Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostanoids are arachidonic acid metabolites and are generally accepted to play pivotal functions in amongst others inflammation, platelet aggregation, and vasoconstriction/relaxation. Inhibition of their production with, for instance, aspirin has been used for over a century to combat a large variety of pathophysiological processes, with great clinical success. Hence, the cellular changes induced by prostanoids have been subject to an intensive research effort and especially prostanoid-dependent signal transduction has been extensively studied. In this review, we discuss the impact of the five basic prostanoids, TxA(2), PGF(2alpha), PGE(2), PGI(2), and PGD(2), via their receptors on cellular physiology. These inflammatory lipids may stimulate serpentine plasma membrane-localized receptors, which in turn affect major signaling pathways, such as the MAP kinase pathway and the protein kinase A pathway, finally resulting in altered cellular physiology. In addition, prostanoids may activate the PPARgamma members of the steroid/thyroid family of nuclear hormone receptors, which act as transcription factors and may thus directly influence gene transcription. Finally, evidence exists that prostanoids act as second messengers downstream of mitogen receptor activation, mediating events, such as cytoskeletal changes, maybe via direct interaction with GTPase activating proteins. The final cellular reaction to prostaglandin stimulation will most likely depend on combined effects of the above-mentioned levels of interaction between prostaglandins and their cellular receptors.
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PMID:Prostanoids and prostanoid receptors in signal transduction. 1510 66

Prostaglandins (PG) are key mediators of diverse functions in the skin and several reports suggest that PG mediate post-inflammatory pigmentary changes through modulation of melanocyte dendricity and melanin synthesis. The proteinase-activated receptor 2 (PAR-2) is important for skin pigmentation because activation of keratinocyte PAR-2 stimulates uptake of melanosomes through phagocytosis in a Rho-dependent manner. In this report, we show that activation of keratinocyte PAR-2 stimulates release of PGE(2) and PGF(2alpha) and that PGE(2) and PGF(2alpha) act as paracrine factors that stimulate melanocyte dendricity. We characterized the expression of the EP and FP receptors in human melanocytes and show that human melanocytes express EP1 and EP3, and the FP receptor, but not EP2 and EP4. Treatment of melanocytes with EP1 and EP3 receptor agonists resulted in increased melanocyte dendricity, indicating that both EP1 and EP3 receptor signaling contribute to PGE(2)-mediated melanocyte dendricity. Certain EP3 receptor subtypes have been shown to increase adenosine 3',5'-cyclic monophosphate (cAMP) through coupling to Gs, whereas EP1 is known to couple to Gq to activate phospholipase C with elevation in Ca(2+). The cAMP/protein kinase A system is known to modulate melanocyte dendrite formation through modulation of Rac and Rho activity. Neither PGF(2alpha) or PGE(2) elevated cAMP in human melanocytes showing that dendricity observed in response to PGE(2) and PGF(2alpha) is cAMP-independent. Our data suggest that PAR-2 mediates cutaneous pigmentation both through increased uptake of melanosomes by keratinocytes, as well as by release of PGE(2) and PGF(2alpha) that stimulate melanocyte dendricity through EP1, EP3, and FP receptors.
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PMID:Proteinase-activated receptor-2 stimulates prostaglandin production in keratinocytes: analysis of prostaglandin receptors on human melanocytes and effects of PGE2 and PGF2alpha on melanocyte dendricity. 1514 Feb 25

8-Isoprostanes are bioactive lipid mediators formed via the nonenzymatic peroxidation of arachidonic acid by free radicals and reactive oxygen species. However, their cognate receptors, biological actions, and signaling pathways are poorly studied. Here, we report the effect of a variety of E- and Falpha-ring 8-isoprostanes on the release of granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) from human airway smooth muscle (HASM) cells stimulated with interleukin-1beta (IL-1beta). The elaboration of GM-CSF and G-CSF by IL-1beta was inhibited and augmented, respectively, in a concentration-dependent manner by 8-iso-prostaglandin (PG) E(1) and 8-iso-PGE(2), but not by 8-iso-PGF(1alpha), 8-iso-PGF(2alpha), and 8-iso-PGF(3)alpha. AH 6809 (6-isopropoxy-9-oxoxanthine-2-carboxylic acid), an EP(1)-/EP(2)-/DP-receptor blocking drug, antagonized the inhibitory effect of 8-iso-PGE(1) and 8-iso-PGE(2) on GM-CSF output with an affinity consistent with an interaction at prostanoid receptors of the EP(2)-subtype. In contrast, the facilitation by 8-iso-PGE(1) and 8-iso-PGE(2) of G-CSF release was unaffected by AH 6809 and the selective EP(4)-receptor antagonist L-161,982 [4'-[3-butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]. However, when used in combination, AH 6809 and L-161,982 displaced 5-fold to the right the 8-iso-PGE and 8-iso-PGE concentration-response curves. The opposing (1)effect of E-ring (2)8-isoprostanes on GM-CSF and G-CSF release was mimicked by 8-bromo-cAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). Together, these data demonstrate that E-ring 8-isoprostanes regulate the secretion of GM-CSF and G-CSF from HASM cells by a cAMP- and PKA-dependent mechanism. Moreover, antagonist studies revealed that 8-iso-PGE(1) and 8-iso-PGE(2) act solely via EP(2) -receptors to inhibit GM-CSF release, whereas both EP(2)- and EP(4)-receptor subtypes positively regulate G-CSF output.
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PMID:E-ring 8-isoprostanes are agonists at EP2- and EP4-prostanoid receptors on human airway smooth muscle cells and regulate the release of colony-stimulating factors by activating cAMP-dependent protein kinase. 1552 3

