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)

In cultured rat aortic smooth muscle cells, angiotensin II (AII) treatment led to increased tyrosine phosphorylation of cellular proteins with apparent molecular masses of 42, 44, 75, and 120 kDa, respectively, as assessed by antiphosphotyrosine immunoblotting. Increased protein tyrosine phosphorylation was observed within 1 min of AII addition and was maximal by 30 min. The overall pattern of AII-stimulated protein tyrosine phosphorylation was distinct from that observed following treatment of rat aortic smooth muscle cells with platelet-derived growth factor-BB. Specific antibodies were used to identify the AII-stimulated 42- and 44-kDa tyrosine-phosphorylated proteins as the "mitogen-activated protein kinases," p42mapk and p44mapk, respectively. Raf-1, a 70-74-kDa serine/threonine protein kinase, was not tyrosine-phosphorylated in response to AII but was found to be hyperphosphorylated as evidenced by retarded protein mobility in SDS gel analysis. Taken together, these data indicate that AII binding to vascular smooth muscle cells leads to rapid activation of a complex cascade of protein kinases, including protein kinase C, Raf-1, MAP kinases, and an undefined intracellular protein tyrosine kinase(s) that may be coordinately involved in signal transduction leading to cell proliferation.
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PMID:Angiotensin II stimulation of rapid protein tyrosine phosphorylation and protein kinase activation in rat aortic smooth muscle cells. 838 3

To evaluate a possible mechanism for the chronic regulation of MAPK/ERK kinase-1 (MEK-1) and p42 mitogen-activated protein kinase (MAPK) we studied the long-term effects of the G-protein-coupled receptor agonist endothelin-1 (ET-1) and the protein tyrosine kinase-coupled receptor agonist platelet-derived growth factor BB (PDGF BB) on MEK-1 and p42 MAPK in glomerular mesangial cells (GMCs). ET-1 and PDGF BB led to a time-dependent increase in MEK-1 mRNA expression without altering p42 MAPK mRNA levels. The effect of ET-1 and PDGF BB on MEK-1 mRNA expression was maximal after 24 h (3.3-fold) or 6 h (2.9-fold). Furthermore, the effect of ET-1 and PDGF BB on MEK-1 mRNA expression was additive (4.2-fold after 6 h) and was inhibited by actinomycin D (5 micrograms/ml). Cycloheximide (10 micrograms/ml) inhibited MEK-1 mRNA induction but stimulated p42 MAPK mRNA expression in both the absence and the presence of ET-1 and/or PDGF BB. The ET-1 and PDGF BB-induced increase in MEK-1 mRNA was accompanied by sustained enhancement of both p45 MEK protein expression after 12 h and by elevation of p42 MAPK activity for up to 24 h. We conclude that, in GMCs, MEK-1 acts like a delayed-early gene, whereas p42 MAPK resembles an immediate-early gene. MEK-1 mRNA and protein levels, as well as p42 MAPK activity, can be chronically regulated by both a seven-transmembrane domain receptor-coupled peptide such as ET-1 and by an agonist binding to a receptor with intrinsic protein tyrosine kinase activity, such as PDGF BB.
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PMID:ET-1 and PDGF BB induce MEK mRNA and protein expression in mesangial cells. 858 80

Mitogen-activated protein (MAP) kinases are involved in controlling a cell's responses to a variety of stimuli and can be activated by both protein tyrosine kinase and G protein-coupled receptors. It was shown previously that Dictyostelium MAP kinase ERK2 is required for normal activation of adenylyl cyclase and erk2 null cells are aggregation-deficient. In this manuscript, we show that the Dictyostelium MAP kinase ERK2 is rapidly and transiently activated in response to the chemoattractant cAMP. This response requires cAMP receptors, but is independent of the coupled G alpha2 subunit and the only known G beta subunit. These data indicate that ligand-mediated receptor activation of adenylyl cyclase requires two receptor-dependent pathways, one of which requires heterotrimeric G proteins, including G alpha2 and the only known G beta subunit, and the second of which requires ERK2. Our results suggest that ERK2 may be activated by a novel receptor-mediated pathway.
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PMID:Seven helix chemoattractant receptors transiently stimulate mitogen-activated protein kinase in Dictyostelium. Role of heterotrimeric G proteins. 863 32

