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)

Prostaglandin E(2) (PGE(2)) is the predominant eicosanoid product released by macrophages at the site of inflammation. Binding of PGE(2) to its cognate 7 transmembrane-spanning G protein-coupled receptors (GPCRs) activates signaling pathways, leading to the synthesis of the Fos transcription factor. Because the Ste20 serine/threonine protein kinase (S/TPK) is a critical signal transducer for the G protein-coupled pheromone receptor in Saccharomyces cerevisiae, we postulated that the PGE(2) GPCRs may activate one of the Ste20 mammalian orthologs. We demonstrate here that the catalytic activity of a hematopoietic cell-restricted, Ste20-related S/TPK, HPK1, is positively regulated by exposure to physiological concentrations of PGE(2). Furthermore, ectopic expression studies implicated HPK1 as a negative regulator of PGE(2)-induced transcription of the fos gene. Our data suggest that PGE(2)-induced activation of HPK1 may represent a novel negative regulatory pathway capable of modulating PGE(2)-mediated gene transcription.
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PMID:Hematopoietic progenitor kinase 1 (HPK1) negatively regulates prostaglandin E2-induced fos gene transcription. 1252 5

Successful implantation requires synergism between the developing embryo and the receptive endometrium. In the baboon, infusion of chorionic gonadotropin (CG) modulates both morphology and physiology of the epithelial and stromal cells of the receptive endometrium. This study explored the signal transduction pathways activated by CG in endometrial epithelial cells from baboon (BE) and human (HES). Incubations of BE and HES cells with CG did not significantly alter adenylyl cyclase activity or increase intracellular cAMP when compared with Chinese hamster ovarian cells stably transfected with the full-length human CG/luteinizing hormone (LH) receptor (CHO-LH cells). However, in BE and HES cells, CG induced the phosphorylation of several proteins, among them, extracellular signal-regulated protein kinases 1 and 2 (ERK 1/2). Phosphorylation of ERK 1/2 in uterine epithelial cells was protein kinase A (PKA) independent. This novel signaling pathway is functional because, in response to CG stimulation, prostaglandin E(2) (PGE(2)) was released into the media and increased significantly 2 h following CG stimulation. CG-stimulated PGE(2) synthesis in epithelial cells was inhibited by a specific mitogen-activated protein kinase (MEK 1/2) inhibitor, PD 98059. In conclusion, immediate signal transduction pathways induced by CG in endometrial epithelial cells are cAMP independent and stimulate phosphorylation of ERK 1/2 via a MEK 1/2 pathway, leading to an increase in PGE(2) release as the possible result of cyclooxygenase-2 activation.
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PMID:Signal transduction pathways activated by chorionic gonadotropin in the primate endometrial epithelial cells. 1253 8

Prostaglandin E(2) (PGE(2)) has a strong protective effect on the gastric mucosa in vivo; however, the molecular mechanism of a direct cytoprotective effect of PGE(2) on gastric mucosal cells has yet to be elucidated. Although we reported previously that PGE(2) inhibited gastric irritant-induced apoptotic DNA fragmentation in primary cultures of guinea pig gastric mucosal cells, we show here that PGE(2) inhibits the ethanol-dependent release of cytochrome c from mitochondria. Of the four main subtypes of PGE(2) receptors, we also demonstrated, using subtype-specific agonists, that EP(2) and EP(4) receptors are involved in the PGE(2)-mediated protection of gastric mucosal cells from ethanol-induced apoptosis. Activation of EP(2) and EP(4) receptors is coupled with an increase in cAMP, for which a cAMP analogue was found here to inhibit the ethanol-induced apoptosis. The increase in cAMP is known to activate both protein kinase A (PKA) and phosphatidylinositol 3-kinase pathways. An inhibitor of PKA but not of phosphatidylinositol 3-kinase blocked the PGE(2)-mediated protection of cells from ethanol-induced apoptosis, suggesting that a PKA pathway is mainly responsible for the PGE(2)-mediated inhibition of apoptosis. Based on these results, we considered that PGE(2) inhibited gastric irritant-induced apoptosis in gastric mucosal cells via induction of an increase in cAMP and activation of PKA, and that this effect was involved in the PGE(2)-mediated protection of the gastric mucosa from gastric irritants in vivo.
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PMID:Prostaglandin E2 protects gastric mucosal cells from apoptosis via EP2 and EP4 receptor activation. 1255 59

