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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several kinases have been shown to phosphorylate tau protein at Ser-262, an important site involved in the regulation of the binding of tau to microtubules. In this study we compared the phosphorylation of tau at Ser-262 by CaMKII, PhK and PKA in vitro as determined by radioimmunoblots developed by the monoclonal antibody 12E8 which recognizes P-Ser-262 and P-Ser-356; and Ab-262, a polyclonal antibody which is specific to unphosphorylated Ser-262 in tau. We found that the phosphorylation at Ser-262 was several times more effective by CaMKII than PKA or PhK. Employing rat brain extract as a source of all brain kinases and KN-62, a specific inhibitor of CaMKII, we found that CaMKII accounts for approximately 45% of phosphorylation at Ser-262. Furthermore, in rat brain slices kept metabolically active in oxygenated artificial CSF, phosphorylation of tau at Ser-262 was (i) increased up to 120% in the presence of bradykinin, a CaMKII activator, and (ii) inhibited by approximately 35% in the presence of KN-62. Thus, CaMKII is a major tau Ser-262 kinase in mammalian brain.
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PMID:Ser-262 in human recombinant tau protein is a markedly more favorable site for phosphorylation by CaMKII than PKA or PhK. 980 Nov 71

We examined the role of fibronectin (FN) and FN-binding integrins in macrophage differentiation. Increased FN and alpha5beta1 integrin gene expression was observed in phorbol 12-myristate 13-acetate PMA-treated HL-60 cells and PMA- or macrophage-CSF-treated blood monocytes before the manifestation of macrophage markers. After treatment of HL-60 cells and monocytes, newly synthesized FN was released and deposited on the dishes. An HL-60 cell variant, HL-525, which is deficient in the protein kinase Cbeta (PKC-beta) and resistant to PMA-induced differentiation, failed to express FN after PMA treatment. Transfecting HL-525 cells with a PKC-beta expression plasmid restored PMA-induced FN gene expression and macrophage differentiation. Untreated HL-525 cells (which have a high level of the alpha5beta1 integrin) incubated on FN differentiated into macrophages. The percentage of cells having a macrophage phenotype induced by PMA in HL-60 cells, by FN in HL-525 cells, or by either PMA or macrophage-CSF in monocytes was reduced in the presence of mAbs to FN and alpha5beta1 integrin. The integrin-signaling nonreceptor tyrosine kinase, p72Syk, was activated in PMA-treated HL-60 and FN-treated HL-525 cells. We suggest that macrophage differentiation involves the activation of PKC-beta and expression of extracellular matrix proteins such as FN and the corresponding integrins, alpha5beta1 integrin in particular. The stimulated cells, through the integrins, attach to substrates by binding to the deposited FN. This attachment, in turn, may through integrin signaling activate nonreceptor tyrosine kinases, including p72Syk, and later lead to expression of other genes involved in evoking the macrophage phenotype.
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PMID:Interaction between alpha 5 beta 1 integrin and secreted fibronectin is involved in macrophage differentiation of human HL-60 myeloid leukemia cells. 988 14