The effects of the protein tyrosine kinase inhibitor genistein on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity in monkey kidney epithelial CV-1 cells were determined. CV-1 cells were pretreated with genistein for 2 hr before treatment with 100 nM TPA. ODC activity was determined 9 hr after TPA treatment. Genistein inhibited TPA-induced ODC activity at 0.1, 1, 10, 25, 50, 100, 200, and 400 microM by 0%, 0%, 42%, 59%, 62%, 81%, 91%, and 100%, respectively (IC50 = 20 microM). Genistein inhibited TPA-induced mitogen-activated protein kinase (MAPK) tyrosine phosphorylation and the accumulation of steady state levels of ODC mRNA at 400 microM but not at 25 microM. Genistein, at 25 microM, did not alter the TPA-induced phosphorylation of p90 ribosomal S6 kinase but caused a approximately 50% decrease of the TPA-induced phosphorylation of p70 S6 kinase (p70S6K), a protein kinase involved in the control of translational efficiency. Taken together, these data indicate that genistein may inhibit TPA-induced ODC activity at the transcriptional and translational levels through the inhibition of MAPK and p70S6K activation, respectively. The regulation of MAPK and p70S6K may be mediated through different protein tyrosine kinases that have differential sensitivity to genistein.
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PMID:Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase activity by genistein, a tyrosine kinase inhibitor. 870 Jan 31

CD40 plays critical roles in B cell proliferation and differentiation in response to T cell-dependent antigenic stimulation. It has been suggested that CD40-mediated biological activities are transduced by a CD40 receptor-associated factor, CRAF1 and probably by protein tyrosine kinase Lyn and its substrates, phospholipase C gamma (PLC gamma) and phosphatidylinositol-3 kinase (PI-3 kinase). Here, we describe the novel finding that a mitogen-activated protein kinase (MAPK) extracellular signal-regulated protein kinase (ERK) cascade is involved in CD40 signaling in mouse B cells. Analysis of ERK activities in the B cell lymphoma cell line WEHI 231, which shows an increase in DNA synthesis or arrest of the cell cycle by cross-linking of CD40 or surface IgM (sIgM) cross-linking, respectively, indicated that one of the ERK isoforms, ERK2, was preferentially and rapidly activated after CD40 cross-linking. The CD40-mediated ERK2 activation was comparable to that after sIgM stimulation, although the activity was reduced toward the basal level within several minutes after stimulation. In contrast, ERK1 and ERK2 were activated to a similar extent by sIgM cross-linking, and the activities remained stable for at least 10 min. Furthermore, similar features of differential activation of ERK isoforms were observed in normal resting B cells in CD40 and sIgM signaling. These results suggest divergent regulatory pathways for ERK1 and ERK2 activation, and they support the notion that CD40 signaling may utilize a limited set of elements in the ERK cascade. Co-stimulation of WEHI 231 cells with anti-CD40 mAb rescues the cells from anti-IgM-mediated apoptosis, whereas this co-stimulation resulted in activation of ERK isoforms comparable to that in sIgM stimulation, without a synergistic effect. This result indicates the dominance of ERK activation in sIgM signaling over that of CD40, and it suggests that ERK activation may not be linked to the biological effect that CD40 stimulation in this cell line.
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PMID:Activation of mitogen-activated protein kinases via CD40 is distinct from that stimulated by surface IgM on B cells. 876 46

Constitutive stimulation of the mitogen-activated protein kinase (MAPK) activator MAPK/ERK kinase (MEK) is sufficient to promote long-term events such as cell differentiation, proliferation, and transformation. To evaluate a possible mechanism for the chronic regulation of MEK and p42 MAPK, we studied the long-term effects of fetal bovine serum (FBS), the G protein-coupled receptor agonist endothelin-1 (ET-1), and the protein tyrosine kinase-coupled receptor agonist platelet-derived growth factor BB (PDGF BB) on MEK and p42 MAPK in glomerular mesangial cells (GMC). FBS, ET-1, and PDGF BB led to a time-dependent increase in MEK-1 mRNA and protein expression without altering p42 MAPK mRNA and protein levels. FBS also induced MEK-1 mRNA expression in diverse cell types, including NIH/3T3 fibroblasts, A7r5 vascular smooth muscle cells, and Chinese hamster ovary cells. In GMC, cycloheximide inhibited MEK-1 mRNA induction but stimulated p42 MAPK mRNA expression in the absence and presence of FBS, ET-1, or PDGF. The FBS-induced increase in MEK-1 mRNA was accompanied by a sustained enhancement of MEK activity, as assessed by the ability of immunoprecipitated p45 MEK to activate recombinant p42 MAPK and hence phosphorylate myelin basic protein, and p42 MAPK activity. We conclude that, in GMC, MEK-1 acts like a delayed-early gene and that it can be chronically induced at the mRNA and protein level.
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PMID:Differential long-term regulation of MEK and of p42 MAPK in rat glomerular mesangial cells. 877 28

