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:3.4.11.18 (MAP)
7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signalling from the growth factor receptor subunit and proto-oncogene c-erbB2 has been shown to inhibit the adhesive function of the collagen receptor integrin alpha(2)beta(1) in human mammary epithelial cells. This anti-adhesive effect is mediated by the MAP ERK kinase 1/2 (MEK1/2) and protein kinase B (PKB) pathways. Here, we show that both pathways mediate suppression of matrix adhesion by causing the extracellular domain of the beta(1) integrin subunit to adopt an inactive conformation. The conformational switch was also dependent on rapid and extensive actin depolymerisation. While neither activation nor inhibition of the Rho GTPase affected this rearrangement, Rho was found to be activated by c-erbB2 and to be necessary for conformation-dependent integrin inactivation and, apparently by a different mechanism, a delayed re-formation of stress fibers which did not restore integrin function. Interestingly, the initial actin depolymerisation as well as its effects on integrin function was shown to be mediated by PKB. These results demonstrate how oncogenic growth factor signalling inhibits matrix adhesion by multiple pathways converging on integrin conformation and how Rho signalling can profoundly influence integrin activation in a cytoskeleton-independent manner.
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PMID:PKB mediates c-erbB2-induced epithelial beta1 integrin conformational inactivation through Rho-independent F-actin rearrangements. 1592 45

Phosphatidylcholine-specific phospholipase D (PLD) is a major cellular source of phosphatidic acid and choline, which regulate various physiopathological processes. PLD activation mediated by chemoattractants involves protein phosphorylation. This study provides pharmacological and biochemical evidence of a major role of p44/42 MAP kinases (ERK1/2) in PLD activation induced by the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP). ERK1/2 inhibition by the MEK1/2 antagonist U0126 in neutrophilic HL-60 cells or HEK 293T cells stably expressing fMLP receptors abolished fMLP-mediated PLD activity. Conversely, a constitutively activated MEK1 mutant expressed in HEK 293T cells potentiated fMLP-induced PLD activity. Expression of inactive PLD mutants showed that PLD2, but not PLD1, contributed to fMLP-mediated PLD activity. PLD2 co-immunoprecipitated with ERK1/2 and became phosphorylated on MAP kinase consensus sites in fMLP-stimulated cells. In cell-free systems, ERK2 gave rise to strong ATP-dependent PLD activity and directly phosphorylated PLD2 that generated two phosphopeptides only after tryptic digestion. Finally, pharmacological inhibition of ERK activation and the inhibition of PLD expression by antisense oligonucleotides in HL-60 cells suggest that the ERK/PLD2 pathway contributes to fMLP-mediated oxidant production. In conclusion, the fMLP-mediated PLD activity is regulated by ERK1/2, involving a predominant contribution of PLD2. The ERK/PLD2 coupling may provide potential pharmacological targets to control PLD-associated cellular dysfunctions.
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PMID:A role of p44/42 mitogen-activated protein kinases in formyl-peptide receptor-mediated phospholipase D activity and oxidant production. 1625 58

The link between membrane phospholipids and different intracellular signal transduction pathways affected by cerebral ischaemia is unclear. CDP-choline, a major neuronal membrane lipid precursor and its intracellular target proteins and transcription factors were studied to further understand its role in ischaemic stroke. Cerebral ischaemia was produced by distal, permanent occlusion of the middle cerebral artery (MCAO) in the rat. Animals receiving 500 mg/kg of CDP-choline in 0.5 ml of 0.9% saline, intraperitoneally, 24 h and 1 h before MCAO and 23 h after MCAO demonstrated a notable reduction in the phosphorylation of MAP-kinase family members, ERK1/2 and MEK1/2, as well as Elk-1 transcription factor, compared with control animals treated with 0.5 ml of 0.9% saline. Immunohistochemistry showed a particular reduction in immunoreactivity in glia. The effects of CDP-choline on intracellular mechanisms of signal transduction, suggests that this molecule may play a key role in recovery after ischaemic stroke.
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PMID:Citicoline inhibits MAP kinase signalling pathways after focal cerebral ischaemia. 1625 56