Nociceptin/orphanin FQ (NOC/oFQ) is a recently discovered endogenous ligand for the opioid like receptor, ORL-1. In the piglet, cGMP activates the ATP sensitive (K(ATP)) while cAMP activates both the K(ATP) and the calcium sensitive (K(ca)) K(+) channel to elicit vasodilation. The present study was designed to characterize the role of cGMP, cAMP, K(ATP), and K(ca) channel activation in NOC/oFQ-induced pial artery dilation in newborn pigs equipped with a closed cranial window. NOC/oFQ (10(-8), 10(-6) M) induced pial arteriole dilation was decreased by the protein kinase A inhibitor Rp 8-Br cAMPs (16+/-1 and 30+/-1 vs. 5+/-1 and 10+/-1%). NOC/oFQ dilation was associated with elevated CSF cAMP (1037+/-58 vs. 1919+/-209 fmol/ml for control and 10(-6) M NOC/oFQ). Glibenclamide and iberiotoxin, K(ATP) and K(ca) channel antagonists, attenuated NOC/oFQ induced dilation (15+/-1 and 28+/-1 vs. 10+/-1 and 19+/-1% before and after iberiotoxin). In contrast, the nitric oxide synthase inhibitor, L-NNA, and the protein kinase G inhibitor, Rp 8-Br cGMPs had no effect on NOC/oFQ dilation while such dilation was not associated with a change in CSF cGMP. The putative ORL-1 receptor antagonist [F/G] NOC/oFQ (1-13)-NH(2) blocked NOC/oFQ dilation while responses were unchanged after naloxone (17+/-1 and 30+/-2 vs. 3+/-1 and 5+/-1%, before and after [F/G] NOC/oFQ (1-13)-NH(2)). Dilation to other opioids (e.g., methionine enkephalin) was unchanged by [F/G] NOC/oFQ (1-13)-NH(2). These data show that NOC/oFQ elicits pial artery dilation, at least in part, via cAMP, K(ATP), and K(ca) channel dependent mechanisms. These data suggest that such a mechanism involves the sequential release of cAMP and subsequent K(ATP) and K(ca) channel activation.
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PMID:Nociceptin/orphanin FQ dilates pial arteries by K(ATP) and K(ca) channel activation. 1041 88

STAT3 (signal transducer and activator of transcription 3) is a latent transcription factor that is activated by tyrosine phosphorylation (Tyr-705) in cells stimulated with cytokines or growth factors. Recent studies suggest that one or more cytoplasmic serine kinases also phosphorylate STAT3 and are necessary for maximal gene activation. Here we demonstrate, with a site-specific antibody, that STAT3 is phosphorylated on Ser-727 in human neutrophils stimulated with chemotactic factors (N-formyl-methionyl-leucyl-phenylalanine and complement C5a), cytokines [granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF)], or a protein kinase C activator (PMA). (2-Amino-3'-methoxyphenyl)oxanaphthalen-4-one (PD 98059), an inhibitor of extracellular signal-regulated protein kinase (ERK) activation, blocked the serine phosphorylation of STAT3 induced by chemotactic factors or PMA. The drug was less effective on cytokines: it virtually abolished the response to GM-CSF that occurred 5 min after stimulation but only partly decreased those at 15-30 min and did not appreciably alter responses to G-CSF regardless of incubation time. 1-(5-Isoquinolinylsulphonyl)-2-methylpiperazine dihydrochloride (H7), an inhibitor of a putative STAT3 serine kinase, and 4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl) 1H-imidazole (SB 203580), an inhibitor of p38 mitogen-activated protein (MAP) kinase, did not dampen any of these serine phosphorylation responses. We propose that neutrophils use both ERK-dependent and ERK-independent pathways to phosphorylate Ser-727 on STAT3. The former pathway is recruited by all ERK-activating stimuli, whereas the latter pathway uses an undefined serine kinase and is recruited selectively by cytokines.
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PMID:Extracellular signal-regulated protein kinase (ERK)-dependent and ERK-independent pathways target STAT3 on serine-727 in human neutrophils stimulated by chemotactic factors and cytokines. 1041 33

Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated neuronal apoptosis was confirmed in pure populations of rat cerebellar granule neurons and was blocked by HA1004, an inhibitor of calcium/calmodulin-dependent protein kinase II, protein kinase A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduction and apoptosis. This process occurs, in part, through CXCR4 and is independent of CD4 binding. T-tropic viruses that traffic in and out of the brain during progressive HIV-1 disease may play an important role in HAD neuropathogenesis.
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PMID:Lymphotropic virions affect chemokine receptor-mediated neural signaling and apoptosis: implications for human immunodeficiency virus type 1-associated dementia. 1048 76

