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)

At the cellular level, the multifunctional cytokine tumor necrosis factor (TNF) modulates growth and activates genes through various intermediates, including protein kinases, protein phosphatases, reactive oxygen intermediates, phospholipases, proteases, sphingomyelinases, and transcription factors. Unlike many cytokine receptors, however, the cytoplasmic domain (CD) of the TNF receptors lacks an intrinsic protein kinase activity and yet on interaction with ligand it phosphorylates various proteins. Although the kinetics of most of these activities differ, their interactions are coordinated through the selective interplay between the CD of the receptors and the associated proteins. A unique pathway has been identified by the ability of the TNF receptors to associate with a novel family of proteins. Two distinct families of proteins have emerged, the TNF receptor-associated factors (TRAFs) and the death domain homologues. The cloning of members of these gene families and the identification of the protein-interaction motifs found within their gene products has initiated the molecular identity of factors (TRADD, FADD/MORT, RIP, FLICE/MACH, and TRAFs) associated with both of the p60 and p80 forms of the TNF receptor and with other members of the TNF receptor superfamily. In this review, we summarize these and other TNF receptor-associated proteins and their potential roles in regulating the activation of nuclear factor-kappaB and apoptosis, two major responses activated by engagement of TNF receptors by the ligand.
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PMID:Early events in TNF signaling: a story of associations and dissociations. 912 4

The mammalian phosphoinositide 3-kinases (PI3Ks) p110alpha, beta, and delta form heterodimers with Src homology 2 (SH2) domain-containing adaptors such as p85alpha or p55(PIK). The two SH2 domains of these adaptors bind to phosphotyrosine residues (pY) found within the consensus sequence pYXXM. Here we show that a heterodimer of the Drosophila PI3K, Dp110, with an adaptor, p60, can be purified from S2 cells with a pYXXM phosphopeptide affinity matrix. Using amino acid sequence from the gel-purified protein, the gene encoding p60 was cloned and mapped to the genomic region 21B8-C1, and the exon/intron structure was determined. p60 contains two SH2 domains and an inter-SH2 domain but lacks the SH3 and breakpoint cluster region homology (BH) domains found in mammalian p85alpha and beta. Analysis of the sequence of p60 shows that the amino acids responsible for the SH2 domain binding specificity in mammalian p85alpha are conserved and predicts that the inter-SH2 domain has a coiled-coil structure. The Dp110.p60 complex was immunoprecipitated with p60-specific antisera and shown to possess both lipid and protein kinase activity. The complex was found in larvae, pupae, and adults, consistent with p60 functioning as the adaptor for Dp110 throughout the Drosophila life cycle.
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PMID:p60 is an adaptor for the Drosophila phosphoinositide 3-kinase, Dp110. 916 20

There is increasing evidence that cellular responses to stress are in part regulated by protein kinases, although specific mechanisms are not well defined. The purpose of these experiments was to investigate potential upstream signaling events activated during heat shock in NIH3T3 fibroblasts. Experiments were designed to ask whether heat shock activates p60 c-Src tyrosine kinase or phosphatidylinositol 3-kinase (PI 3-kinase). Using in vitro protein kinase activity assays, it was demonstrated that heat shock stimulates c-Src and PI 3-kinase activity in a time-dependent manner. Also, there was increased PI 3-kinase activity in anti-phosphotyrosine and anti-c-Src immunoprecipitated immunocomplexes from heated cells. Heat shock activated mitogen-activated protein kinase (MAPK) and p70 S6 kinase (S6K) in these cells. The role of PI 3-kinase in regulating heat shock activation of MAPK and p70 S6K was investigated using wortmannin, a specific pharmacological inhibitor of PI 3-kinase. The results demonstrated that wortmannin inhibited heat shock activation of p70 S6K but only partially inhibited heat activation of MAPK. A dominant negative Raf mutant inhibited activation of MAPK by heat shock but did not inhibit heat shock stimulation of p70 S6K. Genistein, a tyrosine kinase inhibitor, and suramin, a growth factor receptor inhibitor, both inhibited heat shock stimulation of MAPK activity and tyrosine phosphorylation of MAPK. Furthermore, a selective epidermal growth factor receptor (EGFR) inhibitor, tryphostin AG1478, and a dominant negative EGFR mutant also inhibited heat shock activation of MAPK. Heat shock induced EGFR phosphorylation. These results suggest that early upstream signaling events in response to heat stress may involve activation of PI 3-kinase and tyrosine kinases, such as c-Src, and a growth factor receptor, such as EGFR; activation of important downstream pathways, such as MAPK and p70 S6K, occur by divergent signaling mechanisms similar to growth factor stimulation.
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PMID:Heat shock activates c-Src tyrosine kinases and phosphatidylinositol 3-kinase in NIH3T3 fibroblasts. 938 74