Foetal membrane rupture is thought to follow from gene-controlled tissue remodelling and apoptosis. We reported previously that staurosporine, cycloheximide, actinomycin D, as well as more physiological apoptotic agents (lactosylceramide, 15d-PGJ(2)) increase prostaglandin release in parallel with induction of apoptosis in WISH and amnion epithelial cells. Also, inhibition of prostaglandin release by cyclooxygenase inhibitors or PKA activators is accompanied by a parallel decrease in apoptosis. We hypothesize that amnion prostaglandin metabolism is linked with apoptosis in amnion epithelial cells and thus to membrane rupture. Amnion mesenchymal cells are also critical for membrane integrity. Their susceptibility to apoptotic agents is unknown and is the subject of this report. In amnion epithelial cells, lactosylceramide (125 microM) induced 6.5-fold, 20-fold increases in PGE(2) and NMP production (apoptosis), respectively. Conversely, in mesenchymal cells, lactosylceramide doses up to 200 microM had no effect on PGE(2) or NMP release. In both cell types, incubation with 15d-PGJ(2) (5-100 microM) demonstrated dose and time dependent increases in PGE(2) and NMP. PKA activators inhibited 15d-PGJ(2) induced PGE(2) release and apoptotis in epithelial cells, but not in mesenchymal cells, however. Major amnion cell types have different sensitivities to physiological apoptotic agents. Prostaglandin release occurs coincident with apoptosis in both amnion epithelial and mesenchymal cells.
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PMID:Physiological apoptotic agents have different effects upon human amnion epithelial and mesenchymal cells. 1256 44

Prostaglandin E(2) (PGE(2)) mediates its physiological effects by interactions with a subfamily of G-protein-coupled receptors known as EP receptors. These receptors consist of four primary subtypes named EP(1), EP(2), EP(3), and EP(4). The EP(2) and EP(4) subtypes are known to couple to Galpha(s) and stimulate intracellular cyclic 3,5- adenosine monophosphate formation, whereas the EP(1) and EP(3) receptors are known to couple to Galpha(q) and Galpha(i), respectively. Recently we found that EP(2) and EP(4) receptors can activate T-cell factor signaling; however, EP(2) receptors did this primarily through a cAMP-dependent protein kinase-dependent pathway, whereas EP(4) receptors primarily utilized a phosphatidylinositol 3-kinase (PI3K)-dependent pathway (Fujino, H., West, K. A., and Regan, J. W. (2002) J. Biol. Chem. 277, 2614-2619). We now report that PGE(2) stimulation of EP(4) receptors, but not EP(2) receptors, leads to phosphorylation of the extracellular signal-regulated kinases (ERKs) through a PI3K-dependent mechanism. Furthermore, this activation of PI3K/ERK signaling by the EP(4) receptors induces the functional expression of early growth response factor-1 (EGR-1). Under the same conditions induction of EGR-1 protein expression was not observed following PGE(2) stimulation of EP(2) receptors. These findings point to important differences in the signaling potential of the EP(2) and EP(4) receptors, which could be significant with respect to the potential involvement of EP(4) receptors in inflammation and cancer.
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PMID:Prostaglandin E2 induced functional expression of early growth response factor-1 by EP4, but not EP2, prostanoid receptors via the phosphatidylinositol 3-kinase and extracellular signal-regulated kinases. 1256 41

