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)

CRE-BP1 is a transcriptional activator binding to the cyclic AMP response element, which has a putative metal finger structure and the leucine zipper motif linked to a cluster of basic amino acids in the amino and carboxyl-terminal regions, respectively. The activities of a number of transcription factors are known to be controlled through phosphorylation and dephosphorylation. At the first step for understanding of the regulation of CRE-BP1, phosphorylation of CRE-BP1 was studied in vitro. The human recombinant CRE-BP1 was phosphorylated by protein kinase C and cyclic AMP-dependent protein kinase. These two protein kinases recognized distinct seryl residues of CRE-BP1. Amino acid sequence analysis after phosphopeptide map indicated that two seryl residues, Ser-340 and Ser-367, located in the basic region of CRE-BP1 were identified as the major protein kinase C phosphorylation sites, whereas Ser-62 downstream of the metal finger structure was determined as the phosphorylation site by cyclic AMP-dependent protein kinase. The phosphorylation of CRE-BP1 by these two protein kinases may regulate the function of this transcriptional activator protein.
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PMID:Phosphorylation of CRE-BP1, a cyclic AMP response element binding protein, by protein kinase C and cyclic AMP-dependent protein kinase. 145 87

The ATF/CRE binding site can mediate transcriptional activation by cAMP, the adenovirus E1A protein and the human T-cell leukaemia virus 1 (HTLV1) tax protein. A large number of different proteins bind specifically to this element either as homodimers or as heterodimers. Using GAL4-ATF/CREB fusions, we have investigated the regulatory functions of three members of this family. CREB1 (CREB) is strongly activated by cAMP and weakly activated by the E1A protein. In contrast, CREB2 (CRE-BP1, ATF2) is strongly activated by E1A but is insensitive to cAMP stimulation. ATF1 is weakly activated by cAMP but is not activated by E1A. All three proteins are insensitive to activation by the HTLV1 tax protein. The N-terminal region of CREB2, from amino acid residues 19 to 112, is both necessary and sufficient for E1A activation. This region contains a putative C2H2 metal-binding finger, and single amino acid substitutions of the cysteine residues severely decreased CREB2 activity. In contrast, mutations affecting a potential protein kinase A and casein kinase II phosphorylation site within this region had little effect.
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PMID:Differential regulation of three members of the ATF/CREB family of DNA-binding proteins. 165 8

The human recombinant CRE-BP1 was phosphorylated by cAMP-dependent protein kinase and protein kinase C, in vitro. These two protein kinases modified distinct serine residues of CRE-BP1. Ser-62 downstream of a putative metal finger structure of CRE-BP1 was the phosphorylation site by cAMP-dependent protein kinase, whereas two serine residues, Ser-340 and Ser-367, located in the basic region of this protein were the major protein kinase C phosphorylation sites. It seems possible that transcriptional and DNA-binding activities of CRE-BP1 are regulated by phosphorylation with these protein kinases.
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PMID:Phosphorylation of cAMP response element-binding protein, CRE-BP1, by cAMP-dependent protein kinase and protein kinase C. 166 85

The tumor necrosis factor alpha (TNF-alpha) promoter contains an AP-1/CRE-like binding site, TGAGCTCA. AP-1 elements generally transduce signals involving protein kinase C; the CRE site mediates a cAMP response, involving protein kinase A. Thus, this element has the potential to receive signals through divergent signaling pathways. Nuclear protein binding studies using extracts from THP-1 monocytic cells treated with lipopolysaccharide (LPS), which stimulates, or dexamethasone (Dex) or pentoxifylline (PTX), which inhibit TNF production, respectively, suggest that two low-mobility complexes could be involved in regulation through this promoter region. PTX and Dex increase binding of both these complexes compared with untreated cells; approximately 2 hours after LPS induction, the upper complex becomes undetectable. This upper complex is composed of ATF2 (activating transcription factor 2, a cyclic AMP responsive element binding protein) homodimers; the lower is a heterodimer of jun/ATF2. LPS induces c-jun and thus may enhance formation of jun/ATF2 complexes, which could be activating complexes. In this case, the simultaneous presence of both complexes, which would occur in the presence of Dex or PTX, could reduce the amount of TNF transcription through competitive binding. Through in vitro competitive binding studies comparing the binding affinities of the TNF promoter sequence and a consensus CRE, we further suggest how variation of endogenous binding sequences from consensus may be an important property for regulatory control of particular genes.
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PMID:Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF-alpha gene. 802 67

