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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandin H2 (PGH2) and thromboxane A2 (TXA2) are potent activators of platelets and vascular smooth muscle whose responses are mediated through a common G-protein coupled receptor (TXA2/PGH2 receptor). Despite the many studies describing their ability to aggregate platelets and contract vascular smooth muscle, little is known concerning the potential mitogenic capabilities of these autocoids. Mitogen-activated protein kinases (MAP kinases) and ribosomal S6 kinases are well characterized intracellular mediators involved in proliferation of cells. The present study was designed to examine the activation of MAP kinase and S6 kinase in guinea pig coronary artery smooth muscle cells (CASMC) in response to stimulation by a TXA2/PGH2 mimetic, I-BOP ([1S-(1 alpha,2 beta(5Z),3 alpha(1E,3R*),4 alpha)]-7-[3-(3-hydroxy-4-(4'- iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-h eptenoic acid). Equilibrium radioligand binding assays using [125I]BOP defined a single class of high affinity TXA2/PGH2 receptors on monolayers of guinea pig CASMC (Kd = 0.18 +/- 0.03 nM; 26,476 +/- 3,600 sites/cell; 0.08 +/- 0.01 pmol/mg of protein; n = 12). I-BOP produced a concentration-dependent increase in [3H]thymidine incorporation in these cells (EC50 = 0.3 nM) which was inhibited by a series of TXA2/PGH2 receptor antagonists as well as by verapamil and staurosporine. I-BOP also produced a time-dependent increase in the activation of kinases phosphorylating myelin basic protein (MBP; a substrate for MAP kinase) and RRLSSLRA (S6 peptide; a substrate for pp85rsk kinase), reaching a peak activation between 5 and 10 min. Stimulated MBP kinases were identified as ERK1 and ERK2. The activation of these kinases by I-BOP was inhibited by the TXA2/PGH2 receptor antagonist SQ29548 and also by staurosporine. These results indicate that I-BOP, a TXA2/PGH2 mimetic, produces growth of coronary artery vascular smooth muscle cells, which is preceded by activation of MAP kinase and S6 kinase.
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PMID:Thromboxane A2/prostaglandin H2-stimulated mitogenesis of coronary artery smooth muscle cells involves activation of mitogen-activated protein kinase and S6 kinase. 811 6

Somatostatin possesses antisecretory and antiproliferative activity on some human tumors. We herein report that, in a human neuroblastoma cell line, the somatostatin analogue BIM 23014 inhibited mitogen-activated protein (MAP) kinase activity stimulated by either insulin-like growth factor-1, whose receptor bears a tyrosine kinase, or carbachol, which acts at a G-protein coupled receptor. In a human small cell lung carcinoma line BIM inhibited serum-stimulated MAP kinase activation. These inhibitory actions occur in a dose range quite similar to that observed for suppression of proliferation induced by the analogue in the same cell lines. The decrease in cAMP elicited by the analogue in the two cell lines is not responsible for its inhibitory action on MAP kinase and cell growth. Moreover, the analogue did not modify intracellular [Ca2+] and pH. An involvement of a phosphatase activity is suggested.
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PMID:A somatostatin analogue inhibits MAP kinase activation and cell proliferation in human neuroblastoma and in human small cell lung carcinoma cell lines. 895 39

Endothelin (ET) is a potent vasoconstrictor whose responses are mediated through a common G-protein coupled receptor. So far little is known concerning its potential mitogenic capacity. In the present study, experiments were conducted to determine the role of mitogen-activated protein kinase (MAPK) activation in the rabbit thoracic artery smooth muscle cells (VSMC) in response to stimulation by ET-1. It was found that ET-1 produced concentration- and time-dependent increases in 3H-TdR incorporation and in MAPK activity of these cells. All the increases were inhibited by protein kinase C (PKC) inhibitors, such as Staurosporine (STP) and H-7 and by ETA receptor antagonist BQ123, but not by specific tyrosine kinase inhibitor Herbimycin A (Herb). Pre-treatment with PKC activator PMA (phorbol myristate acetate) for 24 h (PKC downregulation) significantly attenuated ET-1-induced MAPK activation. These results indicate that: (1) ET-1-stimulated proliferation of VSMC involves the activation of MAPK and (2) ET-1-induced MAPK activation is mediated through ETA receptor and PKC.
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PMID:[Endothelin-stimulated proliferation of thoracic artery smooth muscle cells involves activation of mitogen-activated protein kinase]. 938 95