Herpes simplex virus 1 encodes two multifunctional regulatory proteins, infected-cell proteins 22 and 0 (ICP22 and ICP0). ICP0 is a promiscuous transactivator, whereas ICP22 is required in vivo and for efficient replication and expression of a subset of late (gamma2) genes in rodent or rabbit cell lines and in primary human cell strains (restrictive cells) but not in HEp-2 or Vero (permissive) cells. We report the identification in the yeast two-hybrid system of a cellular protein designated p60 that interacts with ICP22. This protein (apparent Mr of 60,000) has not been previously described and has no known motifs. Analyses of p60 revealed the following. (i) p60 bound fast-migrating, underprocessed wild-type ICP22 and ICP22 lacking the carboxyl-terminal 24 amino acids but not ICP22 lacking the carboxyl-terminal 40 amino acids, whereas the previously identified cellular protein p78 (R. Bruni and B. Roizman, J. Virol. 72:8525-8531, 1998) bound all forms of ICP22. The interaction of p60 with only one isoform of ICP22 supports that hypothesis that each isoform of herpes simplex virus proteins performs a specific function that may be different from that of other isoforms. (ii) p60 also bound ICP0; the binding of ICP0 was independent of that of ICP22. (iii) p60 localized in uninfected rabbit skin cells in both nuclei and cytoplasm. In rabbit skin cells infected with wild-type virus, p60 was posttranslationally processed to a higher apparent Mr but was not redistributed. Posttranslational processing required the presence of the genes encoding ICP22 and UL13 protein kinase. (iv) In uninfected HEp-2 cells, p60 localized primarily in nuclei. Soon after infection with wild-type virus, the p60 localized in discrete small nuclear structures with ICP0. Late in infection, both ICP0 and p60 tended to disperse but p60 did not change in apparent Mr. The localization of p60 was independent of ICP22, but p60 tended to be more localized in small nuclear structures and less dispersed in cells infected with mutants lacking the genes encoding the UL13 or US3 protein kinases. The results suggest that posttranslational modification of p60 is mediated either by ICP0 (permissive cells) or by ICP22 and UL13 protein kinase (restrictive rabbit skin cells) and that the restrictive phenotype of rabbit skin cells may be related to the failure to process p60 by mutants lacking the genes encoding UL13 or ICP22.
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PMID:A novel cellular protein, p60, interacting with both herpes simplex virus 1 regulatory proteins ICP22 and ICP0 is modified in a cell-type-specific manner and Is recruited to the nucleus after infection. 1019 75

In an experimental model of in vivo hyperthermia, we investigated the involvement of a number of signalling events in rat liver. We report that in vivo heat shock causes a powerful activation of c-Jun N-terminal kinase and p38 kinase but does not trigger poly(ADP-ribose) polymerase cleavage, a signature event of apoptosis. Among the upstream regulators of the kinases, we show that stress-activated protein kinase/extracellular signal-regulated kinase/nitrogen-activated protein kinase kinase 4 SEK1/MKK4 is not involved whereas MKK3 and/or MKK6 are activated. PAK activity displays a transient rise, whereas GCK does not change. PI3-kinase activity increases in anti-phosphotyrosine immunoprecipitates, suggesting a tyrosine kinase-dependent induction mechanism, and the co-immunoprecipitation of PI3-kinase with p60 Src kinase supports the involvement of this latter. GSK3, which may act downstream to PI3-kinase through AKT, undergoes hyperphosphorylation, thus playing a possible role in the protection from apoptosis and in the modulation of heat-shock transcription factor activity.
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PMID:Cellular signalling after in vivo heat shock in the liver. 1077 75

