Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In human polymorphonuclear leukocytes (PMNs), mitogen-activated protein kinases (MAPKs), also known as extracellular signal-regulated kinases (Erks), are activated within minutes upon stimulation with either chemoattractant formyl-Met-Leu-Phe (fMLP) or phorbol 12-myristate 13-acetate (PMA). This activation of MAPKs coincides with the formation of superoxide anion, which occurs through the activation of a multiple-component NADPH oxidase pathway. MAPKs have thus been suggested to be involved in signal transduction leading to the oxidative burst. To investigate whether MAPK activation plays a central role in the oxidative burst, we evaluated the effect of cAMP on MAPK activation induced by fMLP and PMA. cAMP inhibits many PMN functional responses, including the oxidative burst, and has recently been shown to reduce growth factor- and PMA-induced MAPK activities in a variety of cells. We found that in differentiated, neutrophil-like HL-60 cells, while cAMP reduced PMA-induced MAPK activation, it had no effect on fMLP-induced MAPK activation. Despite the presence of unchanged levels of activated MAPKs, the fMLP-induced oxidative burst was substantially diminished by cAMP. By contrast, O2-production induced by PMA remained the same even though MAPK activation was inhibited. In PMNs, although the levels of O2-induced by either 10 ng/ml or 100 ng/ml PMA were similar, only 100 ng/ml could stimulate MAPK activation, suggesting that the oxidative burst could occur in the absence of detectable activation of MAPKs. As in HL-60 cells, cAMP inhibited the O2-production in fMLP-stimulated PMNs but had no effect on MAPK activity. These results demonstrate that, while MAPK activation coincides with PMN activation, it can be dissociated from the oxidative burst.
 ...
PMID:Dissociation of mitogen-activated protein kinase activation from the oxidative burst in differentiated HL-60 cells and human neutrophils. 779 73

Interleukin-1 (IL-1) stimulates a time- and concentration-dependent mitogen-activated protein (MAP) kinase activation in rat mesangial cells. A rapid increase in activity (maximal at 10 min) is followed by a second persistent level of activity which steadily increases over 24 h. The second peak of MAP kinase activity is paralleled by a marked de novo synthesis of p42 MAP kinase as measured by immunoprecipitation of [35S]methionine-labelled mesangial cells and by a 60% increase in total p42 MAP kinase protein as detected by Western blot analysis. We propose that IL-1 induced de novo synthesis of p42 MAP kinase is important for the multiplicity of long-term actions of this cytokine in renal mesangial cells.
 ...
PMID:Interleukin-1 stimulates de novo synthesis of mitogen-activated protein kinase in glomerular mesangial cells. 806 12

PHAS-I is a heat- and acid-stable protein that is phosphorylated on Ser/Thr residues in response to insulin and growth factors. To investigate the phosphorylation of PHAS-I, the protein was expressed in bacteria and purified for use as substrate in protein kinase reactions in vitro. Recombinant PHAS-I was rapidly and stoichiometrically phosphorylated by mitogen-activated protein (MAP) kinase. At saturating MgATP, the Km and Vmax observed with PHAS-I were almost identical to those obtained with myelin basic protein, one of the best MAP kinase substrates. PHAS-I was also phosphorylated at a significant rate by casein kinase II and protein kinase C. To investigate sites of phosphorylation, PHAS-I was digested with collagenase and phosphopeptides were resolved by reverse phase high performance liquid chromatography. Almost all of the phosphate introduced by MAP kinase was recovered in the peptide, Leu-Met-Glu-Cys-Arg-Asn-Ser-Pro-Val-Ala-Lys-Thr. 32P was released in the seventh cycle of Edman degradation, identifying the Ser (Ser64) as the phosphorylated residue. Ser64 was also phosphorylated in response to insulin in rat adipocytes. We conclude that PHAS-I is a substrate for MAP kinase both in vivo and in vitro. As PHAS-I is one of the most prominent insulin-stimulated phosphoproteins in adipocytes, it may qualify as the major MAP kinase substrate in these cells.
 ...
PMID:Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase. Identification of a site phosphorylated by MAP kinase in vitro and in response to insulin in rat adipocytes. 808 23

