongly induced by hyperthermia (42 degrees C), while the simultaneous use of hyperthermia and CuCl(2) had a synergistic effect on p38-MAPK activation. Furthermore, perfusions with the potent antioxidant L-ascorbic acid (100 micromol l(-1)), the antioxidant enzymes catalase (CAT) (150 U ml(-1)) or superoxide dismutase (SOD) (30 U ml(-1)) in the presence of 500 micromol l(-1) CuCl(2) did not attenuate the CuCl(2)-induced p38-MAPK activation, implying that at least the reactive oxygen species (ROS) scavenged by these agents are not implicated in this kinase activation. The p38-MAPK phosphorylation induced by the combined action of CuCl(2) and hyperthermia was partially inhibited by catalase, indicating that hyperthermia possibly activates the kinase through the production of H(2)O(2). Caspase-3, an effector protease of apoptosis, remained inactive in hearts perfused at normal or hyperthermic conditions, in the absence or presence of 500 micromol l(-1) CuCl(2). All the above results suggest that, in the amphibian Rana ridibunda heart, p38-MAPK activation by copper has a possible protective role through the small Hsp27.
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PMID:Cu2+ and acute thermal stress induce protective events via the p38-MAPK signalling pathway in the perfused Rana ridibunda heart. 1723 13

Differentiation of trophoblast cells is a critical process for the proper establishment of the placenta and is, therefore, necessary to maintain embryonic development. Trophoblast stem (TS) cells grown in culture can differentiate into different trophoblast subtypes in vitro mimicking normal trophoblast cell differentiation. Therefore, TS cells are a valuable model system that can be used to elucidate genetic factors that regulate trophoblast cell differentiation. Several transcription factors, when analyzed by targeted gene mutation in mice, have resulted in embryonic lethality due to placental defects and, more specifically, defects of the trophoblast lineages. These studies have helped improve our knowledge about trophoblast cell differentiation, but much is still unknown about the specific mechanisms involved. This study uses TS cell culture to detect proteins with differential expression in proliferating and differentiating TS cells in order to identify proteins with potential roles in the differentiation process. We identified four proteins with differential expression: dimethylarginine dimethylaminohydrolase1 (DDAH1), keratin 8, keratin 18, and HSPB1 (also known as heat shock protein 25, HSP25). Further investigation confirmed the presence of HSPB1 protein during in vitro TS cell differentiation. In addition, we confirmed that phosphorylation of HSPB1 and MAP kinase-activated protein kinase 2 (MAPKAPK2) increased in TS cells during differentiation. Inhibition of MAPK14 (also known as p38 MAPK) resulted in a reduction of HSPB1 phosphorylation and an increase in cell death during TS cell differentiation. These results suggest that HSPB1 and the MAPK14 pathway are important during TS cell differentiation.
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PMID:Heat shock protein 1 and the mitogen-activated protein kinase 14 pathway are important for mouse trophoblast stem cell differentiation. 1726 99


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