In Alzheimer disease brain the activities of protein phosphatase (PP)-2A and PP-1 are decreased and the microtubule-associated protein tau is abnormally hyperphosphorylated at several sites at serine/threonine. Employing rat forebrain slices kept metabolically active in oxygenated artificial CSF as a model system, we investigated the role of PP-2A/PP-1 in the regulation of some of the major abnormally hyperphosphorylated sites of tau and the protein kinases involved. Treatment of the brain slices with 1.0 microM okadaic acid inhibited approximately 65% of PP-2A and produced hyperphosphorylation of tau at Ser 198/199/202, Ser 396/404 and Ser 422. No significant changes in the activities of glycogen synthase kinase-3 (GSK-3) and cyclin dependent protein kinases cdk5 and cdc2 were observed. Calyculin A (0.1 microM) inhibited approximately 50% PP-1, approximately 20% PP-2A, 50% GSK-3 and approximately 30% cdk5 but neither inhibited the activity of cyclin AMP dependent protein kinase A (PKA) nor resulted in the hyperphosphorylation of tau at any of the above sites. Treatment of brain slices with 1 microM okadaic acid plus 0.1 microM calyculin A inhibited approximately 100% of both PP-2A and PP-1, approximately 80% of GSK-3, approximately 50% of cdk5 and approximately 30% of cdc2 but neither inhibited PKA nor resulted in the hyperphosphorylation of tau at any of the above sites. These studies suggest (i) that PP-1 upregulates the phosphorylation of tau at Ser 198/199/202 and Ser 396/404 indirectly by regulating the activities of GSK-3, cdk5 and cdc2 whereas PP-2A regulates the phosphorylation of tau directly by dephosphorylation at the above sites, and (ii) that a decrease in the PP-2A activity leads to abnormal hyperphosphorylation of tau at Ser 198/199/202, Ser 396/404 and Ser 422.
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PMID:Role of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain. 1108 71

Modification of low-density lipoprotein (LDL), for example by oxidation, could be involved in foam cell formation and proliferation observed in atherosclerotic lesions. Macrophage colony-stimulating factor (CSF-1 or M-CSF) has been implicated in foam cell development. It has been reported previously that oxidized LDL (ox.LDL) and CSF-1 synergistically stimulate DNA synthesis in murine bone-marrow-derived macrophages (BMM). The critical signal-transduction cascades responsible for the proliferative response to ox.LDL, as well as their relationship to those mediating CSF-1 action, are unknown. We report here that ox.LDL stimulated extracellular signal-regulated protein kinase (ERK)-1, ERK-2 and phosphoinositide 3-kinase activities in BMM but to a weaker extent than optimal CSF-1 concentrations at the time points examined. Inhibitor studies suggested at least a partial role for these kinases, as well as p70 S6-kinase, in ox.LDL-induced macrophage survival and DNA synthesis. For the DNA synthesis response to CSF-1, the degree of inhibition by PD98059, wortmannin and rapamycin was significant at low CSF-1 concentrations but was reduced as the CSF-1 dose increased. Using BMM from CSF-1-deficient mice (op/op) and a neutralizing antibody approach, we found no evidence for an essential role for endogenous CSF-1 in ox.LDL-mediated survival or DNA synthesis; likewise, with the same approaches, no evidence was obtained for an essential role for endogenous granulocyte/macrophage-CSF in ox.LDL-mediated macrophage survival and, in contrast with the literature, ox.LDL-induced macrophage DNA synthesis.
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PMID:Comparison of macrophage responses to oxidized low-density lipoprotein and macrophage colony-stimulating factor (M-CSF or CSF-1). 1117 Oct 93

A cytoplasmic activity in mature oocytes responsible for second meiotic metaphase arrest was identified over 30 years ago in amphibian oocytes. In Xenopus oocytes CSF activity is initiated by the progesterone-dependent synthesis of Mos, a MAPK kinase kinase, which activates the MAPK pathway. CSF arrest is mediated by a sole MAPK target, the protein kinase p90Rsk which leads to inhibition of cyclin B degradation by the anaphase-promoting complex. Rsk phosphorylates and activates the Bub1 protein kinase, which may cause metaphase arrest due to inhibition of the anaphase-promoting complex (APC) by a conserved mechanism defined genetically in yeast and mammalian cells. CSF arrest in vertebrate oocytes by p90Rsk provides a potential link between the MAPK pathway and the spindle assembly checkpoint in the cell cycle.
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PMID:The pathway of MAP kinase mediation of CSF arrest in Xenopus oocytes. 1173 Mar 19

