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)

Bacterial LPS stimulation of murine macrophages leads to increased tyrosine phosphorylation and activation of the 42- and 44-kDa mitogen-activated protein kinases (MAPK) and the activation of stress-activated protein kinases (SAPK)/c-Jun N-terminal kinase (JNK) and p38, related to the high osmolarity glycerol protein kinase in Saccharomyces cerevisiae (HOG1). LPS caused a rapid increase (10 min) in phosphotransferase activity toward myelin basic protein (MBP), a polypeptide that encompassed the first 169 residues of c-Jun fused to gluthathione S-transferase (GST-c-Jun (1-169)) and 27-kDa heat shock protein (hsp27). MonoQ fractionation of cell extracts resolved phosphotransferase activity peaks toward MBP, GST-c-Jun (1-169), and hsp27, which contained MAPK, SAPK/JNK, and MAPKAPK2, respectively, as indicated by immunoblotting data. In RAW 264.7 macrophages, LPS stimulation of MAPKAPK2, a substrate of p38 HOG1 and MAPK, appeared to occur predominantly via p38 HOG1 and not the MAPK. PMA, which activated the MAPK as potently as LPS, did not strongly activate MAPKAPK2, as assessed by hsp27 phosphorylation. Consistent with p38 HOG1-mediating LPS activation of MAPKAPK2, treatment with LPS, but not PMA, increased the tyrosine phosphorylation of p38 HOG1, a modification known to elevate the enzymatic capacity of this kinase. In LPS-treated cells, the activity of SAPK/JNK was increased 5- to 10-fold, as measured by precipitating SAPK/JNK with Abs or immobilized GST-c-Jun and performing an in vitro kinase assay. In addition, the kinases thought to be upstream of SAPK/JNK, SAPK/ERK kinase 1 (SEK1), and MAPK/ERK kinase kinase 1 (MEKK1), were activated following LPS, but not PMA, exposure (5-fold and 2.5-fold, respectively.
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PMID:Activation of multiple proline-directed kinases by bacterial lipopolysaccharide in murine macrophages. 866 21

Induction of cell proliferation by mitogen or growth factor stimulation leads to the specific stimulation or repression of a large number of genes. To better understand differentiated epithelial cell growth regulation, we have initiated a study to identify genes which are regulated by the thyrotropin-dependent mitogenic pathway in dog thyroid cells. A thyroid cDNA library was prepared from a methimazole and propylthiouracil-treated dog and differentially screened with probes derived from control or stimulated thyroids. Among 19 clones isolated, 6 encode known proteins (inwardly rectifying potassium channel, nucleosome assembly protein, ribosomal protein L7, elongation factor 1alpha, non-muscle myosin light chain, and heat shock protein 90beta). The 13 others correspond to proteins whose function is unknown. Among them, 5 correspond to mRNAs whose expression was modulated by mitogenic stimulation of thyrocytes in primary culture. A preliminary characterization of two of these cDNAs is reported: clone 5, which might represent a novel, atypical protein kinase, and clone 3, which contains ankyrin-like repeats, suggesting that it might interact with other proteins.
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PMID:Identification and characterization of novel genes modulated in the thyroid of dogs treated with methimazole and propylthiouracil. 891 Apr 71

Activation of the latent DNA binding function of human p53 protein by the bacterial Hsp70, DnaK, represents a unique reaction in which a heat shock protein can interact with a native protein to affect its function. We have localized a likely DnaK interaction site on native human p53 tetramers to a motif flanking the COOH-terminal casein kinase II and protein kinase C phosphorylation sites. Murine p53 is less efficiently activated by DnaK, which has permitted a search for factors that might cooperate in p53 activation by DnaK. We show that optimal activation by DnaK may be dependent upon the phosphorylation state of murine p53, in particular, modification of p53 at the cdc2 phosphorylation site by point mutation decreases the extent of activation by DnaK. Additionally, the monoclonal antibody PAb241, binding in the vicinity of the cdc2 phosphorylation site, is able to activate the specific DNA binding function of p53. This has led us to propose a second regulatory motif flanking the tetramerization domain of p53 that cooperates with factors binding at the negative regulatory domain in the extreme COOH terminus.
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PMID:Modification of two distinct COOH-terminal domains is required for murine p53 activation by bacterial Hsp70. 894 78