We examined the effect of several protein kinase inhibitors, such as staurosporine for protein kinase C (PKC), H-89 for protein kinase A (PKA) and genistein for tyrosine kinase (TK) on acid-induced duodenal bicarbonate secretion (DBS) in rats. HCO(-)(3) secretion was measured using the pH-stat method. Mucosal acidification was performed by perfusing the duodenal loop for 10 min with pH 2.2 HCl. Indomethacin, staurosporine and genistein were added to acidified saline and then perfused, respectively. In some cases, genistein and phorbol 12-myristate 13-acetate (PMA) were added to the luminal solution to examine the effect on basal duodenal HCO(-)(3) secretion. PGE(2) (PKA pathway) and PMA (PKC pathway) stimulate basal DBS. Indomethacin, H-89, staurosporine and genistein inhibit acid-induced DBS, indicating involvement of the cyclooxygenase, PKA, PKC and TK pathways.
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PMID:Role of protein kinases on acid-induced duodenal bicarbonate secretion in rats. 1256 54

Cyclic AMP-stimulating agents are powerful vasodilators, but our knowledge of the signal transduction mechanisms of these agents, particularly in human arteries, is limited. We now report direct molecular effects of prostaglandin E(2) (PGE(2)) on cultured human coronary artery smooth muscle cells (HCASMC). Patch-clamp studies revealed that 10 microM PGE(2) opens a high-conductance (approximately 200 pS), calcium-stimulated potassium (BK(Ca)) channel in intact HCASMC. In contrast, PGE(2) had no direct effect on channels in cell-free patches, indicating involvement of a soluble second messenger. Enzyme immunoassay demonstrated that PGE(2) enhances production of cAMP in HCASMC, but does not increase [cGMP]. Furthermore, forskolin, CPT-cAMP, or CPT-cGMP mimicked the stimulatory effect of PGE(2) on BK(Ca) channel activity. Interestingly, the response to PGE(2) was unaffected by inhibiting the cAMP-dependent protein kinase, but was antagonized by inhibitors of the cGMP-dependent protein kinase (PKG). Furthermore, cAMP-stimulated PKG activity mimicked the effect of PGE(2). These studies suggest a novel PGE(2) action in human arteries: opening of BK(Ca) channels via cAMP cross-activation of PKG in HCASMC. It is proposed that this signaling mechanism may mediate the vasodilatory response to cAMP-dependent agents in the human coronary and other vascular beds.
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PMID:PGE2 action in human coronary artery smooth muscle: role of potassium channels and signaling cross-talk. 1256 73

Interleukin (IL)-9 is a pleiotropic cytokine that has been proposed as a candidate gene for asthma. As IL-9 expression is correlated with airway hyperresponsiveness in animals, we examined the effects of IL-9 on cultured human airway smooth muscle (HASM) cells. IL-9 alone had no effect on IL-8 release, but at concentrations of > or =30 ng/ml, IL-9 significantly increased IL-8 release induced by TNF-alpha. IL-9 increased phosphorylation of extracellular signal-regulated protein kinase (ERK, p42 and p44) in a concentration- and time-dependent fashion, and U-0126 (10 micro M), which inhibits ERK phosphorylation, abolished the synergism between TNF-alpha and IL-9 on IL-8 release. IL-9 alone had no effect on eotaxin release into HASM cell supernatants but at concentrations of > or =10 ng/ml caused an approximately 50% increase in release of eotaxin evoked by IL-13 (10 ng/ml). U-0126 blocked the synergism between IL-9 and IL-13 on eotaxin release. IL-9 had no effect on cyclooxygenase-2 (COX-2) expression or PGE(2) release and did not augment the COX-2 expression that was induced by IL-1beta. Our results indicate that airway smooth muscle is a target for IL-9 and that IL-9 amplifies the potential for these cells to recruit eosinophils and neutrophils into the airways by a mechanism involving ERK.
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PMID:Interleukin-9 influences chemokine release in airway smooth muscle: role of ERK. 1258 3