The mechanisms by which mitogenic G-protein-coupled receptors activate the MAP kinase signalling pathway are poorly understood. Candidate protein tyrosine kinases that link G-protein-coupled receptors with MAP kinase include Src family kinases, the epidermal growth factor receptor, Lyn and Syk. Here we show that lysophosphatidic acid (LPA) and bradykinin induce tyrosine phosphorylation of Pyk2 and complex formation between Pyk2 and activated Src. Moreover, tyrosine phosphorylation of Pyk2 leads to binding of the SH2 domain of Src to tyrosine 402 of Pyk2 and activation of Src. Transient overexpression of a dominant interfering mutant of Pyk2 or the protein tyrosine kinase Csk reduces LPA- or bradykinin-induced activation of MAP kinase. LPA- or bradykinin-induced MAP kinase activation was also inhibited by overexpression of dominant interfering mutants of Grb2 and Sos. We propose that Pyk2 acts with Src to link Gi- and Gq-coupled receptors with Grb2 and Sos to activate the MAP kinase signalling pathway in PC12 cells.
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PMID:A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. 884 29

Hepatocyte growth factor (HGF) activated phospholipase D (PLD) in primary-cultured rat hepatocytes, as assessed by the formation of phosphatidylbutanol (PBut), a specific and stable product of PLD activity in the presence of 0.3% butanol. PLD hydrolyzes phosphatidylcholine to choline and phosphatidic acid (PA), which is further metabolized to diacylglycerol (DG) by PA phosphohydrolase (PAP). In HGF-stimulated hepatocytes, butanol prevented the formation of PA and DG. A PAP inhibitor, propranolol, inhibited DG production with a reciprocal increase of PA, implying that PLD played a role in the formation of not only PA but DG. Inhibitors for protein kinase C (PKC), Ro31-8425, H-7, and calphostin C, reduced HGF-induced PLD activation. A protein tyrosine kinase (PTK) inhibitor, genistein but not its inactive analogue daidzein, inhibited PLD activation by HGF. Moreover, depletion of extracellular Ca2+ by omission of Ca2+ or by chelating residual Ca2+ with ethyleneglycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) abolished HGF-induced PLD activation. HGF, phorbol myristate acetate (PMA) and a DG analog, oleylacetylglycerol (OAG), activated the expression of c-jun and c-fos messenger RNAs (mRNAs). Ro31-8425, calphostin C, and genistein, which prevented HGF-induced PLD activation, inhibited induction of these immediate early genes. Butanol and propranolol at concentrations which effectively inhibited the formation of DG, suppressed HGF-induced expression of c-jun and c-fos mRNAs. However, HGF-induced mitogen-activated protein kinase (MAPK) activation was not affected by both butanol and propranolol. These results suggest that PTK, PKC, and Ca2+ regulate HGF-induced PLD activation, and that DG produced by PLD pathway may play a role in the induction of immediate early genes, which is activated in MAPK-independent manner, in rat hepatocytes.
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PMID:Phospholipase D activation in hepatocyte growth factor-stimulated rat hepatocytes mediates the expressions of c-jun and c-fos: involvement of protein tyrosine kinase, protein kinase C, and Ca2+. 890 10

