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

Adenosine inhibits growth of cardiac fibroblasts; however, the adenosine receptor subtype that mediates this antimitogenic effect remains undefined. Therefore, the goals of this study were to determine which adenosine receptor subtype mediates the antimitogenic effects of adenosine and to investigate the signal transduction mechanisms involved. In rat left ventricular cardiac fibroblasts, PDGF-BB (25 ng/mL) stimulated DNA synthesis ((3)H-thymidine incorporation), cellular proliferation (cell number), collagen synthesis ((3)H-proline incorporation), and MAP kinase activity. The adenosine receptor agonists 2-chloroadenosine and 5'-N-methylcarboxamidoadenosine, but not N(6)-cyclopentyladenosine, 4-aminobenzyl-5'-N-methylcarboxamidoadenosine, or CGS21680, inhibited the growth effects of PDGF-BB, an agonist profile consistent with an A(2B) receptor-mediated effect. The adenosine receptor antagonists KF17837 and 1,3-dipropyl-8-p-sulfophenylxanthine, but not 8-cyclopentyl-1,3-dipropylxanthine, blocked the growth-inhibitory effects of 2-chloroadenosine and 5'-N-methylcarboxamidoadenosine, an antagonist profile consistent with an A(2) receptor-mediated effect. Antisense, but not sense or scrambled, oligonucleotides to the A(2B) receptor stimulated basal and PDGF-induced DNA synthesis, cell proliferation, and collagen synthesis. Moreover, the growth-inhibitory effects of 2-chloroadenosine, 5'-N-methylcarboxamidoadenosine, and erythro-9-(2-hydroxy-3-nonyl) adenine plus iodotubericidin (inhibitors of adenosine deaminase and adenosine kinase, respectively) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A(2B) receptor. Our findings strongly support the hypothesis that adenosine causes inhibition of CF growth by activating A(2B) receptors coupled to inhibition of MAP kinase activity. Thus, A(2B) receptors may play a critical role in regulating cardiac remodeling associated with CF proliferation. Pharmacologic or molecular biological activation of A(2B) receptors may prevent cardiac remodeling associated with hypertension, myocardial infarction, and myocardial reperfusion injury after ischemia.
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PMID:A(2b) receptors mediate the antimitogenic effects of adenosine in cardiac fibroblasts. 1123 Mar 62

Ischemic preconditioning has been shown to improve liver resistance to hypoxia/reperfusion damage. A signal pathway involving A(2A)-adenosine receptor, G(i)-proteins, protein kinase C and p38 MAP kinase is responsible for the development of hypoxic preconditioning in hepatocytes. However, the coupling of this signal pathway with the mechanisms responsible for cytoprotection is still unknown. We have observed that stimulation of A(2A)-adenosine receptors or of p38 MAPK by CGS21680 or anisomycin, respectively, appreciably reduced intracellular acidosis and Na(+) accumulation developing during hypoxia. These effects were reverted by p38 MAPK inhibitor SB203580 as well as by blocking vacuolar proton ATPase with bafilomycin A(1). SB203580 and bafilomycin A(1) also abolished the cytoprotective action exerted by both CGS21680 and anisomycin. We propose that the stimulation of p38 MAPK by preconditioning might increase hepatocyte resistance to hypoxia by activating proton extrusion through vacuolar proton ATPase, thus limiting Na(+) overload promoted by Na(+)-dependent acid buffering systems.
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PMID:Stimulation of p38 MAP kinase reduces acidosis and Na(+) overload in preconditioned hepatocytes. 1124 Jan 23

Recent studies suggest that ischemia activates Src and members of the mitogen-activated protein (MAP) kinase superfamily and their downstream effectors, including big MAP kinase 1 (BMK1) and p90 ribosomal S6 kinase (p90RSK). It has also been reported that adenosine is released during ischemia and involved in triggering the protective mechanism of ischemic preconditioning. To assess the roles of Src and adenosine in ischemia-induced MAP kinases activation, we utilized the Src inhibitor PP2 (4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) and the adenosine receptor antagonist 8-(p-sulfophenyl) theophylline (SPT) in perfused guinea pig hearts. PP2 (1 microm) inhibited ischemia-induced Src, BMK1 and JNK activation but not JAK2 and p38 activation. SPT inhibited ischemia-mediated p38 and JNK activation. These results demonstrate that Src family kinase and adenosine regulate MAP kinases by parallel pathways. Preconditioning significantly improved both recovery of developed pressure and dp/dt in isolated guinea pig hearts. Since the protective effect of preconditioning was blocked by PP2 (1 microm) and SPT (50 microm), we next investigated the regulation of Src, MAP kinases and p90RSK during preconditioning. The activity and time course of ERK1/2 was not changed, but p90RSK activation by reperfusion was completely inhibited by preconditioning. In contrast, the activation by ischemia of Src, BMK1, p38 and JNK was significantly faster in preconditioned hearts. Maximal BMK1 activation by ischemia was also significantly enhanced by preconditioning. These data suggest important roles for Src family kinases and adenosine in mediating preconditioning, and suggest specific roles for individual MAP kinases in preconditioning.
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PMID:Src family kinase and adenosine differentially regulate multiple MAP kinases in ischemic myocardium: modulation of MAP kinases activation by ischemic preconditioning. 1170 43