The Schizosaccharomyces pombe pcr1 gene encodes a bZIP protein that apparently belongs to the cyclic AMP response element (CRE)-binding protein/activating transcription factor family. The deduced pcr1 gene product consists of 171 amino acid residues and is most similar to the mammalian CRE-BP1. A glutathione S-transferase-Pcr1 fusion protein produced in Escherichia coli was able to bind specifically to the CRE motif in vitro. Analysis with anti-Pcr1 serum suggested that Pcr1 is included in the major CRE-binding factors present in the S. pombe cell extract. Disruption of the pcr1 gene was not lethal, but the disruptant showed cold-sensitive growth on rich medium. The disruptant was also inefficient in mating and sporulation, though it was not completely sterile. Expression of the ste11 gene, which encodes a key transcription factor for sexual development, was greatly reduced in the disruptant, and overexpression of ste11+ suppressed the deficiency of the pcr1 disruptant in sexual development. It has been shown that expression of ste11 is negatively regulated by cyclic AMP-dependent protein kinase (PKA) and that the loss of PKA activity results in ectopic sexual development. Disruption of pcr1 blocked ectopic sexual development. Furthermore, disruption of pcr1 reduced expression of fbp1, a glucose-repressible gene negatively regulated by PKA. These results suggest that Pcr1 is a putative transcriptional regulator whose activity may be controlled by PKA. Alternatively, its activity may be independent of PKA, and full induction of ste11 and fbp1 expression requires the function of Pcr1 in addition to elimination of the repression by PKA.
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PMID:Schizosaccharomyces pombe pcr1+ encodes a CREB/ATF protein involved in regulation of gene expression for sexual development. 855 99

The presence of a novel 38 kDa protein that is tyrosine phosphorylated in human neutrophils, a terminally differentiated cell, upon stimulation of these cells with low concentrations of lipopolysaccharide (LPS) in combination with serum has been demonstrated. This 38 kDa protein was identified as the mammalian homologue of HOG1 in yeast, the p38 mitogen-activated protein (MAP) kinase. This conclusion is based on the experimental findings that anti-phosphotyrosine (anti-PY) antibody immunoprecipitates a 38 kDa protein that is recognized by anti-p38 MAP kinase antibody, and conversely, anti-p38 MAP kinase antibody immunoprecipitates a 38 kDa protein that can be recognized by anti-PY antibody. Moreover, this tyrosine phosphorylated protein is found associated entirely with the cytosol. It was also found that this p38 MAP kinase is activated following stimulation of these cells with low concentrations of LPS in combination with serum. This conclusion is based on three experimental findings. First, soluble fractions isolated from LPS-stimulated cells phosphorylate heat shock protein 27 (hsp27) in an in vitro assay, and this effect is not inhibited by protein kinase C and protein kinase A inhibitor peptides. This effect is similar to the effect produced by the commercially available phosphorylated and activated MAPKAP kinase-2 (MAP kinase activated protein kinase-2). Secondly, a 27 kDa protein that aligns with a protein recognized by anti-hsp27 antibody is phosphorylated upon LPS stimulation of intact human neutrophils prelabelled with radioactive phosphate. Lastly, immune complex protein kinase assays, using [gamma-32P]ATP and activating transcription factor 2 (ATF2) as substrates, showed increased p38 MAP kinase activity from LPS-stimulated human neutrophils. The phosphorylation and activation of this p38 MAP kinase can be affected by both G-protein-coupled receptors such as platelet-activating factor (PAF) and non-G-protein-coupled receptors such as the cytokine-coupled receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor alpha (TNF-alpha). The effect of low concentrations of PAF is greatly increased in cells pretreated with LPS. The tyrosine phosphorylation of the p38 MAP kinase is not restricted to stimuli that mediate their actions through membrane-associated receptors, but it can be affected by agents that bypass membrane-associated receptors such as the protein translation blocker anisomycin. While anisomycin is known to increase the tyrosine phosphorylation of the 54 kDa SAPK (stress-activated protein kinase), this is the first report that shows that anisomycin also tyrosine phosphorylates the p38 MAP kinase. Cytokine receptors that increase the tyrosine phosphorylation and activation of the erk1 and erk2 MAP kinases have less effect on this p38 MAP kinase than those that do not affect the erk1 and erk2 MAP kinases. The possible role of the p38 MAP kinase in the phosphorylation of cytosolic phospholipase A2 is discussed.
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PMID:Tyrosine phosphorylation and activation of a new mitogen-activated protein (MAP)-kinase cascade in human neutrophils stimulated with various agonists. 876 79

