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)

The possible involvement of different kinases in the alpha(1)-adrenoreceptor (AR)-mediated positive inotropic effect (PIE) was investigated in rat papillary muscle and compared with beta-AR-, endothelin receptor- and phorbol ester-induced changes in contractility. The alpha(1)-AR-induced PIE was not reduced by the inhibitors of protein kinase C (PKC), MAPK (ERK and p38), phosphatidyl inositol 3-kinase, or calmodulin kinase II. However, PKC inhibition attenuated the effect of phorbol 12-myristate 13-acetate (PMA) on contractility. alpha(1)-AR-induced PIE was reduced by approximately 90% during inhibition of myosin light chain kinase (MLCK) by 1-(5-chloronaphthalene-1-sulfonyl)1H-hexahydro-1,4-diazepine (ML-9). Endothelin-induced PIE was also reduced by ML-9, but ML-9 had no effect on beta-AR-induced PIE. The Rho kinase inhibitor Y-27632 also reduced the alpha(1)-AR-induced PIE. The alpha(1)-AR-induced PIE in muscle strips from explanted failing human hearts was also sensitive to MLCK inhibition. alpha(1)-AR induced a modest increase in (32)P incorporation into myosin light chain in isolated rat cardiomyocytes. This effect was eliminated by ML-9. The PIE of alpha(1)-AR stimulation seems to be dependent on MLCK phosphorylation.
 ...
PMID:Alpha(1)-AR-induced positive inotropic response in heart is dependent on myosin light chain phosphorylation. 1223 99

In response to treatment with phorbol-12-myristate-13-acetate (PMA), the half-population of erythromyeloblast D2 cells, a cytokine-independent variant of TF-1 cells, displayed adhesion and differentiated into a monocyte/macrophage-like morphology, while the other half-population remained in suspension and underwent apoptosis. Expression of the cell cycle inhibitor p21(Cip1/Waf1) was induced after PMA treatment in the adherent cells but not in the proapoptotic cells. We investigated the mechanism responsible for the impairment of p21(Cip1/Waf1) induction in PMA-induced proapoptotic cells. We demonstrated that in PMA-induced adherent cells, upregulation of p21(Cip1/Waf1) requires the activation and nuclear translocation of phosphorylated extracellular signal-regulated kinase (phospho-ERK). Although ERK was phosphorylated to comparable levels in PMA-induced proapoptotic and adherent cells, nuclear distribution of phospho-ERK was seen only in the adherent, not in the proapoptotic cells. We also found that only PMA-induced proapoptotic cells contained the phosphorylated form of myosin light chain, which is dependent on Rho-associated kinase (ROCK) activation, and that expression of a dominant-active form of ROCK suppressed activation of the p21(Cip1/Waf1) promoter during PMA induction. Finally, we demonstrated that inhibition of ROCK restores nuclear distribution of phospho-ERK and activation of p21(Cip1/Waf1) expression. Based on these findings, we propose that a ROCK-mediated signal is involved in interfering with the process of ERK-mediated p21(Cip1/Waf1) induction in PMA-induced proapoptotic TF-1 and D2 cells.
 ...
PMID:Cytosolic retention of phosphorylated extracellular signal-regulated kinase and a Rho-associated kinase-mediated signal impair expression of p21(Cip1/Waf1) in phorbol 12-myristate-13- acetate-induced apoptotic cells. 1237 Mar 5

The signal transduction pathways connecting cell surface receptors to the activation of muscle-specific promoters and leading to myogenesis are still largely unknown. Recently, a contribution of the p38 mitogen-activated protein kinase (MAPK) pathway to this process was evoked through the use of pharmacological inhibitors. We used several mutants of the kinases composing this pathway to modulate the activity of the muscle-specific myosin light chain and myogenin promoters in C2C12 cells by transient transfections. In addition, we show for the first time, using a stable C2C12 cell line expressing a dominant-negative form of the p38 activator MAPK kinase (MKK)3, that a functional p38 MAPK pathway is indeed required for terminal muscle cell differentiation. The most obvious phenotype of this cell line, besides the inhibition of the activation of p38, is its inability to undergo terminal differentiation. This phenotype is accompanied by a drastic inhibition of cell cycle and myogenesis markers such as p21, p27, MyoD, and troponin T, as well as a profound disorganization of the cytoskeleton.
 ...
PMID:Regulation of C2C12 myogenic terminal differentiation by MKK3/p38alpha pathway. 1244 16

