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)

It has been reported that activated Th cells express CD40 ligand, and the interaction of the CD40 ligand and CD40 on B cells results in B cell cycle entry. In this report, mechanisms of B cell activation induced by CD40-CD40 ligand interaction were studied by using an activated Th cell membrane as a source of CD40 ligand. The rise in cAMP concentration and tyrosine phosphorylation of a 69-kDa protein were induced in B cells stimulated with the activated Th cell membrane, and both of them were suppressed by the inclusion of soluble CD40 in cultures. The membrane stimulation did not elicit either inositol phosphates metabolism nor elevation of intracellular Ca2+ concentration. Protein kinase C depletion did not affect the proliferation, rise in cAMP level, or the 69-kDa protein tyrosine phosphorylation. Addition of anti-CD45 to the culture resulted in suppression of the B cell proliferation as well as the 69-kDa protein tyrosine phosphorylation. Furthermore, a protein kinase A inhibitor, H-89, suppressed the B cell proliferation induced by the membrane. These results indicate that both protein tyrosine kinase and protein kinase A were involved in the signal transduction pathway for the B cell proliferation evoked by the CD40-CD40 ligand interaction in Th cell contact-dependent B cell proliferation.
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PMID:Mechanisms of T cell contact-dependent B cell activation. 751 Jul 39

Herbimycin A, a benzoquinonoid anasamycin antibiotic, preferentially inhibited the in vitro growth of Ph1-positive leukemia cell lines. On the other hand, genistein, which was developed as an inhibitor of receptor-type tyrosine kinase, and other protein kinase inhibitors showed no selective inhibition of Ph1-positive leukemia cell growth. Herbimycin A also displayed an abrogative effect on the transformation of murine hematopoietic cells by transfection with a bcr/abl oncoprotein-expressing retroviral vector. The antitumor action of herbimycin A on Ph1-positive leukemia cells is related to an inhibition of activity of bcr/abl protein tyrosine kinase and a subsequent reduction of the constitutive phosphotyrosyl proteins, however, the antibiotic has no effect on the expression of bcr/abl mRNA and oncoprotein. Therefore, herbimycin A may provide an important insight into the oncogenic action of bcr/abl oncoprotein and the future development of oncoprotein-targeted therapeutic agents.
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PMID:Effect of herbimycin A, an inhibitor of tyrosine kinase, on protein tyrosine kinase activity and phosphotyrosyl proteins of Ph1-positive leukemia cells. 751 Nov 93

The fate of E-selectin expressed on TNF-activated monolayers of HUVEC was investigated by confocal laser scanning microscopy. Cytokine-activated endothelial cells internalized mAb to E-selectin in a very rapid, energy-dependent fashion. By contrast, mAb against ICAM-1 and VCAM-1 remained surface bound. The E-selectin mAb was recovered in intracellular compartments with a tubular morphology, some of which appeared to be interconnected. Cathepsin B, a ubiquitously expressed lysosomal protease, was found to co-localize in these structures. Functional specificity of E-selectin-internalization was observed upon addition of the fluorescent SLex-oligosaccharide to the activated HUVEC monolayers. Uptake into the same E-selectin-positive compartments was observed, whereas the control oligosaccharide Lex was not internalized at all. The process of internalization was found to be unaffected by most inhibitors of protein kinase C, cAMP-dependent PKA, or protein tyrosine kinase activity. Whereas cytochalasin B preincubation of HUVEC failed to inhibit the internalization process, colchicine and vinblastine, reagents that interfere with the metabolism of tubulin, prevented the formation of the elongated structures in which E-selectin would normally be internalized. Concomitantly, the expression of E-selectin at the cell surface was significantly increased.
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PMID:Cytokine-activated endothelial cells internalize E-selectin into a lysosomal compartment of vesiculotubular shape. A tubulin-driven process. 751 27

We recently identified Vav as a Ras-activating guanine nucleotide exchange factor (GEF) stimulated by a T-cell antigen receptor-coupled protein tyrosine kinase (PTK). Here, we describe a novel, protein kinase-independent alternative pathway of Vav activation. Phorbol ester, 1,2-diacylglycerol, or ceramide treatment of intact T cells, Vav immunoprecipitates, or partially purified Vav generated by in vitro translation or COS-1 cell transfection stimulated the Ras exchange activity of Vav in the absence of detectable tyrosine phosphorylation. GEF activity of gel-purified Vav was similarly stimulated by phorbol myristate acetate (PMA). Stimulation was resistant to PTK and protein kinase C inhibitors but was blocked by calphostin, a PMA and diacylglycerol antagonist. In vitro-translated Vav lacking its cysteine-rich domain, or mutated at a single cysteine residue within this domain (C528A), was not stimulated by PMA but was fully activated by p56lck. This correlated with increased binding of radiolabeled phorbol ester to COS-1 cells expressing wild-type, but not C528A-mutated, Vav. Thus, Vav itself is a PMA-binding and -activated Ras GEF. Recombinant interleukin-1 alpha stimulated Vav via this pathway, suggesting that diglyceride-mediated Vav activation may couple PTK-independent receptors which stimulate production of lipid second messengers to Ras in hematopoietic cells.
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PMID:Direct stimulation of Vav guanine nucleotide exchange activity for Ras by phorbol esters and diglycerides. 751 72

