Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the search for new markers of human endometrial hyperplasia and adenocarcinoma the method of quantitative two-dimensional gel electrophoresis was applied to study the protein expression profiles of metabolically [(35)S]-methionine-labelled proteins of endometrial explants. Approximately 1700 protein spots were resolved by the two-dimensional gel electrophoresis, and the expression pattern of each of these proteins was assessed for increased expression during hyperplasia or adenocarcinoma. In total, six protein spots showed increased expression in hyperplasia, 19 in carcinoma, and eight in both hyperplasia and carcinoma. Twelve of these 33 differentially expressed proteins were identified by peptide mass mapping combined with sequence database searching. Among the identified proteins were proteins involved in cellular transport and chaperoning, i.e. heat shock protein 27 kDa protein, heat shock 70 kDa protein, heat shock cognate 71 kDa protein, and serotransferrin. Other identified proteins were: regulatory chain protein of cAMP-dependent protein kinase, prohibitin, and heterogeneous nuclear ribonucleoprotein A2/B1. Finally we identified proteins associated with the cytoskeleton, vimentin and tropomyosin isoform 3, and the glycolytic pathway, alpha enolase, and phosphoglycerate kinase. The remaining unidentified proteins were either not contained in the database and must be assumed to be novel proteins, or were present in too low amounts to allow characterization.
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PMID:Two-dimensional gel analysis of human endometrial proteins: characterization of proteins with increased expression in hyperplasia and adenocarcinoma. 1042 3

Estrogen is important for the primary prevention of vascular disease in young women, but the mechanisms of protection at the vascular cell are still largely unknown. Although traditionally thought of as a nuclear transcription factor, the estrogen receptor has also been identified in the cell plasma membrane to signal but serve largely undefined roles. Here we show that estradiol (E2) rapidly activates p38beta mitogen-activated protein kinase in endothelial cells (EC), which activates the mitogen-activated protein kinase-activated protein kinase-2 and the phosphorylation of heat shock protein 27. The sex steroid preserves the EC stress fiber formation and actin and membrane integrity in the setting of metabolic insult. E2 also prevents hypoxia-induced apoptosis and induces both the migration of EC and the formation of primitive capillary tubes. These effects are reversed by the inhibition of p38beta, by the expression of a dominant-negative mitogen-activated protein kinase-activated protein kinase-2 protein, or by the expression of a phosphorylation site mutant heat shock protein 27. E2 signaling from the membrane helps preserve the EC structure and function, defining potentially important vascular-protective effects of this sex steroid.
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PMID:Estrogen signals to the preservation of endothelial cell form and function. 1098 97

Transcriptional activation of the p53 target genes plays a critical role in the cellular response to DNA damage, hypoxia, cellular stress and other signals regulating the cell cycle and apoptosis. The discovery of new p53 target genes continues to reveal novel mechanisms of action of this multifaceted protein. We used cDNA arrays to search for p53-regulated genes in prostate cancer cells. In this report, we describe robust induction of heat shock protein 27 (hsp27) in prostate cancer cells (DU145, LNCaP, PC3) following wild-type p53 expression from an adenoviral p53 expression vector (AdWTp53). A mutant p53 (R175H)-containing adenoviral expression vector did not induce hsp27. hsp27 expression was not altered in prostate cancer cells following expression of cyclin-dependent kinase inhibitors: p21(waf1/cip1) and p27(kip1) from adenoviral expression vectors. Treatment of cells with staurosporine, an apoptosis-inducing agent, did no affect hsp27 expression. These observations provide evidence that induction of hsp27 expression was wild-type p53-specific and was not due to non-specific effects of cell growth arrest and/or apoptosis. Previous studies and the experiment reported here show induction of hsp27 expression in response to androgen ablation, a physiological state that induces apoptosis in prostatic epithelial cells. The nature of p53 and hsp27 interactions in the regulation of apoptosis and/or cell growth needs to be further defined.
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PMID:p53-dependent induction of heat shock protein 27 (HSP27) expression. 1100 67