The prostanoid receptors on human airway smooth muscle cells (HASMC) that augment the release by IL-1beta of granulocyte colony-stimulating factor (G-CSF) have been characterized and the signaling pathway elucidated. PCR of HASM cDNA identified products corresponding to EP(2), EP(3), and EP(4) receptor subtypes. These findings were corroborated at the protein level by immunocytochemistry. IL-1beta promoted the elaboration of G-CSF, which was augmented by PGE(2). Cicaprost (IP receptor agonist) was approximately equiactive with PGE(2), whereas PGD(2), PGF(2alpha), and U-46619 (TP receptor agonist) were over 10-fold less potent. Neither SQ 29,548 nor BW A868C (TP and DP(1) receptor antagonists, respectively) attenuated the enhancement of G-CSF release evoking any of the prostanoids studied. With respect to PGE(2), the EP receptor agonists 16,16-dimethyl PGE(2) (nonselective), misoprostol (EP(2)/EP(3) selective), 17-phenyl-omega-trinor PGE(2) (EP(1) selective), ONO-AE1-259, and butaprost (both EP(2) selective) were full agonists at enhancing G-CSF release. AH 6809 (10 microM) and L-161,982 (2 microM), which can be used in HASMC as selective EP(2) and EP(4) receptor antagonists, respectively, failed to displace to the right the PGE(2) concentration-response curve that described the augmented G-CSF release. In contrast, AH 6809 and L-161,982 in combination competitively antagonized PGE(2)-induced G-CSF release. Augmentation of G-CSF release by PGE(2) was mimicked by 8-BrcAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). These data demonstrate that PGE(2) facilitates G-CSF secretion from HASMC through a PKA-dependent mechanism by acting through EP(2) and EP(4) prostanoid receptors and that effective antagonism is realized only when both subtypes are blocked concurrently.
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PMID:Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor. 1564 May 21

Cyclo-oxygenases (COXs) catalyze the first committed step in the synthesis of the prostaglandins PGE(2), PGD(2), PGF(2alpha), PGI(2) and thomboxane A(2). Expression and enzymatic activity of COX-2, the inducible isoform of COX, are observed in several neurological diseases and result in significant neuronal injury. The neurotoxic effect of COX-2 is believed to occur through downstream effects of its prostaglandin products. In this study, we examined the function of PGD(2) and its two receptors DP1 and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) (DP2) in neuronal survival. PGD(2) is the most abundant prostaglandin in brain and regulates sleep, temperature and nociception. It signals through two distinct G protein-coupled receptors, DP1 and DP2, that have opposing effects on cyclic AMP (cAMP) production. Physiological concentrations of PGD(2) potently and unexpectedly rescued neurons in paradigms of glutamate toxicity in cultured hippocampal neurons and organotypic slices. This effect was mimicked by the DP1-selective agonist BW245C but not by the PGD(2) metabolite 15d-PGJ(2), suggesting that neuroprotection was mediated by the DP1 receptor. Conversely, activation of the DP2 receptor promoted neuronal loss. The protein kinase A inhibitors H89 and KT5720 reversed the protective effect of PGD(2), indicating that PGD(2)-mediated neuroprotection was dependent on cAMP signaling. These studies indicate that activation of the PGD(2) DP1 receptor protects against excitotoxic injury in a cAMP-dependent manner, consistent with recent studies of PGE(2) receptors that also suggest a neuroprotective effect of prostaglandin receptors. Taken together, these data support an emerging and paradoxical neuroprotective role of prostaglandins in the CNS.
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PMID:Prostaglandin D2 mediates neuronal protection via the DP1 receptor. 1565 18