Cancer osaka thyroid (COT) is a member of the mitogen-activated protein kinase kinase kinase family of enzymes and plays a pivotal role in tumor necrosis factor-alpha production in macrophages. Consequently, COT is considered to be a promising target for antiinflammatory drug discovery. We describe here the development of in vitro COT assays in several formats and the advantages and disadvantages of each. A cascade assay requires very small amounts of enzyme and can provide a useful tool for high-throughput screening, but it is not desirable for compound mechanistic studies due to complicated kinetics. Direct assays are superior to cascade assays and are suitable for both compound screening and mechanistic studies. Among the direct assays, the homogeneous time-resolved fluorescence (HTRF) format is preferred over the radiometric format due to the robustness, throughput, and ease of use of the HTRF format. When the physiological protein substrate MEK1 (MAP/Erk kinase 1) was used to determine inhibitor potencies, false positives were observed due to compound interference by binding to MEK1. Using a MEK1 peptide substrate, these false positives were eliminated. In addition, we describe a simple method to study the ATP competitiveness of compounds. The knowledge gained through our studies with COT, and the methods described for our assays and compound mechanistic studies, can be readily applied to other kinase targets.
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PMID:Comparative analysis of various in vitro COT kinase assay formats and their applications in inhibitor identification and characterization. 1635 59

N-(4-hydroxyphenyl)retinamide (4HPR), a synthetic retinoid effective in cancer chemoprevention and therapy, is thought to act via apoptosis induction resulting from increased reactive oxygen species (ROS) generation. As ROS can activate MAP kinases and protein kinase C (PKC), we examined the role of such enzymes in 4HPR-induced apoptosis in HNSCC UMSCC22B cells. 4HPR increased ROS level within 1 h and induced activation of caspase 3 and PARP cleavage within 24 h. Activation of MKK3/6 and MKK4, JNK, p38 and ERK was detected between 6 and 12 h, increased up to 24 h and preceded apoptosis. 4HPR-induced activation of these kinases was abrogated by the antioxidants BHA and vitamin C. SP600125, a JNK inhibitor, suppressed 4HPR-induced c-Jun phosphorylation, cytochrome c release from mitochondria and apoptosis. Suppression of JNK1 and JNK2 using siRNA decreased, whereas overexpression of wild type-JNK1 enhanced 4HPR-induced apoptosis. PD169316, a p38, inhibitor suppressed phosphorylation of Hsp27 and apoptosis. PD98059, an MEK1/2 inhibitor, also suppressed ERK1/2 activation and apoptosis induced by 4HPR. Likewise, PKC inhibitor GF109203X suppressed ERK and p38 phosphorylation and PARP cleavage. These data indicate that 4HPR-induced apoptosis is triggered by ROS increase, leading to the activation of the mitogen-activated protein serine/threonine kinases JNK, p38, PKC and ERK, and subsequent apoptosis.
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PMID:N-(4-hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells. 1640 47