Phosphoinositide 3-kinase (PI3-kinase)-dependent phosphorylation of the proapoptotic Bcl-2 family member Bad has been proposed as an important regulator of apoptotic cell death. To understand the importance of this pathway in nontransformed hematopoietic cells, we have examined the effect of survival cytokines on PI3-kinase activity and Bad expression and phosphorylation status in human neutrophils. Granulocyte macrophage-colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) both reduced the rate of apoptosis in neutrophils cultured in vitro for 20 hours. Coincubation with the PI3-kinase inhibitor LY294002, which in parallel experiments abolished GM-CSF-primed, fMLP-stimulated superoxide anion production and GM-CSF-stimulated PtdIns(3,4,5)P(3) accumulation, inhibited the GM-CSF and TNF-alpha survival effect. In contrast, the MAP kinase kinase (MEK1/2) inhibitor PD98059 and the protein kinase A inhibitor H-89 had only a marginal effect on GM-CSF-mediated neutrophil survival. GM-CSF substantially increased Bad phosphorylation at Ser112 and Ser136 and increased the cytosolic accumulation of Bad. GM-CSF also regulated Bad at a transcription level with a marked decrease in mRNA levels at 4 hours. TNF-alpha caused a biphasic effect on the rate of morphologic apoptosis, which corresponded to an early increase, and a late inhibition, of Bad mRNA levels. LY294002 inhibited GM-CSF- and TNF-alpha-mediated changes in Bad phosphorylation and mRNA levels. These data suggest that the survival effect of GM-CSF and TNF-alpha in neutrophils is caused by a PI3-kinase-dependent phosphorylation and cytosolic translocation of Bad, together with an inhibition of Bad mRNA levels. This has important implications for the regulation of neutrophil apoptosis in vivo.
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PMID:Role of PI3-kinase-dependent Bad phosphorylation and altered transcription in cytokine-mediated neutrophil survival. 1223 75

The multipotent cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) is involved in particular in the physiological response to infection and in inflammatory responses. GM-CSF is produced by many cell types, including T lymphocytes responding to T-cell receptor activation and mantle zone B lymphocytes. B-cell receptor and T-cell receptor activation generates two major signals: an increase in intracellular Ca(2+) concentration and a protein kinase cascade. Previous studies have shown that the Ca(2+)/calmodulin-dependent phosphatase calcineurin mediates stimulation of GM-CSF transcription in response to Ca(2+). In this study, we show that Ca(2+) signaling also regulates GM-CSF transcription negatively through Ca(2+)/calmodulin-dependent kinase II (CaMK II) phosphorylation of serines in the autoinhibitory domain for DNA binding of the transcription factor Ets1. Wild-type Ets1 negatively affects GM-CSF transcription on Ca(2+) stimulation in the presence of cyclosporin A, which inhibits calcineurin. Conversely, Ets1 with mutated CaMK II target serines showed an increase in transactivation of the GM-CSF promoter/enhancer. Moreover, constitutively active CaMK II inhibited transactivation of GM-CSF by wild-type Ets1 but not by Ets1 with mutated CaMK II sites. Mutation of CaMK II target serines in Ets1 also relieves inhibition of cooperative transactivation of GM-CSF with the Runx1/AML1 transcription factor. In addition, the Ca(2+)-dependent phosphorylation of Ets1 reduces the binding of Ets1 to the GM-CSF promoter in vivo.
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PMID:Calcium regulation of GM-CSF by calmodulin-dependent kinase II phosphorylation of Ets1. 1247 68


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