Moderate but not heavy drinking has been found to have a protective effect against cardiovascular morbidity. We investigated the effects of ethanol (EtOH) treatment on the cell survival-promoting phosphatidylinositol 3-kinase (PI3K)/Akt pathway in cultured human umbilical vein endothelial cells (HUVEC). Exposure of cells to 2-20 mm EtOH resulted in rapid (<10 min) induction of Akt phosphorylation that could be prevented by pertussis toxin or the PI3K inhibitors wortmannin and LY294002. Among the downstream effectors of PI3K/Akt, p70S6 kinase, glycogen synthase kinase 3alpha/beta, and IkappaB-alpha were phosphorylated, the latter resulting in 3-fold activation of NF-kappaB. EtOH also activated p44/42 mitogen-activated protein kinase in a PI3K-dependent manner. Low concentrations of EtOH increased endothelial nitric-oxide synthase activity, which could be blocked by transfection of HUVEC with dominant-negative Akt, implicating the PI3K/Akt pathway in this effect. The adenosine A1 receptor antagonist 1,3-dipopylcyclopentylxanthine prevented the phosphorylation of Akt observed in the presence of EtOH, adenosine, or the A1 agonist N(6)-cyclopentyladenosine. Incubation of HUVEC with 50-100 mm EtOH resulted in mitochondrial permeability transition and caspase-3 activation followed by apoptosis, as documented by DNA fragmentation and TUNEL assays. EtOH-induced apoptosis was unaffected by DPCPX and was potentiated by wortmannin or LY294002. We conclude that treatment with low concentrations of EtOH activates the cell survival promoting PI3K/Akt pathway in endothelial cells by an adenosine receptor-dependent mechanism and activation of the proapoptotic caspase pathway by higher concentrations of EtOH via an adenosine-independent mechanism can mask or counteract such effects.
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PMID:Dose-dependent activation of antiapoptotic and proapoptotic pathways by ethanol treatment in human vascular endothelial cells: differential involvement of adenosine. 1191 81

The small G protein RAP1 and the kinase B-RAF have been proposed to link elevations of cAMP to activation of ERK/mitogen-activated protein (MAP) kinase. In order to delineate signaling pathways that link receptor-generated cAMP to the activation of MAP kinase, the human A(2A)-adenosine receptor, a prototypical G(s)-coupled receptor, was heterologously expressed in Chinese hamster ovary cells (referred as CHO-A(2A) cells). In CHO-A(2A) cells, the stimulation of the A(2A)-receptor resulted in an activation of RAP1 and formation of RAP1-B-RAF complexes. However, overexpression of a RAP1 GTPase-activating protein (RAP1GAP), which efficiently clamped cellular RAP1 in the inactive GDP-bound form, did not affect A(2A)-agonist-mediated MAP kinase stimulation. In contrast, the inhibitor of protein kinase A H89 efficiently suppressed A(2A)-agonist-mediated MAP kinase stimulation. Neither dynamin-dependent receptor internalization nor receptor-promoted shedding of matrix-bound growth factors accounted for A(2A)-receptor-dependent MAP kinase activation. PP1, an inhibitor of SRC family kinases, blunted both the A(2A)-receptor- and the forskolin-induced MAP kinase stimulation (IC(50) = 50 nm); this was also seen in PC12 cells, which express the A(2A)-receptor endogenously, and in NIH3T3 fibroblasts, in which cAMP causes MAP kinase stimulation. In the corresponding murine fibroblast cell line SYF, which lacks the ubiquitously expressed SRC family kinases SRC, YES, and FYN, forskolin barely stimulated MAP kinase; this reduction was reversed in cells in which c-SRC had been reintroduced. These findings show that activation of MAP kinase by cAMP requires a SRC family kinase that lies downstream of protein kinase A. A role for RAP1, as documented for the beta(2)-adrenergic receptor, is apparently contingent on receptor endocytosis.
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PMID:MAP kinase stimulation by cAMP does not require RAP1 but SRC family kinases. 1208 90