We have examined whether toll-like receptor (TLR)2-mediated stimulation by macrophage-activating lipopeptide-2 (MALP-2), originally purified from Mycoplasma fermentans, induces cyclooxygenase (COX)-2 and prostaglandin (PG)E(2) in human placental trophoblast cells. The signaling mechanism by which MALP-2 exerts its effect has also been examined. Human placental trophoblast cells isolated from term placenta were used. TLR expression in trophoblast cells was confirmed by multiplex PCR and immunocytochemistry, and examined whether MALP-2 induces COX-2 and PGE(2) by Northern blotting, RT-PCR, Western blotting and ELISA, respectively. The activation of NF-kappaB and MAP kinases (ERK1/2 and p38) was examined by Western blotting. The effects of inhibitors of NF-kappaB, MEK1/2 and p38 on MALP-2-induced PGE(2) production were also evaluated. TLR2, TLR6 and TLR4 were expressed in human placental trophoblast cells. MALP-2 significantly induced COX-2 expression and enhanced PGE(2) production in a dose-dependent manner. MALP-2 induced the activation of NF-kappaB, ERK1/2 and p38 MAPK. Inhibitors of NF-kappaB, MEK1/2 and p38 blocked MALP-2-inducible PGE(2) production. TLR2-mediated stimulation by MALP-2 induces COX-2 and PGE(2) in human placental trophoblast cells via NF-kappaB and MAP kinases pathways.
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PMID:Macrophage-activating lipopeptide-2 induces cyclooxygenase-2 and prostaglandin E(2) via toll-like receptor 2 in human placental trophoblast cells. 1660 Mar 83

TNF is implicated in the suppression of neutrophil apoptosis during sepsis. Multiple signaling pathways are involved in TNF-mediated antiapoptotic signaling; a role for the MAP kinases (MAPK), ERK1/2, and p38 MAPK has been suggested. Antiapoptotic signaling is mediated principally through TNF receptor-1 (TNFR-1), and the PKC isotype-delta (delta-PKC) is a critical regulator of TNFR-1 signaling. delta-PKC associates with TNFR-1 in response to TNF and is required for NFkappaB activation and inhibition of caspase 3. The role of delta-PKC in TNF-mediated activation of MAPK is not known. The purpose of this study was to determine whether the MAPK, ERK1/2, and p38 MAPK are involved in TNF antiapoptotic signaling and whether delta-PKC is a key regulator of MAPK activation by TNF. In human neutrophils, TNF activated both p38 MAPK and ERK1/2 principally via TNFR-1. The MEK1/2 inhibitors PD098059 and U0126, but not the p38 MAPK inhibitor SB203580, decreased TNF antiapoptotic signaling as measured by caspase 3 activity. A specific delta-PKC antagonist, V1.1delta-PKC-Tat peptide, inhibited TNF-mediated ERK1/2 activation, but not p38 MAPK. ERK1/2 inhibition did not alter recruitment of delta-PKC to TNFR-1, indicating delta-PKC is acting upstream of ERK1/2. In HL-60 cells differentiated to a neutrophilic phenotype, delta-PKC depletion by delta-PKC siRNA resulted in inhibition of TNF mediated ERK1/2 activation but not p38 MAPK. Thus, ERK1/2, but not p38 MAPK, is an essential component of TNF-mediated antiapoptotic signaling. In human neutrophils, delta-PKC is a positive regulator of ERK1/2 activation via TNFR-1 but has no role in p38 MAPK activation.
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PMID:Regulation of TNF mediated antiapoptotic signaling in human neutrophils: role of delta-PKC and ERK1/2. 1713 60

Sepsis is a systemic response to infection in which toxins, such as bacterial lipopolysaccharide (LPS), stimulate the production of inflammatory mediators like the cytokine tumor necrosis factor alpha (TNF-alpha). Previous studies from our laboratory have revealed that LPS inhibits the intestinal absorption of L-leucine and D-fructose in rabbit when it was intravenously administered, and that TNF-alpha seems to mediate this effect on amino acid absorption. To extend this work, the present study was designed to evaluate the possible effect of TNF-alpha on D-galactose intestinal absorption, identify the intracellular mechanisms involved and establish whether this cytokine mediates possible LPS effects. Our findings indicate that TNF-alpha decreases D-galactose absorption both in rabbit intestinal tissue preparations and brush-border membrane vesicles. Western blot analysis revealed reduced amounts of the Na+/glucose cotransporter (SGLT1) protein in the plasma membrane attributable to the cytokine. On the contrary, TNF-alpha increased SGLT1 mRNA levels. Specific inhibitors of the secondary messengers PKC, PKA, the MAP kinases p38 MAP, JNK, MEK1/2 as well as the proteasome, diminished the TNF-alpha-evoked inhibitory effect. LPS inhibition of the uptake of the sugar was blocked by a TNF-alpha antagonist. In conclusion, TNF-alpha inhibits D-galactose intestinal absorption by decreasing the number of SGLT1 molecules at the enterocyte plasma membrane through a mechanism in which several protein-like kinases are involved.
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PMID:Inhibitory effect of TNF-alpha on the intestinal absorption of galactose. 1717 95