We have previously reported that prostaglandin F2alpha (PGF2alpha) activates p44/p42 mitogen-activated protein (MAP) kinase through protein kinase C (PKC), resulting in the synthesis of vascular endothelial growth factor (VEGF) in osteoblast-like MC3T3-E1 cells, and that incadronate, a bisphosphonate, amplifies the VEGF synthesis. In the present study, we investigated the effects of tiludronate and etidronate, other bisphosphonates, on the PGF2alpha-stimulated VEGF synthesis in these cells. Tiludronate reduced the synthesis of VEGF induced by PGF2alpha. The PGF(2alpha)-stimulated phosphorylation of p44/p42 MAP kinase was suppressed by tiludronate. On the other hand, etidronate affected neither the VEGF synthesis nor the phosphorylation of p44/p42 MAP kinase elicited by PGF2alpha. Tiludronate attenuated the phosphorylation of both Raf-1 and MEK1/2 induced by PGF2alpha. The VEGF synthesis stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), a direct activator of PKC, was suppressed by tiludronate. The TPA-induced phosphorylations of Raf-1, MEK1/2 and p44/p42 MAP kinase were inhibited by tiludronate. These results strongly suggest that tiludronate but not etidronate suppresses the PGF2alpha-stimulated VEGF synthesis in osteoblasts, and that the effect of tiludronate is exerted at the point between PKC and Raf-1.
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PMID:Tiludronate inhibits prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts. 1592 88

Prostaglandin F(2alpha) (PGF(2alpha)) is a vasoactive factor that causes constriction and hypertrophy of vascular smooth muscle cells (VSMCs). However, the mechanism of PGF(2alpha)-induced hypertrophy is largely unknown. Cyclic AMP-response element (CRE)-binding protein (CREB), the best characterized stimulus-induced transcription factor, activates transcription of target genes with CRE and promotes cell growth. We examined the role of CREB in PGF(2alpha)-induced hypertrophy of VSMCs. PGF(2alpha) induced phosphorylation of CREB at serine 133, which is a critical marker of activation, after 5-10min of stimulation in a dose-dependent manner. Pharmacological inhibition of extracellular signal-regulated protein kinase and p38 mitogen-activated protein kinase (p38-MAPK) suppressed PGF(2alpha)-induced CREB phosphorylation. Inhibition of epidermal growth factor receptor (EGFR) and mitogen- and stress-activated protein kinase-1 also suppressed PGF(2alpha)-induced CREB phosphorylation. Overexpression of dominant-negative form of CREB (AdCREB M1), of which serine 133 was replaced with alanine, inhibited PGF(2alpha)-induced c-fos mRNA expression as well as hypertrophy of VSMCs [hypertrophy index (microg/10(4)cell); control 8.13, PGF(2alpha) 9.85, AdCREB M1 7.91, and AdCREB M1+PGF(2alpha) 8.43]. These results suggest that PGF(2alpha) activated CRE-dependent gene transcription through EGFR transactivation, and the CREB pathway plays a critical role in PGF(2alpha)-induced hypertrophy of VSMCs.
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PMID:cAMP-response element-binding protein mediates prostaglandin F2alpha-induced hypertrophy of vascular smooth muscle cells. 1624 6

Fluid percussion brain injury elevates the cerebrospinal fluid (CSF) concentration of the opioid nociceptin/orphanin FQ (N/OFQ), which potentiates vasoconstriction to the prostaglandins U 46619, a thromboxane A(2) mimic, and prostaglandin (PG)F(2a). This study investigated the role of the extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) isoforms of mitogen activated protein kinase (MAPK) in potentiated prostaglandin vasoconstriction after brain injury and the relationship of brain injury induced release of N/OFQ to MAPK. Pial artery diameter was measured with a video microscaler by observation through a glass coverslip cranial window placed in the parietal cortex of newborn pigs. Brain injury potentiated U 46619 induced pial artery vasoconstriction but U 0126 and SB 203580 (10(-6) and 10(-5) M, respectively) (ERK and p38 MAPK inhibitors) blocked the potentiation. In contrast, administration of SP 600125 (10(-6) and 10(-5) M) (JNK MAPK inhibitor) only attenuated brain injury induced U 46619 potentiation and such responses were significantly different than that in the presence of either U 0126 or SB 203580 after FPI. Co-administration of N/OFQ (10(-10) M), the CSF concentration observed after brain injury, with U 46619 or PGF(2a) under non brain injury conditions potentiated prostaglandin vasoconstriction but U 0126 and SB 203580 blocked such potentiation. Administration of SP 600125 modestly attenuated prostaglandin potentiation by N/OFQ. These data show that activation of ERK and p38 primarily contribute to potentiation of prostaglandin constriction after brain injury. These data suggest that N/OFQ differentially activates ERK, p38, and JNK MAPK to contribute to potentiated prostaglandin vasoconstriction after fluid percussion brain injury.
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PMID:Differential activation of ERK, p38, and JNK MAPK by nociceptin/orphanin FQ in the potentiation of prostaglandin cerebrovasoconstriction after brain injury. 1635 4