We found in the present study that stimulation of the A(2A) adenosine receptor (A(2A)-R) using an A(2A)-selective agonist (CGS21680) rescued the blockage of nerve growth factor (NGF)-induced neurite outgrowth when the NGF-evoked MAPK cascade was suppressed by an MEK inhibitor (PD98059) or by a dominant-negative MAPK mutant (dnMAPK). This action of A(2A)-R (designated as the A(2A)-rescue effect) can be blocked by two inhibitors of protein kinase A (PKA) and was absent in a PKA-deficient PC12 variant. Activation of the cAMP/PKA pathway by forskolin exerted the same effect as that by A(2A)-R stimulation. PKA, thus, appears to mediate the A(2A)-rescue effect. Results from cAMP-response element-binding protein (CREB) phosphorylation at serine 133, trans-reporting assays, and overexpression of two dominant-negative CREB mutants revealed that A(2A)-R stimulation led to activation of CREB in a PKA-dependent manner and subsequently reversed the damage of NGF-evoked neurite outgrowth by PD98059 or dnMAPK. Expression of an active mutant of CREB readily rescued the NGF-induced neurite outgrowth impaired by dnMAPK, further strengthening the importance of CREB in the NGF-mediated neurite outgrowth process. Moreover, simultaneous activation of the A(2A)-R/PKA/CREB-mediated and the phosphatidylinositol 3-kinase pathways caused neurite outgrowth that was not suppressed by a selective inhibitor of TrkA, indicating that transactivation of TrkA was not involved. Collectively, CREB functions in conjunction with the phosphatidylinositol 3-kinase pathway to mediate the neurite outgrowth process in PC12 cells.
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PMID:Essential role of cAMP-response element-binding protein activation by A2A adenosine receptors in rescuing the nerve growth factor-induced neurite outgrowth impaired by blockage of the MAPK cascade. 1211 2

The A(2A)-adenosine receptor has an extended carboxy terminus (approximately 120 amino acids), the role of which is poorly defined. In human endothelial cells and in HEK293 cells, the A(2A)-receptor controls at least two independent signalling pathways, i.e. increased cyclic adenosine 3',5'-monophosphate (cAMP) formation via its cognate G protein G(s) and increased phosphorylation of mitogen-activated protein kinase (MAP kinase) by recruiting p21(ras). In order to address the role of the carboxy terminus in signal transfer, we generated HEK293 cells that stably expressed the full-length (wt) receptor and truncated versions [A(2A)-R(1-360) and A(2A)-R(1-311)] at comparable levels (approximately 0.5 pmol/mg) in the plasma membrane. The effects of truncation were divergent with respect to the two effectors regulated by the receptor. In intact cells carrying A(2A)-R(wt) and A(2A)-R(1-360), cAMP accumulation was more potently activated by an A(2A)-agonist than in cells expressing A(2A)-R(1-311). Similarly, A(2A)-R(wt) and A(2A)-R(1-360)--but not A(2A)-R(1-311)--caused constitutive (=agonist-independent) elevation of cAMP which was reversed by the addition of A(2A)-antagonists. In membranes prepared from these cells, however, the three receptors displayed no constitutive activity in stimulating adenylyl cyclase and they did not differ in apparent agonist affinity. Truncation of the A(2A)-receptor did also not decrease the potency of an A(2A)-agonist to stimulate MAP kinase in intact cells. We conclude that the carboxy terminus defines both (a) the level of constitutive activity, i.e. the equilibrium R<--> R*, in intact cells only, indicating a role for a component that is lost upon cell lysis, and (b) the efficiency of signal transfer in alternative pathways.
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PMID:Removal of the carboxy terminus of the A2A-adenosine receptor blunts constitutive activity: differential effect on cAMP accumulation and MAP kinase stimulation. 1223 41