In GN4 rat liver epithelial cells, angiotensin II (Ang II) produces intracellular calcium and protein kinase C (PKC) signals and stimulates ERK and JNK activity. JNK activation appears to be mediated by a calcium-dependent tyrosine kinase (CADTK). To define the ERK pathway, we established GN4 cells expressing an inhibitory Ras(N17). Induction of Ras(N17) blocked EGF- but not Ang II- or phorbol ester (TPA)-dependent ERK activation. In control cells, Ang II and TPA produced minimal increases in Ras-GTP level and Raf kinase activity. PKC depletion by chronic TPA exposure abolished TPA-dependent ERK activation but failed to diminish the effect of Ang II. In PKC-depleted cells, Ang II increased Ras-GTP level and activated Raf and ERK in a Ras-dependent manner. In PKC depleted cells, Ang II stimulated Shc and Cbl tyrosine phosphorylation, suggesting that without PKC, Ang II activates another tyrosine kinase. PKC-depletion did not alter Ang II-dependent tyrosine phosphorylation or activity of p125(FAK), CADTK, Fyn or Src, but PKC depletion or incubation with GF109203X resulted in Ang II-dependent EGF receptor tyrosine phosphorylation. In PKC-depleted cells, EGF receptor-specific tyrosine kinase inhibitors blocked Ang II-dependent EGF receptor and Cbl tyrosine phosphorylation, and ERK activation. In summary, Ang II can activate ERK via two pathways; the latent EGF receptor, Ras-dependent pathway is equipotent to the Ras-independent pathway, but is masked by PKC action. The prominence of this G-protein coupled receptor to EGF receptor pathway may vary between cell types depending upon modifiers such as PKC.
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PMID:Angiotensin II stimulates ERK via two pathways in epithelial cells: protein kinase C suppresses a G-protein coupled receptor-EGF receptor transactivation pathway. 956 40

Sphingosine 1-phosphate (SphP), a metabolite of cellular sphingolipids, has been shown to induce cell proliferation by activating the mitogen-activated protein kinase (MAPK) pathway. Proline-rich tyrosine kinase 2 (Pyk2) is a novel cytosolic tyrosine kinase which mediates activation of the MAPK or c-Jun N-terminal kinase (JNK) signaling pathways in response to a variety of stimuli that elevate intracellular calcium. In this report, we show that SphP stimulates both tyrosine phosphorylation of Pyk2 and MAPK activation in a transient and dose-dependent manner in rat aortic smooth muscle cells. Further studies indicate that Pyk2 phosphorylation, but not MAPK activation, is dependent on a pertussis toxin-sensitive G-protein-coupled receptor as well as partially on actin cytoskeleton. In addition, both intracellular calcium mobilization and protein kinase C (PKC) are required for optimal Pyk2 phosphorylation while either calcium increase or PKC activation is sufficient for MAPK activation in response to SphP. Finally, we show that a tyrosine kinase(s) other than Pyk2 is necessary for MAPK activation by SphP. Together, these results suggest that SphP stimulates tyrosine phosphorylation of Pyk2 through a G-protein coupled receptor, which is dissociated from its activation of the MAPK pathway in these cells.
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PMID:Differential stimulation of proline-rich tyrosine kinase 2 and mitogen-activated protein kinase by sphingosine 1-phosphate. 982 86

Apoptosis as defined by contemporary science describes a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines, (FAS/TNF alpha family of cytokines) and growth factors/energy deprivation. Several complex signal transduction pathways have been implicated in execution of cardiomyocyte apoptosis, including: Fas/TNF alpha receptors signaling, stress or mitogen activated protein kinases (SAPK/MAPK), sphingolipids metabolites (ceramide), G-protein coupled receptor (GPCR) signaling (G alpha i, G alpha q) and NF kappa B activation. Apoptosis of cardiac myocytes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of numerous molecular targets associated with cardiomyocyte apoptosis that are amenable for pharmacologic manipulation, may provide novel therapeutic strategies for diverse cardiac ailments, as recently suggested by pharmacologic studies in experimental animals.
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PMID:Apoptosis in cardiac diseases--new opportunities for novel therapeutics for heart diseases. 1051 63