Enterohemorrhagic Escherichia coli (EHEC) infections are associated with the modification of tight-junction permeability and synthesis of proinflammatory cytokine interleukin-8 (IL-8). In a previous study, it was demonstrated that EHEC-induced IL-8 secretion is due to the involvement of the mitogen-activated protein kinase (MAPK), AP-1, and NF-kappaB pathways. In this study, we investigated the effect of the yeast Saccharomyces boulardii on EHEC infection in T84 cells. For this purpose, cells were (i) incubated with bacteria and yeast at the same time or (ii) incubated overnight with yeast cells that were maintained during infection or eliminated by several washes before infection. Coincubation is sufficient to maintain the transmonolayer electrical resistance (TER) of EHEC-infected cells, whereas the preincubation of cells with the yeast without elimination of the yeast during infection is necessary to significantly decrease IL-8 secretion. We thus analyzed the mechanisms of S. boulardii action. We showed that S. boulardii has no effect on EHEC growth or on EHEC adhesion. Kinetics studies revealed that EHEC-induced myosin light chain (MLC) phosphorylation precedes the decrease of TER. ML-7, an MLC kinase inhibitor, abolishes the EHEC-induced MLC phosphorylation and decrease of TER. Studies show that S. boulardii also abolishes EHEC-induced MLC phosphorylation. We demonstrated that the preincubation of cells with S. boulardii without washes before EHEC infection inhibits NF-kappaB DNA binding activity, phosphorylation and degradation of IkappaB-alpha, and activation of the three members of a MAPK group (extracellular signal-regulated protein kinases 1 and 2, p38, and c-jun N-terminal kinase). These findings demonstrate that S. boulardii exerts a preventive effect on EHEC infection by (i) interfering with one of the transduction pathways implicated in the control of tight-junction structure and (ii) decreasing IL-8 proinflammatory secretion via inhibition of the NF-kappaB and MAPK signaling pathways in infected T84 cells.
 ...
PMID:Saccharomyces boulardii interferes with enterohemorrhagic Escherichia coli-induced signaling pathways in T84 cells. 1254 May 56

Endothelin (ET), derived from the endothelium of blood vessels, is a potent vasoactive peptide. Although it has been reported to be involved in cardiovascular diseases, such as hypertension, the mechanism by which ET evokes vasoconstriction is still unclear. On the other hand, p42/p44 mitogen-activated protein kinase (MAPK) and p38 MAPK are activated by a variety of growth factors and cellular stresses, respectively. However, the role of p42/p44 MAPK and p38 MAPK on the ET-1-induced vasoconstriction is not fully understood. This study was undertaken to determine whether p42/p44 MAPK and p38 MAPK participate in the regulation of vascular smooth muscle contraction by ET-1. The isometric vasoconstriction and intracellular Ca(2+) ([Ca(2+)](i)) were simultaneously measured using CAF-100. Phosphorylation of myosin light chain (MLC) and p42/p44 MAPK, p38 MAPK were determined by Western blots. In rat thoracic aorta, ET-1 induced a sustained contraction. In contrast, [Ca(2+)](i) was decreased with time. Both PD98059, an inhibitor of p42/p44 MAPK, and SB203580, an inhibitor of p38 MAPK, partially attenuated ET-1-induced contractions in concentration-dependent manners. ET-1 increased phosphorylation of both p42/p44 MAPK and p38 MAPK, and PD98059 and SB203580 completely decreased phosphorylation of p42/p44 MAPK and p38 MAPK in response to ET-1 stimulation, respectively. On the other hand, PD98059 and SB203580 did not affect MLC phosphorylation in response to ET-1 stimulation. These results indicate that p38 MAPK, as well as p42/p44 MAPK, may partially regulate the ET-1-induced contraction through a MLC phosphorylation-independent pathway.
 ...
PMID:Mitogen-activated protein kinases partially regulate endothelin-1-induced contractions through a myosin light chain phosphorylation-independent pathway. 1265 18

