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)

MAP KAP kinase 2 (MK2), a Ser/Thr kinase, plays a crucial role in the inflammatory process. We have determined the crystal structures of a catalytically active C-terminal deletion form of human MK2, residues 41-364, in complex with staurosporine at 2.7 A and with ADP at 3.2 A, revealing overall structural similarity with other Ser/Thr kinases. Kinetic analysis reveals that the K(m) for ATP is very similar for MK2 41-364 and p38-activated MK2 41-400. Conversely, the catalytic rate and binding for peptide substrate are dramatically reduced in MK2 41-364. However, phosphorylation of MK2 41-364 by p38 restores the V(max) and K(m) for peptide substrate to values comparable to those seen in p38-activated MK2 41-400, suggesting a mechanism for regulation of enzyme activity.
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PMID:Catalytically active MAP KAP kinase 2 structures in complex with staurosporine and ADP reveal differences with the autoinhibited enzyme. 1279 Dec 49

We report the cloning of the NKIAMRE gene located on human chromosome 5q31.1. It encodes a novel 52kDa Cdc2-related kinase with a 1.5kb open reading frame. Like MAP kinases, NKIAMRE contains a Thr-X-Tyr (TXY) motif in the activation loop domain. Similar to cdks, NKIAMRE contains the putative negative regulatory Ser14 and Tyr15 residues and the cyclin-binding motif, NKIAMRE, from which it derives its name. Human NKIAMRE has significant amino acid identity to related kinases in rat, mouse, Caenorhabditis elegans, and Drosophila, and is widely expressed in human tissues and cell lines. Confocal microscopy demonstrates that NKIAMRE localizes to the cytoplasm. NKIAMRE is activated by treatment of cells with phorbol 12-myristate 13-acetate. Mutation of the ATP-binding Lys-33 to arginine and the Thr-Glu-Tyr motif to Ala-Glu-Phe abolished its ability to phosphorylate myelin basic protein. NKIAMRE is a member of a conserved family of kinases with homology to both MAP kinases and cyclin-dependent kinases.
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PMID:NKIAMRE, a novel conserved CDC2-related kinase with features of both mitogen-activated protein kinases and cyclin-dependent kinases. 1292 87

In cardiac myocytes of new-born rats, the degree of intercellular communication through gap junctional channels closely depends on the metabolic state of the cells. In contrast, in stably transfected HeLa cells expressing rat cardiac connexin43 (Cx43, the main channel-forming protein present in ventricular myocytes), a major part of junctional communication persisted in ATP-depleted conditions, in the presence of a metabolic inhibitor (KCN) or of a broad spectrum inhibitor of protein kinases (H7). However, another metabolic inhibitor, antimycin A, which like cyanide inhibits electron transfer in the respiratory chain, totally interrupted cell-to-cell communication between Cx43-HeLa cells, even in whole-cell conditions, when ATP (5 mM) was present. Antimycin A caused a modest increase in cytosolic calcium concentration; however, junctional uncoupling still occurred when this rise was prevented. Conditions of ischemic insult (e.g. ischemia or chemical hypoxia) frequently cause the activation of protein kinases, particularly of Src and MAP kinases, and such activations are known to markedly disrupt gap junctional communication. Antimycin-induced junctional uncoupling occurred even in the presence of inhibitors of these kinases. Antimycin A appears able to cause junctional uncoupling either through the ATP depletion it induces as a metabolic poison or via a direct action on gap junction constituents.
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PMID:The metabolic inhibitor antimycin A can disrupt cell-to-cell communication by an ATP- and Ca(2+)-independent mechanism. 1450 27

Hippocampal cholinergic neurostimulating peptide precursor protein (HCNP-pp) is a unique multifunctional protein, being not only the precursor of HCNP, which promotes the phenotype development of septo-hippocampal cholinergic neurons, but also the binding protein of phosphatidylethanolamine, ATP, Raf-1 kinase (known as "Raf-1 kinase inhibitory factor" in peripheral organs), and serine protease. We obtained a high-titer retroviral vector harboring HCNP-pp cDNA by the use of a modified packaging cell line and centrifugation, and by injecting it into embryonic mouse ventricles, we investigated the function of its gene product within the central nervous system (CNS). We found that efficient transduction into hippocampal pyramidal neurons can be achieved by injecting the vector into embryonic brain ventricles on embryonic day 14 (E14). Three days after receiving the intraventricular injection of the high-titer HCNP-pp retrovirus vector on E14, the tissues around the ventricles showed an overexpression of HCNP-pp. This was accompanied by a reduced amount of activated MEK and Erk (as analyzed by histochemical and Western blot methods), suggesting that HCNP-pp also regulates the MAP-kinase cascade within the CNS. Surprisingly, mouse brains that received the HCNP-pp retroviral vector showed massive malformation of the hippocampus and cerebellum when examined 30 days after birth. This shows that strictly regulated HCNP-pp gene expression is necessary for the normal development of the mouse brain, and that the moderate overexpression achieved by retroviral vector-mediated gene transfer is sufficient to cause severe abnormality of entire brain structures.
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PMID:Brain malformations caused by retroviral vector-mediated gene transfer of hippocampal cholinergic neurostimulating peptide precursor protein into the CNS via embryonic mice ventricles. 1461 62