Bordetella pertussis generates a bacterial toxin utilized in signal transduction investigation because of its ability to ADP ribosylate specific G proteins. We previously noted that pertussis toxin (PTX) directly activates endothelial cells, resulting in disruption of monolayer integrity and intercellular gap formation via a signaling pathway that involves protein kinase C (PKC). We studied the effect of PTX on the activity of the 42- and 44-kDa extracellular signal-regulated kinases (ERK), members of a kinase family known to be activated by PKC. PTX caused a rapid time-dependent increase in bovine pulmonary artery endothelial cell ERK activity that was significantly attenuated by 1) pharmacological inhibition of MEK, the upstream ERK activating kinase, 2) an MEK dominant-negative construct, and 3) PKC inhibition with bisindolylmaleimide. There was little evidence for the involvement of either Gbetagamma-subunits, Ras GTPases, Raf-1, p60(src), or phosphatidylinositol 3'-kinases in PTX-mediated ERK activation. Both the purified beta-oligomer binding subunit of the PTX holotoxin and a PTX holotoxin mutant genetically engineered to eliminate intrinsic ADP ribosyltransferase activity completely reproduced PTX effects on ERK activation, suggesting that PTX-induced ERK activation involves a novel PKC-dependent signaling mechanism that is independent of either Ras or Raf-1 activities and does not require G protein ADP ribosylation.
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PMID:Pertussis toxin directly activates endothelial cell p42/p44 MAP kinases via a novel signaling pathway. 1128 37

Tumor necrosis factor (TNF) is a pleiotropic cytokine known to regulate cell growth, viral replication, inflammation, immune system functioning, angiogenesis, and tumorigenesis. These effects are mediated through two different receptors, TNFR1 and TNFR2 (also called p60 and p80, respectively), with p60 receptor being expressed on all cell types and p80 receptor only on cells of the immune system and on endothelial cells. Although the role of p60 receptor in TNF signaling is well established, the role of p80 is less clear. In this report, by using macrophages derived from wild-type mice (having both receptors) and mice in which the gene for either p60 (p60(-/-)), or p80 (p80(-/-)), or both (p60(-/-) p80(-/-)) receptor have been deleted, we have redefined the role of these receptors in TNF-induced activation of nuclear factor (NF)-kappa B and of mitogen-activated protein kinases. TNF activated NF-kappa B in a dose- and time-dependent manner in wild-type macrophages but not in p60(-/-), p80(-/-), or p60(-/-) p80(-/-) macrophages. These results correlated with the I kappa B alpha degradation needed for NF-kappa B activation. We also found that TNF activated c-Jun N-terminal protein kinase in a dose- and time-dependent manner in wild-type macrophages but not in p60(-/-), p80(-/-), or p60(-/-) p80(-/-) macrophages. TNF activated p38 MAPK and p44/p42 MAPK in wild-type but not in p60(-/-), p80(-/-), or p60(-/-) p80(-/-) macrophages. TNF induced the proliferation of wild-type macrophages, but for p60(-/-) and p80(-/-) macrophages proliferation was lower, and in p60(-/-) p80(-/-) it was absent. Overall, our studies suggest that both types of TNF receptors are needed in macrophages for optimum TNF cell signaling.
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PMID:Genetic deletion of the tumor necrosis factor receptor p60 or p80 abrogates ligand-mediated activation of nuclear factor-kappa B and of mitogen-activated protein kinases in macrophages. 1143 47

In vivo activation of client proteins by Hsp90 depends on its ATPase-coupled conformational cycle and on interaction with a variety of co-chaperone proteins. For some client proteins the co-chaperone Sti1/Hop/p60 acts as a "scaffold," recruiting Hsp70 and the bound client to Hsp90 early in the cycle and suppressing ATP turnover by Hsp90 during the loading phase. Recruitment of protein kinase clients to the Hsp90 complex appears to involve a specialized co-chaperone, Cdc37p/p50(cdc37), whose binding to Hsp90 is mutually exclusive of Sti1/Hop/p60. We now show that Cdc37p/p50(cdc37), like Sti1/Hop/p60, also suppresses ATP turnover by Hsp90 supporting the idea that client protein loading to Hsp90 requires a "relaxed" ADP-bound conformation. Like Sti1/Hop/p60, Cdc37p/p50(cdc37) binds to Hsp90 as a dimer, and the suppressed ATPase activity of Hsp90 is restored when Cdc37p/p50(cdc37) is displaced by the immunophilin co-chaperone Cpr6/Cyp40. However, unlike Sti1/Hop/p60, which can displace geldanamycin upon binding to Hsp90, Cdc37p/p50(cdc37) forms a stable complex with geldanamycin-bound Hsp90 and may be sequestered in geldanamycin-inhibited Hsp90 complexes in vivo.
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PMID:Regulation of Hsp90 ATPase activity by the co-chaperone Cdc37p/p50cdc37. 1191 74