Bacterial LPS stimulates human monocytes to secrete inflammatory cytokines, which are involved in several disease processes. However, the mechanism of LPS activation of cytokine expression and secretion is not completely understood. In this study, we investigated the signal transduction pathways involved in LPS-stimulated TNF-alpha and IL-1 beta secretion. TNF-alpha and IL-1 beta secretion were completely blocked by protein kinase C (PKC) and cyclic nucleotide-dependent protein kinase inhibitor, H-7, but were not affected by H-89, a specific cyclic nucleotide-dependent protein kinase inhibitor. In addition, LPS was found to induce activation of PKC, reaching maximal activity at 30 min and returning to unstimulated levels after 60 min. LPS stimulation only slightly increased intracellular levels of diacylglycerol, the natural activator of PKC, and pretreatment of monocytes with the diacylglycerol-kinase inhibitor, R59022, did not affect LPS-stimulated TNF-alpha secretion. LPS-induced PKC activation was found not to be affected by blocking of the LPS receptor, CD14, with mAb or by inhibition of protein tyrosine kinase with herbimycin A. However, these agents suppressed LPS-induced TNF-alpha secretion and TNF-alpha mRNA accumulation. The results suggest that TNF-alpha and IL-1 beta secretion after LPS stimulation of human monocytes requires the activation of protein tyrosine kinase and PKC, upstream to the activation of gene transcription. The activation of PKC by LPS is probably mediated by a diacylglycerol-independent pathway.
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PMID:Involvement of protein kinase C and protein tyrosine kinase in lipopolysaccharide-induced TNF-alpha and IL-1 beta production by human monocytes. 751 14

Selective cell death plays a critical role in the development of the immune repertoire and in the elimination of target cells expressing foreign Ags. The apoptosis induced by ligation of the Fas Ag, a member of the TNFR/nerve growth factor receptor superfamily, contributes to both of these modes of cell loss. However, in spite of the molecular cloning of the Fas Ag and the identification of a specific cytoplasmic domain required for its function, it remains unclear as to which Fas-induced second messengers mediate the development of programmed cell death. We, therefore, evaluated Fas-initiated signal transduction in susceptible cell types. We determined that Fas ligation induces the rapid tyrosine phosphorylation of multiple cellular proteins. These phosphorylation events occur within 1 min and decline toward baseline by 30 min. In addition, Fas ligation increases the in vitro protein kinase activity of the tyrosine phosphorylated proteins. Pharmacologic inhibitors of protein tyrosine kinases block, in a concentration-dependent manner, Fas-induced DNA fragmentation and prolong cell survival. These results suggest that protein tyrosine kinase activation is an early and obligatory signal in Fas-induced apoptosis.
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PMID:Tyrosine kinase activation provides an early and requisite signal for Fas-induced apoptosis. 751 37

CD28 is a 44-kD homodimer expressed on the surface of the majority of human T cells that provides an important costimulus for T cell activation. The biochemical basis of the CD28 accessory signals is poorly understood. Triggering of the T cell antigen receptor (TCR) activates the p21ras proteins. Here we show that ligation of CD28 by a monoclonal antibody (mAb) also stimulates p21ras and induces Ras-dependent events such as stimulation of the microtubule-associated protein (MAP) kinase ERK2 and hyperphosphorylation of Raf-1. One physiological ligand for CD28 is the molecule B7-1. In contrast to the effect of CD28 mAb, the present studies show that interactions between CD28 and B7-1 do not stimulate p21ras signaling pathways. Two substrates for TCR-regulated protein tyrosine kinases (PTKs) have been implicated in p21ras activation in T cells: p95vav and a 36-kD protein that associates with a complex of Grb2 and the Ras exchange protein Sos. Triggering CD28 with both antibodies and B7-1 activates cellular PTKs, and we have exploited the differences between antibodies and B7-1 for p21ras activation in an attempt to identify critical PTK-controlled events for Ras activation in T cells. The data show that antibodies against TCR or CD28 induce tyrosine phosphorylation of both Vav and p36. B7-1 also induces Vav tyrosine phosphorylation but has no apparent effect on tyrosine phosphorylation of the Grb2-associated p36 protein. The intensity of the Vav tyrosine phosphorylation is greater in B7-1 than in TCR-stimulated cells. Moreover the kinetics of Vav tyrosine phosphorylation is prolonged in the B7-1-stimulated cells. These studies show that for CD28 signaling, the activation of p21ras correlates more closely with p36 tyrosine phosphorylation than with Vav tyrosine phosphorylation. However, the experiments demonstrate that Vav is a major substrate for B7-activated PTKs and hence could be important in CD28 signal transduction pathway.
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PMID:The role of p21ras in CD28 signal transduction: triggering of CD28 with antibodies, but not the ligand B7-1, activates p21ras. 752 Apr 66