Angiotensin II is a potent growth factor for vascular smooth muscle cells and shares many signal transduction mechanisms with mitogens, including stimulation of mitogen-activated protein (MAP) kinases and protein tyrosine phosphorylation. Regulation of tyrosine phosphorylation involves both protein-tyrosine kinases and protein-tyrosine phosphatases (PTPases). To investigate the role of PTPases in angiotensin II-mediated events, we studied the expression of a transcriptionally regulated PTPase, 3CH134, which has selective activity toward MAP kinase. Angiotensin II rapidly induced 3CH134 mRNA (30 min maximum) in a concentration-dependent manner (100 nM maximum). Platelet-derived growth factor, alpha-thrombin, hydrogen peroxide, phorbol 12-myristate 13-acetate, and ionomycin also induced 3CH134 but to levels lower than angiotensin II. Induction of 3CH134 by angiotensin II was partially inhibited after down-regulating protein kinase C but was fully inhibited after chelating intracellular Ca2+. Treatment with both phorbol 12-myristate 13-acetate and ionomycin induced 3CH134 mRNA to levels seen with angiotensin II, indicating that Ca2+ mobilization and protein kinase C activation can act synergistically to induce 3CH134. Angiotensin II stimulated 3CH134 protein synthesis after 1 h as measured by immunoprecipitation of 3CH134 from [35S]methionine-labeled cells using affinity-purified antibodies. These results establish 3CH134 as a dynamically regulated, immediate early gene in vascular smooth muscle cells and suggest a role for PTPases in regulating angiotensin II-stimulated events mediated by MAP kinases and tyrosine kinases.
 ...
PMID:Angiotensin II induces 3CH134, a protein-tyrosine phosphatase, in vascular smooth muscle cells. 825 12

Mechanisms of neutrophil activation in response to chemoattractants remain incompletely understood. We have recently reported a Ras-mediated c-Raf pathway leading to the activation of mitogen-activated protein (MAP) kinase in human neutrophils stimulated with the chemoattractant formyl-Met-Leu-Phe (FMLP). However, concern that Raf activation may not fully account for the early FMLP-mediated human neutrophil responses prompted us to investigate the activation of MAP kinase/ERK kinase (MEK) by MEK kinase (MEKK). In cell lysates we identified protein species at 180, 160, 110, 72, and 54 kDa with a monoclonal antibody to MEKK. Activation of MEKK was determined on immunoprecipitates from FMLP-stimulated neutrophils by in vitro kinase assay, which utilized both MEK1 and MEK2 as substrates. It was rapid, detectable at 30 s and reaching a plateau at 5 min, and it was inhibited in a dose-dependent fashion by a specific phosphatidylinositol 3-kinase inhibitor, wortmannin. Partial inhibition by pertussis toxin was observed. We were unable to show inhibition of the MEKK response by GF 109203X, a protein kinase C-specific inhibitor. These data indicate that in neutrophils activation of MEKK in addition to Raf may underlie stimulation of MAP kinase and other MAP kinase homologues by FMLP.
 ...
PMID:Activation of MEKK by formyl-methionyl-leucyl-phenylalanine in human neutrophils. Mapping pathways for mitogen-activated protein kinase activation. 896 28