Phosphorylation of heat shock protein 27 (Hsp27) in human platelets by mitogen-activated protein kinase-activated protein kinase (MAPKAP) 2 is associated with signaling events involved in platelet aggregation and regulation of microfilament organization. We now show that Hsp27 is also phosphorylated by cGMP-dependent protein kinase (cGK), a signaling system important for the inhibition of platelet aggregation. Stimulation of washed platelets with 8-para-chlorophenylthio-cGMP, a cGK specific activator, resulted in a time-dependent phosphorylation of Hsp27. This is supported by the ability of cGK to phosphorylate Hsp27 in vitro to an extent comparable with the cGK-mediated phosphorylation of its established substrate vasodilator-stimulated phosphoprotein. Studies with Hsp27 mutants identified threonine 143 as a yet uncharacterized phosphorylation site in Hsp27 specifically targeted by cGK. To test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAPKAP kinase phosphorylation of Hsp27, the known MAPKAP kinase 2-phosphorylation sites (Ser15, Ser78, and Ser82) as well as Thr143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization. Mutation of the cGK-specific site Thr143 alone had no effect on actin polymerization, but in the MAPKAP kinase 2 phosphorylation-mimicking mutant, this mutation reduced the stimulation of actin polymerization significantly. These data suggest that phosphorylation of Hsp27 and Hsp27-dependent regulation of actin microfilaments contribute to the inhibitory effects of cGK on platelet function.
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PMID:Heat shock protein 27 is a substrate of cGMP-dependent protein kinase in intact human platelets: phosphorylation-induced actin polymerization caused by HSP27 mutants. 1138 10

Angiotensin II (AII, 100 nM) stimulation of bovine adrenal chromaffin cells (BACCs) produced angiotensin II receptor subtype 1 (AT1)-mediated increases in extracellular regulated protein kinase 1/2 (ERK1/2) and stress-activated p38MAPK (p38 kinase) phosphorylation over a period of 10 min. ERK1/2 and p38 kinase phosphorylation preceded Ser31 phosphorylation on tyrosine hydroxylase (TOH). The inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) activation, PD98059 (0.1-50 microM) and UO126 (0.1-10 microM), dose-dependently inhibited both ERK2 and Ser31 phosphorylation on TOH in response to AII, suggesting MEK1/2 involvement. The p38 kinase inhibitor SB203580 (20 microM, 30 min) abolished Ser31 and Ser19 phosphorylation on TOH and partially inhibited ERK2 phosphorylation produced by AII. In contrast, 1 microM SB203580 did not affect AII-stimulated TOH phosphorylation, but fully inhibited heat shock protein 27 (HSP27) phosphorylation produced by AII. Also, 1 microM SB203580 fully inhibited Ser19 phosphorylation on TOH and HSP27 phosphorylation in response to anisomycin (30 min, 10 microg/mL). The results suggest that ERKs mediate Ser31 phosphorylation on TOH in response to AII, but p38 kinase is not involved. Previous studies suggesting a role for p38 kinase in the phosphorylation of Ser31 are explained by the non-specific effects of 20 microM SB203580 in BACCs. The p38 kinase pathway is able to phosphorylate Ser19 on TOH in response to anisomycin, but does not do so in response to AII.
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PMID:Tyrosine hydroxylase phosphorylation in bovine adrenal chromaffin cells: the role of MAPKs after angiotensin II stimulation. 1148 51