The aim of this study was to investigate different protein kinase inhibitors (secondary metabolite-derived substances, synthetic compounds, and substrate-based peptides) for their potency to inhibit the mammalian small heat shock protein (HSP25) kinase (E.C. 2.7.1.37) isolated from Ehrlich ascites tumor cells. Among the secondary metabolite-derived inhibitors (staurosporine, K-252a, K-252b, KT5926, KT5720, erbstatin analog, and quercetin) and synthetic compounds (H-9, H-89, HA 1004, KN-62, ML-7, tyrphostin A25, and tyrphostin B42), KT5926, staurosporine, and K-252a inhibited HSP25 kinase most efficiently. Kinetic analysis revealed that inhibition by staurosporine (Ki = 32.4 nM) and K-252a (Ki = 13.7 nM) was competitive with ATP. Inhibition by KT5926 was competitive with the substrate peptide KKKALNRQLSVAA (Ki = 27.2 nM) and noncompetitive with respect to ATP (Ki = 38.8 nM). In comparison with other protein kinases, HSP25 kinase was relatively resistant to most of the inhibitors. KT5926 was the only tested inhibitor with certain preference for HSP25 kinase when compared with protein kinases A, C, and G. Among the tested substrate-based peptides, we identified one peptide (KKKALNRQLGVAA), which preferentially inhibited HSP25 kinase in comparison with protein kinases A and C and mitogen-activated protein kinase. This peptide inhibited HSP25 kinase competitively with the substrate peptide (Ki = 8.1 microM) and noncompetitively with ATP (Ki = 134 microM). A peptide (SRVLKEDKERWEDVK) derived from the putative autoinhibitory domain of the closely related human mitogen-activated protein kinase-activated protein kinase-2 did not inhibit HSP25 kinase activity, suggesting the existence of several species of HSP25 kinases. Furthermore, the data identified structural requirements for inhibitors of HSP25-kinase.
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PMID:Effect of protein kinase inhibitors on activity of mammalian small heat-shock protein (HSP25) kinase. 921 84

Protein kinase B (PKB, also named as Akt or RAC-protein kinase), that is activated by cellular stress such as heat shock and hyperosmotic treatment, was revealed to be activated by oxidative stress and by chemical stressors of CdCl2 and NaAsO2 by measuring the activity of the enzyme immunoprecipitated from the transfected COS-7 cells. Upon stress treatment, a 30-kDa phosphoprotein was co-immunoprecipitated with PKB from the cells metabolic labeled with [32P]orthophosphate. The phosphoprotein was identified as Hsp27, a small heat shock protein, by immunoblot analysis and co-immunoprecipitation. The association of Hsp27 was specific to PKB as the heat shock protein was not co-immunoprecipitated with other protein kinases such as protein kinase C and PKN. When the cells were treated with H2O2, PKB was activated gradually and the association of Hsp27 with PKB increased concurrently with the enhancement of PKB activity. In heat-shocked cells, activation of PKB and the association of Hsp27 were detected immediately after the treatment, and the association of the heat shock protein decreased while PKB kept stimulated activity when the cells were further incubated at 37 degrees C. These results suggest that Hsp27 is involved in the activation process of PKB in the signal transduction pathway of various forms of stress.
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PMID:Activation of protein kinase B (Akt/RAC-protein kinase) by cellular stress and its association with heat shock protein Hsp27. 923 90

The Raf-1-MEK-MAPK pathway plays an important role in transducing extracellular growth factor signaling into altered nuclear transcription factor function. The benzoquinone ansamycin Geldanamycin (GA) specifically binds to the heat shock protein HSP90 and alters its complex with Raf-1. This leads to a decrease in Raf-1 levels and to disruption of the Raf-1-MEK-MAPK signaling pathway. The enhanced degradation of Raf-1 protein was prevented by inhibitors of the proteasome, while inhibition of lysosomal or other proteases was ineffective. Raf-1 that was protected from GA-induced degradation was of higher molecular weight and showed a laddering pattern consistent with its polyubiquitination. Unlike Raf-1 in untreated cells, the protein was insoluble in Triton X100- or NP40-based buffers. Signaling through this pathway was inhibited by GA, concomitant with loss of Raf-1 protein, but was restored if Raf-1 was protected from GA-induced degradation by proteasome inhibitors.
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PMID:Geldanamycin-induced destabilization of Raf-1 involves the proteasome. 936 23