The B-cell antigen CD40 transduces signals, which synergize with interleukin (IL)-4 to induce IgE synthesis in human B cells. IL-4 induces epsilon germline transcription but not mature epsilon transcripts or IgE protein synthesis in B cells. Addition of anti-CD40 monoclonal antibody to IL-4-treated B cells results in deletional S mu--> S epsilon switch recombination, expression of mature epsilon transcripts, and IgE synthesis and secretion. Because both IL-4 and anti-CD40 induce protein tyrosine phosphorylation in B cells, we investigated the role of protein tyrosine kinase in IL-4/CD40-mediated IgE synthesis. The protein tyrosine kinase inhibitors genistein and herbimycin A, but not the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) or the protein kinase A inhibitor N-2-guanidinoethyl-5-isoquinolinesulfonamide, inhibited IgE synthesis in B cells stimulated with IL-4 and CD40. Genestein and herbimycin, but not H7, inhibited IL-4-driven epsilon germline transcription in B cells. Both genestein and herbimycin, but not H7, inhibited CD40-mediated IgE synthesis in B cells pretreated for 4 days with IL-4 to allow optimal expression of epsilon germline transcripts. Inhibition of IgE synthesis in these cultures was accompanied by inhibition of S mu--> S epsilon deletional switch recombination as assayed by nested polymerase chain reactions. These results suggest that activation of protein tyrosine kinase plays an important role in both the IL-4 and the CD40 signalling pathways that lead to IgE isotype switching in B cells.
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PMID:Role of protein tyrosine kinases in CD40/interleukin-4-mediated isotype switching to IgE. 752 75

The M(r) 38,000 RNA-binding protein (P38) is the major component of translationally repressed messenger ribonucleoproteins in cryptobiotic gastrulae of the brine shrimp Artemia. Partial elucidation of the amino acid sequence of P38 reveals that it is homologous to A/B-type hnRNP proteins. This was confirmed by immunodetection with antibodies specific for A/B-type hnRNP proteins from Drosophila melanogaster. P38 can be phosphorylated in vitro by a src-related protein tyrosine kinase on multiple tyrosine residues located predominantly in the glycine-rich domain. Tyrosine phosphorylated P38 can be efficiently dephosphorylated by a specific protein tyrosine phosphatase (1B-like) and by protein phosphatase 2A activated by the phosphotyrosyl phosphatase activator. Tyrosine phosphorylation of P38 slightly influences its subsequent phosphorylation by casein kinase II. The latter phosphorylation site is located in the glycine-rich domain of P38. Two-dimensional gel electrophoresis resolves P38 into multiple isoforms which shift to more acidic pI values after phosphorylation by protein tyrosine kinase or casein kinase II. From nitrocellulose filter binding and UV cross-linking analysis, evidence was obtained that tyrosine phosphorylation of P38 impairs its binding to poly(A) but not to poly(U). This demonstrates the involvement of tyrosine residues in polynucleotide-specific RNA binding that can be regulated by phosphorylation/dephosphorylation.
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PMID:Tyrosine phosphorylation of a M(r) 38,000 A/B-type hnRNP protein selectively modulates its RNA binding. 752 88

The present study characterizes mechanisms involved with the induction of nitric oxide (NO) production, nitric oxide synthase (NOS) enzymatic activity and mRNA expression in human articular chondrocytes. Activation of chondrocytes with lipopolysaccharide (LPS) or IL-1 resulted in time- and dose-dependent increases in iNOS mRNA followed by increased NOS enzymatic activity and NO release. The protein tyrosine kinase (PTK) inhibitors herbimycin A or genistein reduced IL-1 or LPS-induced NO release and NOS enzymatic activity. This was associated with inhibition of iNOS mRNA expression as determined by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. In contrast, inhibitors of protein kinase C (PKC) or protein kinase A (PKA) did not affect these responses. These results were confirmed in experiments with second messenger agonists where neither activation of PKC, nor increases in cyclic adenosine monophosphate (cAMP) or increased intracellular calcium levels were associated with the induction of iNOS mRNA or NO release. These results suggest that PKC, PKA and calcium-dependent signals are not required or sufficient for the stimulation of NO production. However, NO production is dependent on tyrosine kinases due to their role in the expression of iNOS mRNA.
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PMID:Tyrosine kinases are involved with the expression of inducible nitric oxide synthase in human articular chondrocytes. 753 12


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