Human skin is exposed to an environment that varies in humidity from 100 to 0%, leading to seasonal variations in the condition of the skin. Exposure to a low humidity environment creates an osmotic gradient across the stratum corneum, which is known to modulate cutaneous barrier function. Heat shock proteins protect against stress-induced destabilization of proteins. We investigated whether osmotic shock (sorbitol) induced a heat shock protein response in normal human keratinocytes, and used heat shock as a positive control. Both heat shock and osmotic stress (200 and 300 mM sorbitol) clearly induced heat shock proteins 70 and 27 mRNA levels. The induction of heat shock protein 70 mRNA levels by osmotic stress peaked at 16 h and persisted until 24 h, whereas upregulation of heat shock protein 70 mRNA levels by heat peaked at 2 h and returned to baseline levels by 6 h. Sorbitol also increased heat shock protein 70 levels in a concentration-dependent manner. The kinetics of heat shock protein 27 mRNA induction by osmotic stress and heat were similar with peak induction at 6 h. The mitogen activated protein kinase family of proteins plays an important part in the coordination of gene responses to various stress conditions. We have demonstrated that the p38 mitogen activated protein kinase was strongly activated by 200 mM and 300 mM sorbitol. The specific p38 mitogen activated protein kinase inhibitor PD169316 almost completely blocked heat shock protein 70 mRNA induction by 200 mM and 300 mM sorbitol and completely suppressed heat shock protein 27 mRNA induction with 200 mM sorbitol. PD169316 also counteracted upregulation of heat shock protein 70 levels by sorbitol. These data indicate that keratinocytes respond to osmotic stress by p38 mitogen activated protein kinase regulated induction of heat shock proteins. This molecular pathway may be relevant for the mechanisms regulating the response of human skin to variations in environmental humidity.
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PMID:Human keratinocytes respond to osmotic stress by p38 map kinase regulated induction of HSP70 and HSP27. 1171 Sep 46

We demonstrated previously that 5-lipoxygenase (5-LO), a key enzyme in leukotriene biosynthesis, can be phosphorylated by p38 MAPK-regulated MAPKAP kinases (MKs). Here we show that mutation of Ser-271 to Ala in 5-LO abolished MK2 catalyzed phosphorylation and clearly reduced phosphorylation by kinases prepared from stimulated polymorphonuclear leukocytes and Mono Mac 6 cells. Compared with heat shock protein 27 (Hsp-27), 5-LO was a weak substrate for MK2. However, the addition of unsaturated fatty acids (i.e. arachidonate 1-50 microm) up-regulated phosphorylation of 5-LO, but not of Hsp-27, by active MK2 in vitro, resulting in a similar phosphorylation as for Hsp-27. 5-LO was phosphorylated also by other serine/threonine kinases recognizing the motif Arg-Xaa-Xaa-Ser (protein kinase A, Ca(2+)/calmodulin-dependent kinase II), but these activities were not increased by fatty acids. HeLa cells expressing wild type 5-LO or S271A-5-LO, showed prominent 5-LO activity when incubated with Ca(2+)-ionophore plus arachidonate. However, when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO. It appears that phosphorylation at Ser-271 is more important for 5-LO activity induced by a stimulus that does not prominently increase intracellular Ca(2+) and that arachidonic acid stimulates leukotriene biosynthesis also by promoting this MK2-catalyzed phosphorylation.
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PMID:Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). 1184 97

Cholecystokinin (CCK) acting through its G protein-coupled receptor is now known to activate a variety of intracellular signaling mechanisms and thereby regulate a complex array of cellular functions in pancreatic acinar cells. The best studied mechanism is the coupling through heterotrimeric G proteins of the Gq family to activate a phospholipase C leading to an increase in inositol trisphosphate and release of intracellular Ca2+. This pathway along with protein kinase C activation in response to the increase in diacylglycerol stimulates the secretion of digestive enzymes by the process of exocytosis. CCK also activates signaling pathways in acini more related to other processes. The three mitogen activated protein kinase cascades leading to ERKs, JNKs and p38 MAPK are all activated by CCK. CCK activates the ERK cascade by PKC activation of Raf which in turn activates MEK and ERKs. JNKs are activated by a distinct mechanism which requires higher concentrations of CCK. Both ERKs and JNKs are presumed to regulate gene expression. CCK activation of p38 MAPK also plays a role in regulating the actin cytoskeleton through phosphorylation of the small heat shock protein HSP27. The PI3K-PKB-mTOR pathway is activated by CCK and plays a major role in regulating protein synthesis at the translational level. This includes both activation of p70 S6K leading to phosphorylation of ribosomal protein S6 and the phosphorylation of the binding protein for initiation factor 4E leading to formation of the mRNA cap binding complex. Other signaling pathways activated by CCK receptors include NF-kappaB and a variety of tyrosine kinases. Further work is needed to understand how CCK receptors activate most of the above pathways and to better understand the biological events regulated by these diverse signaling pathways.
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PMID:Cholecystokinin activates a variety of intracellular signal transduction mechanisms in rodent pancreatic acinar cells. 1268 72