Neurologic complications after severe brain injuries are the result of primary injuries in the moment of impact and secondary injuries which evolve over the minutes and days later. According to statistics, secondary injuries were documented in about 90 percent of patients who died after traumatic brain injury. Low oxygen delivery in hypotension, hypoxia, oedema, intracranial hypertension or changes in cerebral blood flow all account for development of secondary injuries. Primary injuries are more or less complete, but secondary injuries could be prevented with adequate therapy. Understanding mechanisms of secondary injuries could help identify potentially beneficial therapies. Important elements of therapy are: head position, normoglycemia, osmotherapy, normal body temperature, optimal blood pressure, adequate oxygenation, barbiturate therapy. Neutral head and neck position is recommended to prevent intracranial hypertension. Hyperglycemia with less ATP leads to ishaemic acidosis, hypoglycemia enhances decomposition of phospholipids and release of fat acids, what makes the cellular damage worse. Normocapnia is recommended and adequate oxygenation (PaO2 higher than 90%). To prevent dehydration and electrolyte imbalance, serum electrolytes should be examined every 4-6 h as well as osmolarity. Moderate therapeutic hypothermia could be of benefit, and maintaining of optimal blood pressure (MAP above 90 mmHg), especially in the first period after injury. As these have a lot of adverse effects, barbiturates are recommended only when conventional therapies show no effect. Patients should be hydrated well before induction of barbiturates. In organized trauma centers and with adequate intensive care the mortality from traumatic brain injury decreased from 50% in 1970, to about 30% now days.
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PMID:[Prevention of secondary brain injuries]. 1501 66

BMS-191095, reportedly a selective mitoK(ATP) channel opener which is free from the known side effects of the prototype mitoK(ATP) channel opener diazoxide, induced acute and delayed preconditioning against glutamate excitotoxicity and delayed preconditioning against oxygen-glucose deprivation in primary cultures of rat cortical neurons. BMS-191095 dose dependently depolarized the mitochondria, increased the phosphorylation of PKC isoforms, but had no detectable effects on the activation of MAP kinases and did not influence the expressions of HSP70 and Mn-SOD. In BMS-191095-preconditioned neurons the glutamate-induced free-radical production was abolished. Our data give the first evidence that selective opening of mitoK(ATP) channels with BMS-191095 leads to remarkable neuroprotection via mechanisms that involve mitochondrial depolarization, PKC activation and attenuated free radical production during neuronal stress.
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PMID:The mitochondrial K(ATP) channel opener BMS-191095 induces neuronal preconditioning. 1507 66

The hematopoietic class III receptor tyrosine kinase (RTK) Flt3 (Flk2, STK1) has recently received much attention as a potential drug target. Activation of Flt3 by different types of mutations plays an important role for proliferation, resistance to apoptosis, and prevention of differentiation of leukemic blasts in acute myeloid leukemia (AML). At least one type of such mutations - an internal tandem duplication in the Flt3 juxtamembrane domain (Flt3-ITD) - has been associated with an unfavorable prognosis. Signal transduction of Flt3 involves activation of several conserved pathways, including the RAS/MAP-Kinase and the phosphoinositide-3-kinase/Akt signaling cascades. Transforming versions of Flt3 exhibit altered signaling, for example a very pronounced activation of STAT5, ultimately resulting in alternate profiles of gene expression and cell transformation. Selective inhibitors of Flt3 tyrosine kinase activity have the potential to suppress aberrant Flt3 signaling. Although highly homologous to other class III RTKs, Flt3 is resistant to the phenylaminopyrimidine STI571 (Gleevec, Imatinib), a potent inhibitor of other RTKs in the family, such as the PDGFbeta-receptor or c-Kit. STI571 binding to Flt3 is prevented by the phenylalanine 691 side-chain in the ATP binding center and mutating this site to threonine renders the corresponding Flt3 mutant sensitive to STI571. Compounds of several other structural families, including the quinoxaline AG1296, the bis(1H-2-indolyl)-1-methanone D-65476, the indolinones SU5416 and SU11248, the indolocarbazoles PKC412 and CEP-701, and the piperazonyl quinazoline CT53518, are potent inhibitors of Flt3 kinase. They exhibit different selectivity profiles, both with respect to other kinases and among wildtype Flt3 and its activated versions. These compounds hold promise as novel drugs against AML and as probes for understanding activation mechanisms and signaling pathways in the class III RTK family.
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PMID:Flt3 receptor tyrosine kinase as a drug target in leukemia. 1518 May 25