Trichostatin A (TSA) inhibits the activity of histone deacetylase and blocks both oncogenic ras-induced and nerve growth factor-induced (NGF-induced) outgrowth of neurites from PC12 cells. Cells of the PC12D subline extend neurites very rapidly in response to NGF, basic fibroblast growth factor (bFGF), dibutyryl cAMP (dbcAMP) and to staurosporine, even in the presence of an inhibitor of RNA synthesis, as do primed PC12 cells or cultured sympathetic neurons. TSA at 100 nM selectively blocked the NGF- and bFGF-induced outgrowth of neurites from PC12D cells, but not the outgrowth induced by dbcAMP or staurosporine. The NGF-induced changes in morphology with the relocalization of F-actin, were not inhibited by TSA. However, the subsequent formation of growth cones and the outgrowth of neurites was blocked. The activation of mitogen-activated protein (MAP) kinases in NGF-stimulated cells was also unaffected by TSA. When TSA was added to cells that were extending neurites in response to NGF, the number of neurite-bearing cells decreased after a lag period. In the presence of inhibitors of RNA or protein synthesis namely, actinomycin D, cordycepin, and cycloheximide, TSA no longer blocked the NGF- and bFGF-dependent outgrowth of neurites from PC12D cells. Regardless of the effect of TSA, the rapid outgrowth of neurites from PC12D cells was unaffected by the presence of cycloheximide, which inhibited protein synthesis by 97%, as determined by monitoring the incorporation of [35S]methionine/cysteine. This study provides proof that the NGF-induced elongation of neurites does not require protein synthesis de novo. These observations suggest that TSA might not inhibit the early signal-transduction pathway of NGF, but might block the late pathway, which is related to the formation of growth cones and/or neurites. Cellular conditions that no longer allow the NGF- and bFGF-mediated elongation of neurites might be produced by TSA via synthesis of some specific protein(s) due to changes in RNA(s) synthesis de novo.
 ...
PMID:Inhibition of the nerve growth factor-induced outgrowth of neurites by trichostatin A requires protein synthesis de novo in PC12D cells. 911 95

Hepatocyte growth factor/scatter factor (HGF/SF) treatment of the Madin-Darby canine kidney epithelial cell line causes scattering of cells grown in monolayer culture and the formation of branching tubules by cells grown in collagen gels. HGF/SF causes prolonged activation of both the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase 2 (ERK2) and the phosphoinositide 3-OH kinase (PI 3-kinase) target protein kinase B (PKB)/Akt; inhibition of either the MAP kinase pathway by the MAP kinase/ERK kinase inhibitor PD98059 or the PI 3-kinase pathway by LY294002 blocks HGF/SF induction of scattering, although in morphologically distinct ways. Expression of constitutively activated PI 3-kinase, Ras, or R-Ras will cause scattering, but activated Raf will not, indicating that activation of the MAP kinase pathway is not sufficient for this response. Downstream of PI 3-kinase, activated PKB/Akt and Rac are both unable to induce scattering, implicating a novel pathway. Scattering induced by Ras or PI 3-kinase is sensitive to PD98059, as well as to LY294002, suggesting that basal MAP kinase activity is required, but not sufficient, for the scattering response. Induction of MDCK cell tubulogenesis in collagen gels by HGF/SF is inhibited by PD98059; expression of activated Ras and Raf causes disorganized growth in this system, but activated PI 3-kinase or R-Ras causes branching tubule formation similar to that seen with HGF/SF treatment. These data indicate that multiple signaling pathways acting downstream of Met and Ras are needed for these morphological effects; scattering is induced primarily by the PI 3-kinase pathway, which acts through effectors other than PKB/Akt or Rac and requires at least basal MAP kinase function. Elevated PI 3-kinase activity induces tubulogenesis, but total inhibition and excess activation of the MAP kinase pathway both oppose this effect.
 ...
PMID:Phosphoinositide 3-kinase induces scattering and tubulogenesis in epithelial cells through a novel pathway. 966 53

The role of protein tyrosine kinase activity in ErbB3-mediated signal transduction was investigated. ErbB3 was phosphorylated in vivo in response to either heregulin (HRG) in cells expressing both ErbB3 and ErbB2, or epidermal growth factor (EGF) in cells expressing both ErbB3 and EGF receptor. A recombinant receptor protein (ErbB3-K/M, in which K/M stands for Lys-->Met amino acid substitution) containing an inactivating mutation in the putative ATP-binding site was also phosphorylated in response to HRG and EGF. Both the wild-type ErbB3 and mutant ErbB3-K/M proteins transduced signals to phosphatidylinositol 3-kinase, Shc and mitogen-activated protein kinases. Separate kinase-inactivating mutations in the EGF receptor and ErbB2 proteins abolished ErbB3 phosphorylation and signal transduction activated by EGF and HRG respectively. Hence the protein tyrosine kinase activity necessary for growth factor signalling via the ErbB3 protein seems to be provided by coexpressed EGF and ErbB2 receptor proteins.
 ...
PMID:Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein. 969 19