Increasing evidence supports the hypothesis that tannic acid, a plant polyphenol, exerts anticarcinogenic activity in chemically induced cancers. In the present study, tannic acid was found to strongly inhibit tyrosine kinase activity of epidermal growth factor receptor (EGFr) in vitro (IC50 = 323 nM). In contrast, the inhibition by tannic acid of p60(c-src) tyrosine kinase (IC50 = 14 microM) and insulin receptor tyrosine kinase (IC50 = 5 microM) was much weaker. The inhibition of EGFr tyrosine kinase by tannic acid was competitive with respect to ATP and non-competitive with respect to peptide substrate. In cultured cells, growth factor-induced tyrosine phosphorylation of growth factor receptors, including EGFr, platelet-derived growth factor receptor, and basic fibroblast growth factor receptor, was inhibited by tannic acid. No inhibition of insulin-induced tyrosine phosphorylation of insulin receptor and insulin-receptor substrate-1 was observed. EGF-stimulated growth of HepG2 cells was inhibited in the presence of tannic acid. The inhibition of serine/threonine-specific protein kinases, including cAMP-dependent protein kinase, protein kinase C and mitogen-activated protein kinase, by tannic acid was only detected at relatively high concentration, IC50 being 3, 325 and 142 microM respectively. The molecular modeling study suggested that tannic acid could be docked into the ATP binding pockets of either EGFr or insulin receptor. These results demonstrate that tannic acid is an in vitro potent inhibitor of EGFr tyrosine kinase.
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PMID:Tannic acid, a potent inhibitor of epidermal growth factor receptor tyrosine kinase. 1656 14

In this report, we demonstrate the application of Au nanoparticles in the electrochemical detection of protein phosphorylation. The method is based on the labeling of a specific phosphorylation event with Au nanoparticles, followed by electrochemical detection. The phosphorylation reaction is coupled with the biotinylation of the kinase substrate using a biotin-modified adenosine 5'-triphosphate [gamma]-biotinyl-3,6,9-trioxaundecanediamine (ATP) as the co-substrate. When the phosphorylated and biotinylated kinase substrate is exposed to streptavidin-coated Au nanoparticles, the high affinity between the streptavidin and biotin resulted in the attachment of Au nanoparticles on the kinase substrate. The electrochemical response obtained from Au nanoparticles enables monitoring the activity of the kinase and its substrate, as well as the inhibition of small molecule inhibitors on protein phosphorylation. We determined the activity of Src non-receptor protein tyrosine kinase, p60(c-Src) and protein kinase A in combination with their highly specific substrate peptides Raytide EL and Kemptide, respectively. The detection limits for Raytide EL and Kemptide were determined as 5 and 10 microM, (S/N=3), and the detection limits for the kinase activity of p60(c-Src) and protein kinase A (PKA) were determined as 5 and 10 U mL(-1), (S/N=3), respectively. Tyrosine kinase reactions were also performed in the presence of a well-defined inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine (PP2), and its negative control molecule, 4-amino-7-phenylpyrazol[3,4-d] pyrimidine (PP3), which had no inhibition effect. Based on the dependency of Au nanoparticle signal on inhibitor concentration, IC(50) value, half-maximal inhibition of the inhibitors was estimated. IC(50) values of PP2, genistein and herbimycin A to p60(c-Src) were detected as 5 nM, 25 microM and 900 nM, respectively. The inhibition of PKA activity on Kemptide using ellagic acid was monitored with an IC(50) of 3.5 microM. The performance of the biosensor was optimized including the kinase reaction, incubation with streptavidin-coated Au nanoparticles, and the small molecule inhibitors. Kinase peptide-modified electrochemical biosensors are promising candidates for cost-effective kinase activity and inhibitor screening assays.
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PMID:Gold nanoparticle-based electrochemical detection of protein phosphorylation. 1738 90


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