Adenosine is released from the myocardium, endothelial cells, and skeletal muscle in ischemia and is an important regulator of coronary blood flow. We have already shown that acute (2 min) activation of A2a purinoceptors stimulates NO production in human fetal umbilical vein endothelial cells (1) and now report a key role for p42/p44 mitogen-activated protein kinases (p42/p44MAPK) in the regulation of the l-arginine-nitric oxide (NO) signaling pathway. Expression of mRNA for the A2a-, A2b-, and A3-adenosine receptor subtypes was abundant whereas A1-adenosine receptor mRNA levels were negligible. Activation of A2a purinoceptors by adenosine (10 microM) or the A2a receptor agonist CGS21680 (100 nM) resulted in an increase in l-arginine transport and NO release that was not mediated by changes in intracellular Ca2+, pH, or cAMP. Stimulation of endothelial cells with adenosine was associated with a membrane hyperpolarization and phosphorylation of p42/p44MAPK. l-NAME abolished the adenosine-induced hyperpolarization and stimulation of l-arginine transport whereas sodium nitroprusside activated an outward potassium current. Genistein (10 microM) and PD98059 (10 microM), an inhibitor of MAPK kinase 1/2 (MEK1/2), inhibited adenosine-stimulated l-arginine transport, NO production, and phosphorylation of p42/p44MAPK. We found no evidence for activation of eNOS via the serine/threonine kinase Akt/PKB (protein kinase B) in adenosine-stimulated cells. Our results provide the first evidence that adenosine stimulates the endothelial cell l-arginine-NO pathway in a Ca2+-insensitive manner involving p42/p44MAPK, with release of NO leading to a membrane hyperpolarization and activation of l-arginine transport.
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PMID:Early activation of the p42/p44MAPK pathway mediates adenosine-induced nitric oxide production in human endothelial cells: a novel calcium-insensitive mechanism. 1237 81

Adenosine activates four different receptors, the A(1), A(2A), A(2B), and the A(3) receptors, all of which are G protein-coupled. We have previously shown that stimulation of the human adenosine A(3) receptor can induce phosphorylation of extracellular signal-regulated kinase (ERK1/2). Here we show that the adenosine receptor agonist 5' N-ethylcarboxamidoadenosine (NECA) induces phosphorylation and activation of ERK1/2 in Chinese hamster ovary (CHO) cells expressing the human adenosine A(3) receptor (CHO A(3) cells) with the same potency. Pretreatment with pertussis toxin abolished the effect, which also could be blunted by overexpressing the betagamma-sequestering peptide beta-adrenergic receptor kinase-ct, implicating the involvement of betagamma subunits released from G(i/o) proteins. Activation of phosphatidylinositol-3-kinase (PI3K) by adenosine A(3) receptors is inferred from a dose-dependent Ser-phosphorylation of the protein kinase B (Akt). Furthermore the ERK1/2 phosphorylation was sensitive to the PI3K inhibitors wortmannin and LY294002 (2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride) and the MEK inhibitor PD98059 (2'-amino-3'-methoxyflavone), whereas chelation of Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) and long-term treatment with phorboldibutyrate did not decrease the adenosine A(3) receptor-mediated ERK1/2 phosphorylation. Thus, Ca(2+) mobilization and conventional and novel protein kinase C (PKC) isoforms are not involved in this pathway. The atypical PKCzeta was not activated by NECA and thus not involved in the A(3) receptor-mediated ERK1/2 phosphorylation. NECA stimulation of CHO A(3) cells activated the small G protein Ras and the dominant negative mutant RasS17N prevented the phosphorylation of ERK1/2. In conclusion, the adenosine A(3) receptor recruits a pathway that involves betagamma release from G(i/o), PI3K, Ras, and MEK to induce ERK1/2 phosphorylation and activation, whereas signaling is independent of Ca(2+), PKC, and c-Src.
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PMID:Signaling pathway from the human adenosine A(3) receptor expressed in Chinese hamster ovary cells to the extracellular signal-regulated kinase 1/2. 1239 Dec 77

Endothelial cells exhibit an autonomous proliferative response to hypoxia, independent of paracrine effectors. In cultured endothelial cells of porcine aorta, we analyzed the signaling and compared hypoxia with mitochondrial inhibition by rotenone. Particularly, roles of the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway and cytosolic Ca2+ were studied. Hypoxia resulted in increased proliferation by 65+/-2%. Hypoxia induced transient activation of p42 MAPK (phosphorylation rose from 11+/-5 to 51+/-7%), followed by translocation of p42 MAPK into the nucleus. The proliferative response was diminished after inhibition of the MEK/MAPK pathway by PD 98059 (20 microM) or UO 126 (10 microM) but not sensitive to 8-phenyl-theophillin (10 microM), an adenosine receptor blocker, nor to a neutralizing antibody for vascular endothelial growth factor (VEGF). Inhibition of intracellular Ca2+ release, capacitive Ca2+ influx, or removal of extracellular Ca2+ prevented hypoxic Ca2+ overload and the proliferative response. Suppression of cytosolic Ca2+ rise did not interfere with activation of p42 MAPK but abolished its nuclear translocation. Effects of hypoxia were mimicked by rotenone (10 microM. Transient hypoxic inhibition of mitochondria induces a proliferative endothelial response mediated through Ca2+-independent activation and Ca2+-dependent nuclear translocation of p42 MAPK. This proliferative response is independent of adenosine or VEGF.
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PMID:Signaling of hypoxia-induced autonomous proliferation of endothelial cells. 1263 83


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