In Sertoli epithelial cells, the IL-1beta induces prostaglandins (PG) PGE(2), PGF(2alpha) and PGI(2) (7-, 11-, and 2-fold, respectively), but not PGD(2), production. Cyclohexamide pretreatment inhibiting protein synthesis prevents IL-1beta increases in PG levels, indicating that induction requires de novo protein synthesis. IL-1beta-regulated PGE(2) and PGF(2alpha) production and cytokine expression require activation of cyclooxygenase-2 (COX-2) and c-Jun NH(2)-terminal kinase, as shown using specific enzyme inhibition. PGE(2) and PGF(2alpha) stimulate expression of IL-1alpha, -1beta, and -6, findings consistent with PG involvement in IL signaling within the seminiferous tubule. PGE(2) and PGF(2alpha) reverse COX-2-mediated inhibition of IL-1beta induction of cytokine expression and PG production. Sertoli PG receptor expression was determined; four known E-prostanoid receptor (EP) subtypes (1-4) and the F-prostanoid and prostacyclin prostanoid receptors were demonstrated using RNA and protein analyses. Pharmacological characterization of Sertoli PG receptors associated with cytokine regulation was ascertained by quantitative real-time RT-PCR analyses. IL-1beta regulates both EP(2) mRNA and protein levels, data consistent with a regulatory feedback loop. Butaprost (EP(2) agonist) and 11-deoxy PGE(1) (EP(2) and EP(4) agonist) treatments show that EP(2) receptor activation stimulates Sertoli cytokine expression. Consistent with EP(2)-cAMP signaling, protein kinase A inhibition blocks both IL-1beta- and PGE(2)-induced cytokines. Together, the data indicate an autocrine-amplifying loop involving IL-1beta-regulated Sertoli function mediated by COX-2-induced PGE(2) and PGF(2alpha) production. PGE(2) activates EP(2) and/or EP(4) receptor(s) and the protein kinase A-cAMP pathway; PGF(2alpha) activates F-prostanoid receptor-protein kinase C signaling. Further identification of the molecular mechanisms subserving these mediators may offer new insights into physiological events as well as proinflammatory-mediated pathogenesis in the testis.
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PMID:A multistep kinase-based sertoli cell autocrine-amplifying loop regulates prostaglandins, their receptors, and cytokines. 1642 68

In our previous study, we showed that prostaglandin F2alpha (PGF2alpha) stimulates vascular endothelial growth factor (VEGF) synthesis via activation of p44/p42 mitogen-activated protein (MAP) kinase via protein kinase C (PKC) in osteoblast-like MC3T3-E1 cells. In addition, we demonstrated that incadronate amplified, and tiludronate suppressed PGF2alpha-induced VEGF synthesis among bisphosphonates, while alendronate or etidronate had no effect. In the present study, we investigated the effects of minodronate, a newly developed bisphosphonate, on PGF (2alpha)-induced VEGF synthesis in MC3T3-E1 cells. Minodronate significantly reduced VEGF synthesis induced by PGF2alpha dose-dependently at levels between 3 and 100 microM. PGF2alpha-stimulated phosphorylation of Raf-1, MEK1/2 and p44/p42 MAP kinase were suppressed by minodronate. 12-O-tetradecanoylphorbol-13-acetate (TPA), a direct activator VEGF synthesis induced by PKC, was inhibited by minodronate. Minodronate inhibited Raf-1, MEK1/2 and p44/p42 MAP kinase phosphorylation induced by TPA. Mevalonate failed to affect the suppressive effect of minodronate on PGF2alpha-induced VEGF synthesis. Taken together, these results indicate that minodronate suppresses PGF2alpha-stimulated VEGF synthesis at the point between PKC and Raf-1 in osteoblasts.
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PMID:Minodronate suppresses prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts. 1667 5


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