FKBP52 (HSP56, p59, HBI) is the 59-kDa immunosuppressant FK506-binding protein and has peptidyl prolyl isomerase as well as a chaperone-like activity in vitro. FKBP52 associates with the heat shock protein HSP90 and is included in the steroid hormone receptor complexes in vivo. FKBP52 possesses a well conserved phosphorylation site for casein kinase II (CK2) that was previously shown to be associated with HSP90. Here we examined whether FKBP52 is phosphorylated by CK2 both in vivo and in vitro. Recombinant rabbit FKBP52 was phosphorylated by purified CK2. We expressed and purified deletion mutants of FKBP52 to determine the site(s) phosphorylated by CK2. Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. A synthetic peptide corresponding to this region was phosphorylated by CK2, and the peptide competitively inhibited the phosphorylation of other substrates by CK2. The [32P]phosphate labeling of FKBP52-expressing cells revealed that the same site is also phosphorylated in vivo. FK506 binding to FKBP52 did not affect the phosphorylation by CK2 and, conversely, the FK506-binding activity of FKBP52 was not affected by the phosphorylation. Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90. These results indicate that CK2 phosphorylates FKBP52 both in vitro and in vivo and thus may regulate the protein composition of chaperone-containing complexes such as those of steroid receptors and certain protein kinases.
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PMID:Phosphorylation of the immunosuppressant FK506-binding protein FKBP52 by casein kinase II: regulation of HSP90-binding activity of FKBP52. 940 42

Several stresses cause additional activation to the glucose-stimulated plasma membrane H+-ATPase activity of yeast, but it is not clear how this is achieved. We recently reported that cells lacking the integral plasma membrane heat shock protein Hsp30 display enhanced increases in plasma membrane H+-ATPase activity with either heat shock or weak organic acid stress (Piper, P.W., Ortiz-Calderon, C., Holyoak, C., Coote, P. and Cole, M. (1997) Cell Stress and Chaperones 2, 12-24), indicating that the stress induction of Hsp30 acts to reduce stress stimulation of the H+-ATPase. In this study it is shown that Hsp30 acts to reduce the Vmax of H+-ATPase in heat shocked cells. Its action is lost with deletion of the C-terminal 11 amino acids of the H+-ATPase, a deletion that does not abolish the stress stimulation of this enzyme. Mutation of the Thr-912 residue within the C-terminal domain of H+-ATPase, a potential site of phosphorylation by the Ca2+-calmodulin-dependent protein kinase, also abolishes any effect of Hsp30. Hsp30 may therefore be acting on a Thr-912 phosphorylated form of the H+-ATPase.
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PMID:The C-terminus of yeast plasma membrane H+-ATPase is essential for the regulation of this enzyme by heat shock protein Hsp30, but not for stress activation. 941 9

FKBP65 is a member of the FK506-binding protein class of immunophilins and is the only member reported to contain four peptidylprolyl cis-trans isomerase domains and an unrelated COOH-terminal domain. In this report, we show that the heat shock protein hsp90 and the serine/threonine protein kinase c-Raf-1 are components of FKBP65 immune complexes. The NH2-terminal regulatory domain of c-Raf-1 appears to be required for its interaction with FKBP65. Using GST-FKBP65 fusion protein and purified Raf proteins, we show that full-length FKBP65 can interact with c-Raf-1 but not B-Raf. The activation kinetics of c-Raf-1 after v-H-RasV12 injection of Xenopus oocytes appear to correlate with FKBP65/c-Raf-1 interaction, suggesting that FKBP65 may preferentially associate with forms of c-Raf-1 that are more posttranslationally modified. The interaction of FKBP65 with the c-Raf-heat shock protein 90 heterocomplex implicates this immunophilin in signal-transduction processes.
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PMID:The immunophilin FKBP65 forms an association with the serine/threonine kinase c-Raf-1. 943 87

This study investigates the possibility that FSH activates the p38 mitogen-activated protein kinase (MAPK) pathway in immature granulosa cells (GC). FSH induced the phosphorylation (activation) of p38 MAPK as evaluated by immunoprecipitation and by phosphorylation-specific immunoblotting. FSH-induced phosphorylation of p38 MAPK was blocked by pretreatment with the protein kinase A (PKA) inhibitor H89 and mimicked by the cAMP generating agonist forskolin, indicating that FSH-induced cAMP production and PKA activation are necessary and sufficient for the activation of p38 MAPK in GC. The small heat shock protein HSP-27 comprises a downstream phosphorylation target for the p38 MAPK pathway. FSH-induced phosphorylation of HSP-27 was blocked by pretreatment with the p38 MAPK inhibitor SB 203580, indicating that p38 MAPK activation is necessary for FSH-induced HSP-27 phosphorylation. FSH-induced GC rounding/aggregation was blocked by pretreatment with SB 203580 indicating that p38 MAPK activation is necessary for FSH-induced GC cell shape change. The results of these experiments show that the p38 MAPK pathway is activated in GC in response to FSH in a cAMP/PKA-dependent manner, and that p38 MAPK activity is required for FSH-induced HSP-27 phosphorylation as well as rounding/aggregation in GC.
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PMID:Follicle stimulating hormone (FSH) activates the p38 mitogen-activated protein kinase pathway, inducing small heat shock protein phosphorylation and cell rounding in immature rat ovarian granulosa cells. 964 11


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