Fusion proteins between the human A(1) adenosine receptor and the pertussis toxin resistant (Cys351Gly) mutant of the G-protein alpha subunit G(i1)alpha (A1/Gi), and between the human A(1) adenosine receptor, the Aequorea victoria green fluorescent protein (GFP) and Cys351Gly G(i1)alpha (A1/GFP/Gi), were expressed in CHO cells. The agonist NECA caused a stimulation of [(35)S]GTPgammaS binding at both fusion proteins with similar concentration dependence as at the native receptor. However in the presence of pertussis toxin NECA stimulation of [(35)S]GTPgammaS binding was only seen at the A1/GFP/Gi fusion protein. The regulation of the adenylyl cyclase and MAP kinase effector systems by both fusion proteins was attenuated following pertussis toxin treatment. These studies demonstrate for the first time the characterisation of a fusion protein between a G-protein coupled receptor, GFP and a G-protein alpha subunit.
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PMID:Functional analysis of a human A(1) adenosine receptor/green fluorescent protein/G(i1)alpha fusion protein following stable expression in CHO cells. 1058 92

Caveolae have been implicated in growth factor receptor and G-protein coupled receptor signaling in vascular cells. It has been postulated that caveolin, the structural protein of caveolae, may act as a general tyrosine kinase inhibitor by binding and inhibiting signaling molecules involved in the activation of the MAP kinase proliferation cascade. Using an in vitro model of VSMC proliferation, we found that serum stimulation caused a dose dependent decrease in both caveolin-1 and caveolin-2 protein levels in human coronary artery smooth muscle cells. Heparin, an inhibitor of VSMC proliferation, inhibited the serum-induced loss of caveolin-1 and caveolin-2. In addition, heparin caused an increase in both caveolin-1 and caveolin-2 localization to caveolae-enriched sucrose gradient membrane fractions when compared to serum alone. Taken together, caveolin may play an important role in the regulation of VSMC proliferation and heparin and serum have opposing effects on caveolin expression and localization in VSMC.
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PMID:The regulation of caveolin expression and localization by serum and heparin in vascular smooth muscle cells. 1060 Apr 87

Opioid receptors, members of the G-protein coupled receptor (GPCR) super family, bind to endogenous opioid peptides or opiate drugs and induce a wide variety of signal transduction processes by inhibiting adenylyl cyclase, modulating cation channels, and activating the mitogen-activated protein (MAP) kinases. Similar to other GPCRs, agonist binding causes rapid internalization and down-regulation of opioid receptors. The interdependence between receptor endocytosis and activation of MAP kinase pathway are increasingly being examined. We have examined these using ligands that exhibit differential extent of endocytosis as well as mutants of mu and delta opioid receptors that are unable to internalize. We find that ligands, including morphine, that do not induce receptor internalization are able to stimulate MAP kinase phosphorylation not only in heterologous cells but also in neuronal cell lines that express endogenous mu and delta receptors. Moreover, mutant receptors that fail to undergo agonist-mediated internalization are able to efficiently phosphorylate MAP kinases. Taken together, these data are consistent with the notion that the activation of MAP kinase pathway is an internalization independent phenomenon in the case of opioid receptors and that GPCR internalization and activation of MAP kinase are governed by complex regulatory mechanisms.
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PMID:Opioid receptor endocytosis and activation of MAP kinase pathway. 1076 97

We examined the effect of recovery following reversible ATP depletion on MAP kinase activity in cultured renal cells of proximal tubular origin (LLC-PK1). We induced ATP depletion by 0.1 micromol/l antimycin A in combination with substrate deprivation, and obtained recovery by restoration of substrate supply. MAP kinase activity increased from 374+/-45 pmol/mg protein/mm during ATP depletion to 768 +/- 77 pmol/mg protein/mm after 15 min of recovery. We used ATP to activate a representative G-protein coupled receptor, or epidermal growth factor (EGF) to activate receptors with intrinsic tyrosine kinase activity, and measured the effect of these manipulations on MAP kinase activity during ATP depletion or following recovery. ATP and EGF stimulated MAP kinase activity under control conditions, but not during ATP depletion or after recovery. This shows that two distinct signal transduction pathways represented by ATP and EGF are blocked during ATP depletion and recovery. The lack of energy during ATP depletion and the already maximally stimulated MAP kinase during recovery is likely to be the reason for these results. In summary, these findings suggest that MAP kinase may be involved in the physiological response of cells injured by hypoxia.
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PMID:Activation of MAP kinase after reversible ATP depletion in LLC-PK 1 cells. 1084 98


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