EC:2.7.11.13 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenylephrine and noradrenaline (alpha-adrenergic agonism) or isoprenaline (beta-adrenergic agonism) stimulated protein synthesis rates, increased the activity of the atrial natriuretic factor gene promoter and activated mitogen-activated protein kinase (MAPK). The EC50 for MAPK activation by noradrenaline was 2-4 microM and that for isoprenaline was 0.2-0.3 microM. Maximal activation of MAPK by isoprenaline was inhibited by the beta-adrenergic antagonist, propranolol, whereas the activation by noradrenaline was inhibited by the alpha1-adrenergic antagonist, prazosin. FPLC on a Mono-Q column separated two peaks of MAPK (p42MAPK and p44MAPK) and two peaks of MAPK-activating activity (MEK) activated by isoprenaline or noradrenaline. Prolonged phorbol ester exposure partially down-regulated the activation of MAPK by noradrenaline but not by isoprenaline. This implies a role for protein kinase C in MAPK activation by noradrenaline but not isoprenaline. A role for cyclic AMP in activation of the MAPK pathway was eliminated when other agonists that elevate cyclic AMP in the cardiac myocyte did not activate MAPK. In contrast, MAPK was activated by exposure to ionomycin, Bay K8644 or thapsigargin that elevate intracellular Ca2+. Furthermore, depletion of extracellular Ca2+ concentrations with bis-(o-aminophenoxy)ethane-NNN'N'-tetra-acetic acid (BAPTA) or blocking of the L-type Ca2+ channel with nifepidine or verapamil inhibited the response to isoprenaline without inhibiting the responses to noradrenaline. We conclude that alpha- and beta-adrenergic agonists can activate the MEK/MAPK pathway in the heart by different signalling pathways. Elevation of intracellular Ca2+ rather than cyclic AMP appears important in the activation of MAPK by isoprenaline in the cardiac myocyte.
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PMID:Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. 866 Feb 71

In ventricular myocytes cultured from neonatal rat hearts, bradykinin (BK), kallidin or BK(1-8) [(Des-Arg9)BK] stimulated PtdinsP2 hydrolysis by 3-4-fold. EC50 values were 6 nM (BK), 2 nM (kallidin), and 14 microM [BK(1-8)]. BK or kallidin stimulated the rapid (less than 30 s) translocation of more than 80% of the novel protein kinase C (PKC) isoforms nPKC-delta and nPKC-epsilon from the soluble to the particulate fraction. EC50 values for nPKC-delta translocation by BK or kallidin were 10 and 2 nM respectively. EC50 values for nPKC-epsilon translocation by BK or kallidin were 2 and 0.6 nM respectively. EC50 values for the translocation of nPKC-delta and nPKC-epsilon by BK(1-8) were more than 5 microM. The classical PKC, cPKC-alpha, and the atypical PKC, nPKC-zeta, did not translocate. BK caused activation and phosphorylation of p42-mitogen-activated protein kinase (MAPK) (maximal at 3-5 min, 30-35% of p42-MAPK phosphorylated). p44-MAPK was similarly activated. EC50 values for p42/p44-MAPK activation by BK were less than 1 nM whereas values for BK(1-8) were more than 10 microM. The order of potency [BK approximately equal to kallidin >> BK (1-8)] for the stimulation of PtdInsP2 hydrolysis, nPKC-delta and nPKC-epsilon translocation, and p42/p44-MAPK activities suggests involvement of the B2 BK receptor subtype. In addition, stimulation of all three processes by BK was inhibited by the B2BK receptor-selective antagonist HOE140 but not by the B1-selective antagonist Leu8BK(1-8). Exposure of cells to phorbol 12-myristate 13-acetate for 24 h inhibited subsequent activation of p42/p44-MAPK by BK suggesting participation of nPKC (and possibly cPKC) isoforms in the activation process. Thus, like hypertrophic agents such as endothelin-1 (ET-1) and phenylephrine (PE), BK activates PtdInsP2 hydrolysis, translocates nPKC-delta, and nPKC-epsilon, and activates p42/p44-MAPK. However, in comparison with ET-1 and PE, BK was only weakly hypertrophic as assessed by cell morphology and patterns of gene expression. This difference could not be attributed to dissimilarities between the duration of activation of p42/p44-MAPK by BK or ET-1. Thus activation of these signalling pathways alone may be insufficient to induce a powerful hypertrophic response.
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PMID:Stimulation of phosphatidylinositol hydrolysis, protein kinase C translocation, and mitogen-activated protein kinase activity by bradykinin in rat ventricular myocytes: dissociation from the hypertrophic response. 869 51