The effect of prostaglandin E(2) (PGE(2)) on chemical stimulation-evoked calcium (Ca(2+)) transient was investigated in isolated vagal sensory neurons of the rat using fura-2-based ratiometric Ca(2+) imaging. Application of capsaicin (3 x 10(-8) to 10(-7) M; 15 s) caused a rapid surge of intracellular Ca(2+) concentration in small- and medium-size neurons; the response was reproducible when >10 min elapsed between two challenges and was absent in nominally Ca(2+)-free solution. After pretreatment with PGE(2) (3 x 10(-7) M; 5 min), the peak of this capsaicin-evoked Ca(2+) transient was increased by almost fourfold, and its duration was also prolonged. This augmented response to capsaicin induced by PGE(2) gradually declined but remained higher than control after 15-min washout. Similarly, PGE(2) pretreatment also markedly enhanced the Ca(2+) transients induced by other chemical stimulants to C neurons, such as phenylbiguanide (PBG), adenosine 5'-triphosphate (ATP), and KCl. The Ca(2+) transients evoked by PBG, ATP, and KCl were potentiated after the pretreatment with PGE(2) to 242, 204, and 163% of their control, respectively. This potentiating effect of PGE(2) could be mimicked by forskolin (10(-6) M; 5 min), an activator of adenylyl cyclase, and 8-(4-chlorophenylthio)adenosine-3'-5'-cyclic monophosphate (CPT-cAMP; 3 x 10(-6) M, 10 min), a membrane-permeable cAMP analogue. Furthermore, the potentiating effects of PGE(2), forskolin, and CPT-cAMP were abolished by N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89; 10(-5) M; 15-20 min), a protein kinase A (PKA) inhibitor. In summary, these results show that PGE(2) reversibly potentiates the chemical stimuli-evoked Ca(2+) transients in cultured rat vagal sensory neurons, and this potentiating effect is mediated through the cyclic AMP/PKA transduction cascade.
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PMID:Ca2+ transient evoked by chemical stimulation is enhanced by PGE2 in vagal sensory neurons: role of cAMP/PKA signaling pathway. 1261 39

In this study, we investigated the role of PGE(2) in mouse mastocytoma P-815 cell adhesion to extracellular matrix proteins (ECMs) in vitro. We report that PGE(2) accelerated ProNectin F(TM) (a proteolytic fragment of fibronectin)-mediated adhesion, which was abolished by addition of the GRGDS peptide, an inhibitor of the RDG binding site of ProNectin F(TM). We show that the cAMP level and cAMP-regulated protein kinase (PKA) activity are critical mediators of this PGE(2) effect, because the cell-permeable cAMP analogue 8-Br-cAMP accelerated P-815 cell adhesion to ProNectin F(TM) and the pharmacological inhibitor of PKA, H-89, blocked PGE(2)-mediated adhesion. Consistent with mRNA expression of the G(s)-coupled EP4- and G(i)-coupled EP3-PGE receptor subtypes, P-815 cell adhesion was accelerated by treatment with a selective EP4 agonist, ONO-AE1-329, but not a selective EP1/EP3 agonist, sulprostone. However, simultaneous treatment with ONO-AE1-329 and sulprostone resulted in augmentation of both the cAMP level and cell adhesion. The augmentation of EP3-mediated cAMP synthesis was dose-dependent, without affecting the half-maximal concentration for EP4-mediated G(s)-activity, which was inhibited by a G(i) inhibitor, pertussis toxin. In conclusion, these findings suggest that PGE(2) accelerates RGD-dependent adhesion via cooperative activation between EP3 and EP4 and contributes to the recruitment of mast cells to the ECM during inflammation.
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PMID:Induction of adherent activity in mastocytoma P-815 cells by the cooperation of two prostaglandin E2 receptor subtypes, EP3 and EP4. 1263 75


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