We investigated whether tumor necrosis factor-alpha (TNF-alpha) stimulates the induction of heat shock protein 27 (HSP27) in human neutrophils and the mechanism underlying this induction. In intact neutrophils, almost no HSP27 was detected. Stimulation of neutrophils by TNF-alpha increased the levels of HSP27 in the presence, but not in the absence, of cycloheximide. Reverse transcription-polymerase chain reaction (RT-PCR) experiments showed that TNF-alpha also induced HSP27 mRNA in the presence of cycloheximide. TNF-alpha induced the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. The HSP27 accumulation induced by TNF-alpha was significantly suppressed by 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580) or 4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole (PD169316); both are specific inhibitors of p38 MAP kinase, but not by 2'-amino-3'-methoxyflavone (PD098059, a specific inhibitor of the upstream kinase that activates p44/p42 MAP kinase). The accumulation of HSP27 induced by TNF-alpha plus cycloheximide was also suppressed by pretreatment with a specific protein kinase C (PKC) inhibitor. Furthermore, phorbol myristate acetate (PMA), a PKC stimulant, but not dibutyryl cyclic AMP, a protein kinase A stimulant, stimulated the accumulation of HSP27. Interestingly, SB203580 did not inhibit PMA-stimulated HSP27 induction. These results strongly suggest that TNF-alpha may act as the regulator of HSP27 induction in neutrophils. p38 MAP kinase (but not p44/p42 MAP kinase) and PKC take part in TNF-alpha-stimulated HSP27 induction in human neutrophils.
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PMID:Involvement of p38 mitogen-activated protein kinase in heat shock protein 27 induction in human neutrophils. 1269 7

Evidence suggests that p38 mitogen-activated protein kinase (MAPK) activation influences cardiac function on an acute basis. The characterization and mechanisms by which this occurs were investigated in the present study. Adult rat ventricular myocytes treated with 1 mM arsenite for 30 min had a 16-fold increase in p38 MAPK phosphorylation that was attenuated by SB-203580 (a p38 MAPK inhibitor). Extracellular signal-regulated protein kinase (ERK) and c-Jun NH2-terminal kinase (JNK) were also minimally activated, but this activation was not sensitive to SB-203580. In addition, arsenite caused a p38 MAPK-independent translocation/activation of protein phosphatase 2a (PP2a) and decrease in phosphorylation of myosin light chain 2 (LC2). Arsenite-p38 MAPK activation led to translocation of heat shock protein 27 but not alpha B-crystallin to the myofilaments. Using isolated cardiomyocytes, we determined that arsenite reduces isometric tension without a change in Ca2+ sensitivity of tension via p38 MAPK and lowers myofibrillar actomyosin Mg2+-ATPase activity in a p38 MAPK-independent manner. Thus arsenite induces a p38 MAPK-independent change in PP2a and LC2 that may account for the arsenite-dependent decrease in ATPase and a p38 MAPK-dependent modification of the myofilaments that decreases myocardial force development.
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PMID:Acute p38 MAPK activation decreases force development in ventricular myocytes. 1288 Dec 12


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