1. Activation of mitogen-activated protein (MAP) kinase is an early response to a wide variety of stimuli and plays an important role in the regulation of cellular functions. In the present study we investigated the activation of MAP kinase in human polymorphonuclear neutrophils (PMNs). 2. Activity of MAP kinase and protein kinase C (PKC) was measured radiometrically from the rate of phosphorylation of specific peptide substrates. Protein phosphorylation was measured by immunoprecipitation and Western blot analysis. 3. N-Formyl-Met-Leu-Phe (fMLP), phorbol 12-myristate, 13-acetate (PMA) and the Ca2+-ATPase inhibitors thapsigargin (Tg) and cyclopiazonic acid (CPA) increased MAP kinase activity significantly. The tyrosine kinase inhibitors erbstatin and herbimycin A partially inhibited the effects of fMLP and PMA, and completely abolished the effects of both Tg and CPA. The specific PKC inhibitor calphostin C suppressed activation of MAP kinase produced by fMLP and PMA, but had no effect on that produced by Tg and CPA. Tg and CPA were without effect on PKC activity. 4. Immunoprecipitation and Western blot analysis indicated that the 42 and 44 kDa tyrosine-phosphorylated proteins found after stimulation of PMNs were both members of the MAP kinase family. Pretreatment of PMNs with staurosporine, EGTA or erbstatin significantly reduced the tyrosine phosphorylation of MAP kinase(s). 5. These results suggest that in human PMNs, MAP kinase can be stimulated in both a PKC-dependent and a PKC-independent manner. The Ca2+ signal leads to activation of tyrosine kinases, which contribute to the activation of MAP kinase. However, a PMA-sensitive Ca2+-independent pathway also exists. Mobilization of Ca2+ and activation of PKC synergistically induce maximal MAP kinase activation and tyrosine phosphorylation.
 ...
PMID:Involvement of tyrosine kinases, Ca2+ and PKC in activation of mitogen-activated protein (MAP) kinase in human polymorphonuclear neutrophils. 980 88

p38 is a member of the mitogen-activated protein (MAP) kinase family and is a critical enzyme in the proinflammatory cytokine pathway. Other MAP kinase group members that share both structural and functional homology to p38 include the c-Jun NH2-terminal kinases (JNKs or SAPKs) and the extracellular-regulated protein kinases (ERKs). In this study, we determined the molecular basis for p38alpha inhibitor specificity exhibited by five compounds in the diarylimidazole, triarylimidazole, and triarylpyrrole classes of protein kinase inhibitors. These compounds are significantly more potent inhibitors of p38 compared to the JNKs and ERKs. Three active site ATP-binding domain residues in p38, T106, M109, and A157, selected based on primary sequence alignment, molecular modeling, and X-ray crystal structure data, were mutated to assess their role in inhibitor binding and enzymatic catalysis. All mutants, with the exception of T106M, had kinase activity within 3-fold of wild-type p38. Mutation of T106 to glutamine, the residue present at the corresponding position in ERK-2, or methionine, the corresponding residue in p38gamma, p38delta, and the JNKs, rendered all five inhibitors ineffective. The diarylimidazoles had approximately a 6-fold decrease in potency toward M109A p38. For the mutant A157V, all diarylimidazoles and triarylimidazoles tested were 5-10-fold more potent compared with wild-type p38. In contrast, two triarylpyrroles were 15-40-fold less potent versus A157V p38. These results showed that the molecular basis for the specificity of the p38 inhibitors was attributed largely to threonine 106 in p38 and that methionine 109 contributes to increased binding affinity for imidazole based inhibitors.
 ...
PMID:Molecular basis for p38 protein kinase inhibitor specificity. 984 24


1 2 3 4 5 Next >>