Fibroblasts plated on a type I collagen gel can reduce the size of the gel in a way that mimics the reorganization of the collagen matrix that accompanies the wound healing process. We demonstrated previously that lactoferrin (Lf) specifically binds to WI-38 human fibroblasts and enhances their collagen gel contractile activity. The effect of Lf correlated with the phosphorylation of myosin light chain (MLC), suggesting that Lf promotes fibroblast contractile activity by regulating MLC phosphorylation. We found here that the binding of Lf to WI-38 cells was inhibited by recombinant receptor-associated protein (RAP), a universal competitor for ligand binding to LRP (LDL receptor-related protein), and RAP can also promote the collagen gel contractile activity. These observations suggest that LRP is a receptor that mediates the Lf-induced enhancement of collagen gel contractile activity in WI-38 fibroblasts. To confirm the hypothesis, we utilized LRP antisense oligonucleotide, which was modified by morpholino linkage. Suppression of LRP expression abrogated the Lf-induced enhancement the contractile activity in fibroblasts. Treatment of fibroblasts with Lf enhanced the phosphorylation of ERK1/2 and the activation of MLC kinase (MLCK). These effects were attenuated by suppression of LRP expression. These findings suggest that LRP is involved in the Lf-enhanced collagen gel contractile activity of WI-38 fibroblasts by converting the Lf binding signal into the activation of ERK1/2 and MLCK.
 ...
PMID:Low density lipoprotein receptor-related protein (LRP) is required for lactoferrin-enhanced collagen gel contractile activity of human fibroblasts. 1267 16

This review examines signal transduction pathways mediating agonist-induced contraction of circular muscle in the body of the esophagus and in the lower esophageal sphincter (LES). In the LES, circular muscle agonists activate a well-defined contractile pathway, involving calcium (Ca(2+))-induced activation of calmodulin and myosin kinase, causing phosphorylation of 20-kDa myosin light chains (MLCs) and contraction. In this pathway, phosphorylation and contraction may be modulated by other factors, resulting, for instance, in inhibition of phosphatase activity, which may potentiate MLC phosphorylation. The agonist-activated contractile pathway of circular muscle from the esophageal body is not as well defined, and it is different from the LES contractile pathway, as it depends on activation of a Ca(2+)-independent protein kinase C (PKC), PKC-epsilon. In this pathway, agonist-induced Ca(2+) influx and/or release activate phospholipases to produce second messengers, such as diacylglycerol and arachidonic acid. The second messengers, however, activate a PKC-epsilon and a contractile pathway, which is Ca(2+) independent. This contractile pathway depends on activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2 and of p38 MAP kinase. These kinases are, in turn, linked to the small heat-shock protein HSP27, to integrin-linked kinase, and perhaps to other Ca(2+)-independent kinases, such as zipper kinase capable of producing MLC phosphorylation and contraction.
 ...
PMID:Calcium-dependent and calcium-independent contractions in smooth muscles. 1292 71

The ATP-gated P2X1 ion channel is the only P2X subtype expressed in human platelets. Via transmission electron microscopy, we found that P2X1 mediates fast, reversible platelet shape change, secretory granule centralization, and pseudopodia formation. In washed human platelets, the stable P2X1 agonist alpha,beta-methylene ATP (alpha,beta-meATP) causes rapid, transient (2-5 s), and dose-dependent myosin light chain (MLC) phosphorylation, requiring extracellular Ca2+. Phosphorylation was inhibited by the calmodulin (CaM) inhibitor W-7, but not by the Rho kinase inhibitor HA-1077, i.e. it is exclusively regulated by Ca2+/CaM-dependent MLC kinase. Correspondingly, the P2X1-induced platelet shape change was inhibited by W-7 and by the MLC kinase inhibitor ML-7 but not by HA-1077. W-7, ML-7, the protein kinase C inhibitor GF109203-X, and the Src family kinase inhibitor PP1 inhibited the collagen and convulxin-induced early platelet degranulation, shape change, and subsequent aggregation, indicating a role for Ca2+/CaM and MLC kinase in these glycoprotein VI-related platelet responses. The secreted ATP-mediated P2X1-dependent ERK2 activation induced by low collagen concentrations contributes to MLC kinase activation since P2X1 desensitization or blockade of ERK2 phosphorylation by U0126 strongly attenuated MLC phosphorylation, degranulation, and aggregation. We therefore conclude that at low doses of collagen, glycoprotein VI activation leads to early protein kinase C- and MLC kinase-dependent degranulation. Rapidly released ATP triggers P2X1 -mediated Ca2+ influx, activating ERK2, in turn amplifying platelet secretion by reinforcing the early MLC kinase phosphorylation. Hence, the P2X1-ERK2-MLC axis contributes to collagen-induced platelet activation by enhancing platelet degranulation.
 ...
PMID:P2X1-mediated ERK2 activation amplifies the collagen-induced platelet secretion by enhancing myosin light chain kinase activation. 1450 Jul 14