Kinases of mitogen-activated protein kinase (MAPK) cascades, including extracellular signal-regulated protein kinase (ERK), represent likely targets for pharmacological intervention in proliferative diseases. Here, we report that FR148083 inhibits ERK2 enzyme activity and TGFbeta-induced AP-1-dependent luciferase expression with respective IC50 values of 0.08 and 0.05 microM. FR265083 (1'-2' dihydro form) and FR263574 (1'-2' and 7'-8' tetrahydro form) exhibited 5.5-fold less and no activity, respectively, indicating that both the alpha,beta-unsaturated ketone and the conformation of the lactone ring contribute to this inhibitory activity. The X-ray crystal structure of the ERK2/FR148083 complex revealed that the compound binds to the ATP binding site of ERK2, involving a covalent bond to Sgamma of ERK2 Cys166, hydrogen bonds with the backbone NH of Met108, Nzeta of Lys114, backbone C=O of Ser153, Ndelta2 of Asn154, and hydrophobic interactions with the side chains of Ile31, Val39, Ala52, and Leu156. The covalent bond motif in the ERK2/FR148083 complex assures that the inhibitor has high activity for ERK2 and no activity for other MAPKs such as JNK1 and p38MAPKalpha/beta/gamma/delta which have leucine residues at the site corresponding to Cys166 in ERK2. On the other hand, MEK1 and MKK7, kinases of the MAPKK family which also can be inhibited by FR148083, contain a cysteine residue corresponding to Cys166 of ERK2. The covalent binding to the common cysteine residue in the ATP-binding site is therefore likely to play a crucial role in the inhibitory activity for these MAP kinases. These findings on the molecular recognition mechanisms of FR148083 for kinases with Cys166 should provide a novel strategy for the pharmacological intervention of MAPK cascades.
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PMID:Role of a cysteine residue in the active site of ERK and the MAPKK family. 1719 51

The cardiotoxic adverse effects of anthracycline antibiotics limit their therapeutic utility as essential components of chemotherapy regimens for hematologic and solid malignancies. Here we show that the hematopoietic cytokine erythropoietin attenuates doxorubicin-induced apoptosis of primary neonatal rat ventricular cardiomyocytes in a dose-dependent manner. Erythropoietin treatment induced rapid, time-dependent phosphorylation of MAP kinases (MAPK) Erk1/2 and the phosphatidylinositol 3-kinase substrate Akt. Treatment of cardiomyocytes with inhibitors of phosphatidylinositol 3-kinase (LY294002) or Akt (Akti-1/2) abolished the protective effect of erythropoietin, whereas treatment with MAPK kinase (MEK1) inhibitor U0126 did not. Erythropoietin also induced the phosphorylation of GSK-3beta, a downstream target of PI3K-Akt. Because phosphorylation is known to inactivate GSK-3beta, we investigated whether GSK-3beta inhibition is cardioprotective. We found that GSK-3beta inhibitors SB216763 or lithium chloride blocked doxorubicin-induced cardiomyocyte apoptosis in a manner similar to erythropoietin, suggesting that GSK-3beta inhibition is involved in erythropoietin-mediated cardioprotection. Erythropoietin may serve as a novel cardioprotective agent against anthracycline-induced cardiotoxicity.
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PMID:Erythropoietin protects cardiac myocytes against anthracycline-induced apoptosis. 1725 Aug 9


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