The stress-activated Wis1-Spc1 protein kinase cascade links mitotic control with environmental signals in Schizosaccharomyces pombe. Fission yeast spc1- mutants are delayed in G2 during normal growth and undergo G2 arrest when exposed to osmotic or oxidative stress. Here we report that Spc1 also has an important role in regulating sexual development in S. pombe. This discovery arose from the observation that Spc1 is activated in response to nitrogen limitation, a key signal that promotes conjugation in fission yeast. Mutant spc1- cells are defective at arresting in G2 during nitrogen starvation and exhibit a poor mating ability. These deficiencies correlate with a failure to induce transcription of ste11+, a gene that encodes a transcription factor responsible for expression of various meiotic genes. Two genes, atf1+ and atf21+, were cloned as multicopy suppressors of the spc1- mating defect. Atf1 and Atf21 are bZIP transcription factors that are most closely related to human ATF-2/CRE-BP1. Spc1 is required for stress-induced phosphorylation of Atf1. Atf1 is required for induction of meiotic genes and stress-response genes, such as gpd1+ and pyp2+, that are transcriptionally regulated by Spc1. atf1- and spc1- mutants are sensitive to osmotic stress and impaired for sexual development, showing that fission yeast uses a common pathway to respond to cytotoxic stress and nitrogen starvation. However, unlike spc1- mutants, atf1- cells have no mitotic cell-cycle defect, indicating that the stress response pathway bifurcates at Spc1 to regulate independently meiosis and mitosis.
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PMID:Conjugation, meiosis, and the osmotic stress response are regulated by Spc1 kinase through Atf1 transcription factor in fission yeast. 882 87

p38 has been shown to be a critical enzyme in the pro-inflammatory cytokine pathway and is a member of the mitogen-activated protein (MAP) kinase family. While the details for p38 activation and subsequent signal transduction have begun to be elucidated, little is known about the kinetic mechanism for p38. In this study, we have determined the kinetic mechanism for p38 MAP kinase. Data from initial velocity patterns in the presence and absence of a dead-end inhibitor and two triarylimidazole p38 inhibitors were consistent with an ordered sequential mechanism for p38 with protein substrate, glutathione S-transferase-activating transcription factor 2 (GST-ATF2), binding before ATP. The ATP analog, adenylyl methylenediphosphonate (AMP-PCP), and two triarylimidazoles were competitive inhibitors versus ATP and uncompetitive inhibitors versus GST-ATF2. Equilibrium binding studies utilizing a tritiated ATP-competitive inhibitor were also consistent with this mechanism and suggest an inability of ATP to bind to p38 in the absence of protein substrate. Moreover, the Michaelis constant for GST-ATF2 was 12-fold greater than the dissociation constant, indicating that the binding of ATP affected the binding of GST-ATF2. An ordered sequential mechanism with protein substrate binding first is unique to p38 compared to cyclic AMP-dependent protein kinase (cAPK) and most tyrosine kinases and helps to explain the interaction between enzyme, substrates, and inhibitors.
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PMID:Kinetic mechanism for p38 MAP kinase. 926 22

Rapid activation of intracellular signaling cascades is induced in cardiac myocytes in response to various external stresses. Vascular endothelial growth factor (VEGF) is a potent angiogenic mitogen secreted from tumor cells and cells exposed to hypoxia such as ischemic myocardial cells. To clarify the mechanisms of how cardiac myocytes respond and adapt to ischemic stresses, we investigated the intracellular signaling cascades in cultured rat cardiac myocytes in response to VEGF. We show that rapid activation of mitogen-activated protein kinase kinase kinase (MAPKKK) of Raf-1, MAP kinases, and S6 kinase (p90rsk) was induced in cardiac myocytes in response to VEGF. This activation of MAP kinases was also induced in fibroblasts. VEGF also caused phosphorylation of the activating transcription factor 2. Furthermore, VEGF strongly induced a transcription factor jun-B mRNA in cardiac myocytes. These results indicated that MAP kinase pathway is rapidly activated in cardiac myocytes and fibroblasts in response to VEGF. It is strongly suggested that cardiac myocytes are one of the targets of VEGF and that cardiac response to ischemic stresses may be at least partly mediated by VEGF.
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PMID:Vascular endothelial growth factor (VEGF) activates Raf-1, mitogen-activated protein (MAP) kinases, and S6 kinase (p90rsk) in cultured rat cardiac myocytes. 957 68

Elevated concentrations of cyclic AMP (cAMP) in the human myometrium may promote uterine quiescence during pregnancy by protein kinase A (PKA)-mediated phosphorylation and subsequent inactivation of myosin light-chain kinase, as well as by the phosphorylation and activation of cAMP-dependent transcription factors. In this context, we show that the altered expression of cAMP response-element binding protein (CREB), cAMP response-element modulator protein (CREM) and activating transcription factor 2 (ATF2) are implicated in the maintenance of myometrial quiescence during fetal maturation and the switch to uterine activation at term. Using electrophoretic mobility shift and super shift assays, as well as immunoblotting of paired myometrial tissue samples from non-pregnant, pregnant non-labouring and spontaneous labouring women, we defined the patterns of expression of various isoforms of these proteins in the human uterus. Here, we report spatio-temporal changes in the expression of a 43 kDa form of CREB, a 28 kDa CREM-like protein, and a novel 28 kDa ATF2-like protein which are differentially expressed, depending on the gestational state of the uterus. Changes in the pattern of expression of these potent transcription factors may have an important role in the control of uterine activity throughout pregnancy.
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PMID:Expression of the cyclic AMP-dependent transcription factors, CREB, CREM and ATF2, in the human myometrium during pregnancy and labour. 1087 53


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