The purpose of this investigation was to pharmacologically probe the signaling pathways thought to be involved in protein kinase C (PKC)-stimulated superoxide anion (O2-) generation in all-trans retinoic acid-treated human promyelocytic HL-60 cell line (HL-60), targeting PKC, mitogen-activated protein kinase (MAPK), MAPK kinase (MEK), protein serine-threonine phosphatase(s) (PSP), protein tyrosine kinase(s) (PTK) and phosphatase(s) (PTP), secretory phospholipase A2, cyclooxygenase (CO) and 5-lipoxygenase with selected inhibitors. The following agents inhibited phorbol 12-myristate 13-acetate-stimulated O2- generation significantly in the all-trans retinoic acid-treated HL-60 cells (expressed as percentage of control, P < .05): 1) PKC inhibitors: staurosporine (100 nM, 3 +/- 1%); Ro 31-8220 (1 microM, 3 +/- 2%); sphingosine (100 microM, 15 +/- 7%); 2) PSP 1 and 2a inhibitors, okadaic acid (10 microM, 35 +/- 1%); calyculin A (10 microM, 73 +/- 1%); 3) MAPK inhibitor: SB-203580 (100 microM, 62 +/- 1%); 4) PTP inhibitors: phenylarsine oxide (1 microM, 12 +/- 9%); diamide (1 mM, 21 +/- 11%); and 5) secretory phospholipase A2 inhibitors: manoalide (1 microM, 24 +/- 10%); scalaradial (1 microM, 11 +/- 4%). Exogenously added arachidonic acid-stimulated O2- generation in a time- and dose-dependent manner. The following inhibitors enhanced or did not significantly affect phorbol 12-myristate 13-acetate-stimulated O2- generation (expressed as percentage of control): 1) PTK inhibitors: genistein (100 microM, 69 +/- 12%); CGP 53716 (100 microM, 67 +/- 10%); herbimycin A (10 microM, 67.4 +/- 1%); 2) PSP 2b inhibitors: cyclosporin A (30 microM, 71 +/- 5%); FK506 (30 microM, 88 +/- 7%); 3) CO inhibitor: indomethacin (100 microM, 111 +/- 12%); 4) 5-lipoxygenase inhibitor: WY 50,295 (100 microM, 140 +/- 23%); 5) MEK inhibitor: PD98059 (100 microM, 94 +/- 6.7%); and 6) the PTP inhibitor: orthovanadate (100 microM, 131 +/- 25%). Our pharmacological study suggests that, in neutrophil-like HL-60 cells, the signaling pathways leading to PMA-stimulated O2- generation appear to involve PKC, MAPK, phospholipase A2, arachidonic acid, PSP 1 and 2a and PTP. Furthermore, PTK, MEK, CO, 5-lipoxygenase and PSP 2b do not appear to participate in the modulation of PKC-stimulated O2- generation.
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PMID:Pharmacological targeting of signaling pathways in protein kinase C-stimulated superoxide generation in neutrophil-like HL-60 cells: effect of phorbol ester, arachidonic acid and inhibitors of kinase(s), phosphatase(s) and phospholipase A2. 893 Jan 66

In cardiac myocytes, B-type natriuretic peptide (BNP) expression is induced with the rapid kinetics of a primary response gene. Like many other primary response gene transcripts, the BNP mRNA possesses destabilizing elements and is believed to be short-lived. The rapid induction of a short-lived transcript could be achieved partty by agonist-mediated increases in mRNA t1/2. Accordingly, the present study was undertaken to evaluate whether the alpha 1-adrenergic receptor agonist, phenylephrine (PE), a known inducer of BNP expression, could stabilize the BNP mRNA and, if so, what signaling pathways might be involved. In primary myocardial cells treated with a transcription inhibitor, the t1/2 of the BNP mRNA was found to be about 1 h in the absence of PE; however, in the presence of PE, the t1/2 increased to 5 h. It was shown that neither the calmodulin kinase inhibitor, KN-62, nor the protein tyrosine kinase inhibitor, tyrphostin, blocked PE-mediated stabilization of the BNP mRNA. However, either the protein kinase C (PKC) inhibitor, GF 109203X, or the mitogen-activated protein kinase kinase (MAPKK) inhibitor, PD 098059, effected some blockade of the stabilizing effects of PE. While maximal doses of PD 098059 nearly completely blocked PE-activated MAPK, stabilization was only partially inhibited. Moreover, maximal doses of GF 109203X, which only partially blocked PE-activated MAPK, nearly completely inhibited stabilization. Thus, while MAPK appears to be required for maximal agonist-mediated stabilization, PKC seems to play a dominant role, participating through both MAPK-dependent and -independent pathways. These results establish roles for both the PKC and MAPK families in alpha 1-adrenergic receptor-mediated stabilization of the BNP mRNA, suggesting that the rapid induction of BNP expression might be due, in part, to this agonist-mediated increase in mRNA t1/2.
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PMID:Stabilization of the B-type natriuretic peptide mRNA in cardiac myocytes by alpha-adrenergic receptor activation: potential roles for protein kinase C and mitogen-activated protein kinase. 896 Dec 80


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