This study was designed as a prospective laboratory experiment to evaluate the effects of the ATP-sensitive potassium-channel inhibitor glibenclamide on hemodynamics and end-organ function in an ovine model of hemorrhagic shock. Twenty-four adult sheep were anesthetized and surgically prepared to measure hemodynamics of the systemic and pulmonary circulation. The anterior surface of the abdominal aorta was exposed at a location 6 cm superior to the iliac bifurcation. After a 60-min period of stabilization, this location was punctured with a 14-G needle. To induce a hemorrhagic hypotension (mean arterial pressure [MAP] less than 50 mmHg) via bleeding, the needle was left in place for 15 s to insure good blood flow. Thereafter, it was removed, and the abdomen closed. The animals were then randomized to receive either glibenclamide (4 mg/kg over 15 min) or an equal volume of the vehicle, started 1 h postinjury. Hemodynamic variables were measured every 30 min. Compared with the control group, MAP and systemic vascular resistance index (SVRI) were significantly higher in the intervention group throughout the entire 6-h study period. Ileal pH and urine output were higher in treated than in control animals (4 h, ileal pH 7.29 +/- 0.31 vs. 7.17 +/- 0.6; 6 h, urine output 36 +/- 9 vs. 7.5 +/- 2 mL; P value less than 0.05 each). Because glibenclamide improved both hemodynamics and organ function, it may be a beneficial component in the acute treatment of hemorrhagic shock.
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PMID:The ATP-sensitive potassium-channel inhibitor glibenclamide improves outcome in an ovine model of hemorrhagic shock. 1537 97

Stimulation of the P2X7 receptor by ATP induces cell membrane depolarization, increase in intracellular Ca2+ concentration, and, in most cases, permeabilization of the cell membrane to molecules up to 900 Da. After the activation of P2X7, at least two phenomena occur: the opening of low-conductance (8 pS) cationic channels and pore formation. At least two conflicting hypotheses have been postulated to reconcile these findings: 1) the P2X7 pore is formed as a result of gradual permeability increase (dilation) of cationic channels, and 2) the P2X7 pore represents a distinct channel, possibly activated by a second messenger and not directly by extracellular nucleotides. In this study, we investigated whether second messengers are necessary to open the pore associated with the P2X7 receptor in cells that expressed the pore activity by using the patch-clamp technique in whole cell and cell-attached configurations in conjunction with fluorescent imaging. In peritoneal macrophages and 2BH4 cells, we detected permeabilization and single-channel currents in the cell-attached configuration when ATP was applied outside the membrane patch in a condition in which oxidized ATP and Lucifer yellow were maintained within the pipette. Our data support Ca2+ as a second messenger associated with pore formation because the permeabilization depended on the presence of intracellular Ca2+ and was blocked by BAPTA-AM. In addition, MAPK inhibitors (SB-203580 and PD-98059) blocked the permeabilization and single-channel currents in these cells. Together our data indicate that the P2X7 pore depends on second messengers such as Ca2+ and MAP kinases.
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PMID:Are second messengers crucial for opening the pore associated with P2X7 receptor? 1564 49

The purpose of the study was to examine the stability of variables associated with the metabolic syndrome from adolescence to adulthood. The sample included 48 subjects from the Aerobics Center Longitudinal Study who had one clinical visit during adolescence (mean age = 15.8 years) and a follow-up visit during adulthood (mean age = 26.6 years). The following variables were considered: treadmill time to exhaustion (TM), body mass index (BMI), waist circumference (WC), percent body fat (%BF), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), TC:HDL-C, triglycerides (TG), glucose (GLU), and systolic (SBP), diastolic (DBP), and mean (MAP) blood pressure. A composite risk factor score using variables consistent with the WHO and ATP III definition of the metabolic syndrome (WC, HDL-C, TG, MAP, and GLU) was calculated. Tracking coefficients were computed as partial correlations, controlling for length of follow-up (mean = 11 years). Tracking coefficients (r values) were moderate for all variables (TM, 0.53; BMI, 0.64; WC; 0.79;%BF, 0.44; TC, 0.62; HDL-C, 0.60; TG, 0.54; TC:HDL-C, 0.78; SBP, 0.45; and MAP, 0.41), except GLU (0.26) and DBP (0.21). The composite risk factor score also tracked moderately well (0.56) from adolescence into adulthood. The results support previous findings that variables associated with the metabolic syndrome track moderately well from adolescence to adulthood. The findings support the prevention and treatment of obesity, atherosclerosis, type 2 diabetes, and the metabolic syndrome during childhood and adolescence.
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PMID:Stability of variables associated with the metabolic syndrome from adolescence to adulthood: the Aerobics Center Longitudinal Study. 1549 27


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