Renal nephron segments are heterogeneous, and receptors for endothelin (ET)-1, ET-3, Angiotensin II (AII), epidermal growth factor (EGF), and insulin-like growth factor I distribute differently along the nephron segments. Recently, growth factors and vasoactive substances are reported to stimulate mitogen-activated protein kinase (MAP-K). In this study, we showed that mRNA and proteins of MEK-K, Raf-1-K, MAPK-K, MAP-K (p42 and p44), and S6-K are expressed ubiquitously in intact nephron segment. We demonstrated that four tiers of a cascade composed of the Raf-1-K, MAP-K, MAP-K, and S6-K are stimulated by ET-1 and ET-3 in rat intact glomeruli (Glm) via primarily B-type ET receptors and PKC. The stimulatory effect of EGF and IGF-I to MAP-K activity is inhibited by a tyrosine kinase inhibitor in Glm. IGF-I significantly stimulates MAP-K activity and EGF and All moderately stimulate MAP-K activity in the proximal convoluted tubule (PCT). EGF significantly increased MAP-K cascades and ET-1 and ET-3 slightly increased MAP-K cascades in the medullary thick ascending limb (MTAL). EGF significantly stimulated MAP-K cascades, and ET-1 and ET-3 moderately stimulate MAP-K cascades in the outer medullary collecting duct (OMCD) and the inner medullary collecting duct (IMCD). MAPK-K and S6-K are similarly stimulated by these agonists in each segment. This study shows that MAP-K cascades are expressed in every nephron segment. ET-1, ET-3, All, EGF, and IGF-I stimulate MAP-K cascades heterogeneously along the nephron segment. It was concluded that MAP-K cascades play an important role in the regulation of renal function.
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PMID:Presence and regulation of Raf-1-K (Kinase), MAPK-K, MAP-K, and S6-K in rat nephron segments. 874 82

Both noradrenaline administration to rats and rapid cardiac pacing in dogs induces delayed protection of the heart against ischaemia-induced ventricular arrhythmias. In an attempt to establish molecular mechanisms underlying the delayed cardioprotection, we have examined the potential role of two kinases, PKC epsilon and p42/44MAPK. These protein kinases are expressed in the ventricles of the heart and are characterised by their ability to regulate ion-flux and gene transcription. In the rat p42MAPK is predominantly localised in the high-speed supernatant fraction of the ventricle homogenate, whereas p44MAPK is enriched in the nuclear low speed pellet. A small proportion of the p42MAPK is activated even in hearts from control animals. However, neither kinase is relocalised or activated by noradrenaline administration and this provides preliminary evidence the p42/44MAPK may not play a significant role in delayed protection in this species. In contrast, noradrenaline does induce the translocation of PKC epsilon to cell membranes, a response that is sustained for up to 4 h. However, PKC epsilon is down-regulated from the cytoplasm after 24 h post noradrenaline treatment. PKC epsilon is also translocated to the membrane in dogs that have been classically pre-conditioned and cardiac paced. In the latter case, translocation of PKC epsilon from the cytoplasm to the cell membrane is evident 24 h after pacing. These results indicate that the release of endogenous mediators may either inhibit down-regulation or elicit an increase in PKC epsilon mRNA expression. Therefore, in dog heart the subcellular relocalisation of PKC epsilon persists into the 'second window' and may play a central role in the molecular mechanism governing delayed cardioprotection. It is important in the future to identify either the gene products that are induced or the target protein(s) that are phosphorylated by PKC epsilon.
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PMID:Delayed cardioprotection is associated with the sub-cellular relocalisation of ventricular protein kinase C epsilon, but not p42/44MAPK. 890 77

Rat-1 fibroblasts were used to study the role of the sustained activation of extracellular signal-regulated kinase 1 (ERK1) in lysophosphatidic acid (LPA)-stimulated mitogenic signalling. Mitogenic doses of LPA, like serum, stimulated biphasic, sustained, ERK activation that persisted towards the G1/S boundary. The EC50 for LPA-stimulated ERK activation after 10 min, the time of peak response, was 2 orders of magnitude to the left of that for the sustained response after 3 h or that for DNA synthesis after 22 h, with the result that non-mitogenic doses stimulated a maximal peak response but no second phase. To complement these studies, we examined the role of different signal pathways in regulating the sustained and acute phases of ERK activation using defined biochemical inhibitors and mimetics. Activation of protein kinase C and Ca2+ fluxes played a minor and transient role in regulation of ERK1 activity by LPA in Rat-1 cells. Sustained ERK1 activation stimulated by LPA was completely inhibited by pertussis toxin, whereas the early peak response was only partly affected; this is correlated with the specific inhibition of LPA-stimulated DNA synthesis by pertussis toxin. The selective tyrosine kinase inhibitor herbimycin A completely inhibited sustained ERK1 activation by LPA but, again, the early phase of the response was only partially inhibited. In addition, low doses of staurosporine inhibited ERK1 activation by LPA. The effects of herbimycin A and staurosporine were selective for the response to LPA but did not affect that to epidermal growth factor. The results suggest a strong correlation between sustained ERK1 activation and DNA synthesis in LPA-stimulated Rat-1 cells. Furthermore, the two discrete phases of ERK activation by LPA are regulated by a combination of at least two different signalling pathways; the sustained activation of ERK1 in Rat-1 cells proceeds via a G1- or Gzero-mediated pathway which may also involve a tyrosine kinase.
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PMID:Kinetic and biochemical correlation between sustained p44ERK1 (44 kDa extracellular signal-regulated kinase 1) activation and lysophosphatidic acid-stimulated DNA synthesis in Rat-1 cells. 894 93