The bioactive sphingolipid sphingosine-1-phosphate (S1P) that is increased in airways of asthmatic subjects markedly induced contraction of human airway smooth muscle (HASM) cells embedded in collagen matrices in a Gi-independent manner. Dihydro-S1P, which binds to S1P receptors, also stimulated contractility. S1P induced formation of stress fibers, contraction of individual HASM cells, and stimulated myosin light chain phosphorylation, which was inhibited by the Rho-associated kinase inhibitor Y-27632. S1P-stimulated HASM cell contractility was independent of the ERK1/2 and PKC signaling pathways, important regulators of airway smooth muscle contraction. However, removal of extracellular calcium completely blocked S1P-mediated contraction and Y-27632 reduced it. S1P also induced calcium mobilization that was not desensitized by repeated additions. Pretreatment with thapsigargin to deplete InsP3-sensitive calcium stores partially blocked increases in [Ca2+]i induced by S1P, yet did not inhibit S1P-stimulated contraction. In sharp contrast, the L-type calcium channel blocker verapamil markedly decreased S1P-induced HASM cell contraction, supporting a role for calcium influx from extracellular sources. Collectively, our results suggest that S1P may regulate HASM contractility, important in the pathobiology of asthma.
 ...
PMID:Sphingosine-1-phosphate stimulates contraction of human airway smooth muscle cells. 1451 58

The family of CRH-related peptides are suggested to play important roles in the control of myometrial contractility during pregnancy and labor. In this study we investigated the expression of urocortin II (UCN II) in human myometrium and its ability to phosphorylate intracellular components that can be involved in modulating myometrial contractility. Using RT-PCR and fluorescent in situ hybridization, we demonstrated that UCN II and type-2 CRH receptor (CRH-R2) mRNAs were expressed in human nonpregnant and pregnant myometrium. Immunofluorescent studies confirmed protein expression of UCN II in human pregnant myometrial cells, whereas chemical cross-linking studies with radiolabeled UCN II confirmed the presence of CRH-R2 sites with an apparent molecular mass of 50 kDa. Treatment of primary human myometrial cells with UCN II to specifically activate CRH-R2 resulted in a dose-dependent increase of myosin light chain (MLC(20)) phosphorylation. Activation of protein kinase C (PKC) and ERK1/2 was required for the UCN II-induced activation of MLC(20), because treatment of myometrial cells with inhibitors of MAPK kinase 1 (U0126) and PKC (bisindolylmaleimide) inhibited the UCN II-induced phosphorylation of MLC(20). Furthermore, the UCN II effect on MLC(20) was dependent on RhoA translocation to the membrane and subsequent activation of RhoA-associated kinase, as shown by the use of the specific inhibitors exoenzyme C3 and Y27632. Collectively, our data suggest a distinctive role for CRH-R2- specific agonists like UCN II in the control of myometrial contractility during human pregnancy involving sequential activation of PKC, MAPK kinase 1, ERK1/2, RhoA, and RhoA-associated kinase, leading to the MLC(20) phosphorylation.
 ...
PMID:Urocortin II is expressed in human pregnant myometrial cells and regulates myosin light chain phosphorylation: potential role of the type-2 corticotropin-releasing hormone receptor in the control of myometrial contractility. 1459 50


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>