Stimulation of Rat-1 cells with lysophosphatidic acid (LPA) or epidermal growth factor (EGF) results in a biphasic, sustained activation of extracellular signal-regulated kinase 1 (ERK1). Pretreatment of Rat-1 cells with either cycloheximide or sodium orthovanadate had little effect on the early peak of ERK1 activity but potentiated the sustained phase. Cycloheximide also potentiated ERK1 activation in Rat-1 cells expressing DeltaRaf-1:ER, an estradiol-regulated form of the oncogenic, human Raf-1. Since cycloheximide did not potentiate MEK activity but abrogated the expression of mitogen-activated protein kinase phosphatase (MKP-1) normally seen in response to EGF and LPA, we speculated that the level of MKP-1 expression may be an important regulator of ERK1 activity in Rat-1 cells. Inhibition of LPA-stimulated MEK and ERK activation with PD98059 and pertussis toxin, a selective inhibitor of Gi-protein-coupled signaling pathways, reduced LPA-stimulated MKP-1 expression by only 50%, suggesting the presence of additional MEK- and ERK-independent pathways for MKP-1 expression. Specific activation of the MEK/ERK pathway by DeltaRaf-1:ER had little or no effect on MKP-1 expression, suggesting that activation of the Raf/MEK/ERK pathway is necessary but not sufficient for MKP-1 expression in Rat-1 cells. Activation of PKC played little part in growth factor-stimulated MKP-1 expression, but LPA- and EGF-induced MKP-1 expression was blocked by buffering [Ca2+]i, leading to a potentiation of the sustained phase of ERK1 activation without potentiating MEK activity. In Rat-1DeltaRaf-1:ER cells, we observed a strong synergy of MKP-1 expression when cells were stimulated with estradiol in the presence of ionomycin, phorbol 12-myristate 13-acetate, or okadaic acid under conditions where these agents did not synergize for ERK activation. These results suggest that activation of the Raf/MEK/ERK pathway is insufficient to induce expression of MKP-1 but instead requires other signals, such as Ca2+, to fully reconstitute the response seen with growth factors. In this way, ERK-dependent and -independent signals may regulate MKP-1 expression, the magnitude of sustained ERK1 activity, and therefore gene expression.
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PMID:Regulation of mitogen-activated protein kinase phosphatase-1 expression by extracellular signal-related kinase-dependent and Ca2+-dependent signal pathways in Rat-1 cells. 914 52

Sustained activation of extracellular signal-regulated kinase 1/2 (ERK1/2) is critical for initiating differentiation of the PC12 cell to a sympathetic-like neurone. The neuropeptide, pituitary adenylyl cyclase-activating peptide (PACAP), has been demonstrated to cause cells to adopt a neuronal phenotype, although the mechanism of this activity is unclear. PACAP through its type I receptor stimulates a biphasic activation of ERK1/2; a >10-fold increase within 5 min, followed by a >5-fold increase that is sustained for >/=60 min. An equivalent stimulation is seen in PC12 cells expressing a dominant negative Ras mutant. However, the mitogen-activated kinase/ERK kinase 1/2 (MEK1/2) inhibitor PD98059 blocked both PACAP-induced stimulation of ERK1/2 activity and neurite outgrowth. Thus, the activation signal from the PACAP type I receptor on the ERK1/2 cascade pathway is received downstream of Ras, either at Raf or MEK. Down-regulation of protein kinase C or its inhibition by calphostin C blocked the ability of PACAP to stimulate ERK1/2. We conclude that activation of PACAP type I receptor activates protein kinase C, which then activates the ERK1/2 cascade in a Ras-independent manner at either Raf or MEK1/2.
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PMID:Pituitary adenylyl cyclase-activating peptide stimulates extracellular signal-regulated kinase 1 or 2 (ERK1/2) activity in a Ras-independent, mitogen-activated protein Kinase/ERK kinase 1 or 2-dependent manner in PC12 cells. 924 21

Mitogen-activated protein (MAP) kinases play a role in cell growth and are activated in the heart by cardiac stretch and various growth factors, but their role in signal transduction pathways once the heart has undergone hypertrophy is uncertain. To investigate the regulation of MAP kinases in the heart in response to angiotensin II (ang II), once cardiac hypertrophy has become established, ventricular and skeletal muscle explants were studied from Dahl S salt-sensitive and Dahl R salt-resistant rats that were on a high (6% NaCl) salt supplement in their diet. Cardiac hypertrophy was produced in the Dahl S but not R rat through NaCl-induced hypertension. MAP kinases were assayed by myelin protein phosphotransferase activity in MonoQ fractions of cell extracts. Ang II increased MAP kinases mainly in extracts from nonhypertrophic ventricles of Dahl R rats on a high-salt diet. Immunoblots revealed predominantly p44ERK1 with lower amounts p42MAPK in rat ventricle, and no apparent changes with hypertrophy. In hypertrophied hearts, ang II-induced MAP kinase activity was less markedly increased and more rapidly fell to baseline levels in comparison to the response in nonhypertrophied hearts. Prolonged ang II exposure did not produce the same effect on MAP kinase activity in ventricles from Dahl S rats on a low-salt diet, or skeletal muscle from salt-fed Dahl R and S rats. The ability of phorbol myristate acetate to simulate MAP kinase and ang II to simulate translocation of protein kinase C from the cytosole to the membrane was similarly compromised in hypertrophied ventricles. These results are consistent with a disturbance in the regulation of cell-signalling pathways in cardiac hypertrophy in which the MAP kinase response to ang II is dramatically altered.
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PMID:Reduction of angiotensin II-induced activation of mitogen-activated protein kinase in cardiac hypertrophy. 944 48

A small number of signaling cascades represented by mitogen-activated protein kinases, phosphoinositol-3-kinase, protein kinase C, signal transducers and activators of transcription, Ca2+/calcineurin, and a few other molecules are linked to an incomparably large number of surface receptors. Parallel activation of several of these pathways and the existence of isozymes for a number of signal transmitting molecules generate the required complexity and specificity matching the receptor variety. Here we show that the proinflammatory mediator TNF-alpha and the growth factor IL-5 are activated along common and distinct signaling cascades in allergically stimulated murine mast cells. Both of them are dependent on Ca2+ influx, activation of calcineurin and nuclear factor of activated T cells as well as a member of the atypical PKC family, most likely PKCmu. Additionally, mitogen-activated protein kinases for TNF-alpha and members of the classical or nonclassical PKCs for IL-5, respectively, were identified as additional required pathways. Inhibition of the classical and nonclassical PKCs, however, does not abrogate IL-5 induction but instead leads to a switch to mitogen-activated protein kinases, which then become essential. The activated branches of this "salvage" signaling cascade are represented by extracellular signal-regulated kinase 1/2 and c-jun NH2 terminal kinase 1 in allergically stimulated mast cells.
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PMID:Common and distinct signaling pathways mediate the induction of TNF-alpha and IL-5 in IgE plus antigen-stimulated mast cells. 955 81

1. We have previously found that human chymase cleaves big endothelins (ETs) at the Tyr31-Gly32 bond and produces 31-amino acid ETs (1-31), without any further degradation products. In this study, we investigated the effect of synthetic ET-1 (1-31) on the proliferation of cultured human coronary artery smooth muscle cells (HCASMCs). 2. ET-1 (1-31) increased [3H]-thymidine incorporation and cell numbers to a similar extent as ET-1 at 100 nM. This ET-1 (1-31)-induced [3H]-thymidine uptake was not affected by phosphoramidon, an inhibitor of ET-converting enzyme. It was, however, inhibited by BQ123, an endothelin ET(A) receptor antagonist, but not by BQ788, an endothelin ET(B) receptor antagonist. 3. By using an in-gel kinase assay, we demonstrated that ET-1 (1-31) activated extracellular signal-regulated kinase 1/2 (ERK1/2) in a concentration-dependent manner (100 pM to 1 microM) in HCASMCs. ET-1 (1-31)-induced ERK1/2 activation was inhibited by BQ123, but not by BQ788 and phosphoramidon. Inhibition of protein kinase C (PKC) and ERK kinase also caused a reduction of ET-1 (1-31)-induced ERK1/2 activation, whereas tyrosine kinase inhibition had little effect. 4. Gel-mobility shift analysis revealed that the ERK1/2 activation was followed by an increase in transcription factor activator protein-1 DNA binding activity in HCASMCs. 5. Our results strongly suggest that ET-1 (1-31) itself stimulates HCASMC proliferation probably through endothelin ET(A) or ET(A)-like receptors. The underlining mechanism of cell growth by ET-1 (1-31) may be explained in part by PKC-dependent ERK1/2 activation. Since human chymase has been proposed to play a role in atherosclerosis, ET-1 (1-31) may be one of the mediators.
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PMID:Effect of endothelin-1 (1-31) on extracellular signal-regulated kinase and proliferation of human coronary artery smooth muscle cells. 984 40

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