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)

Stereo-specific perturbation of the IgE-receptor (shown in previous studies) produces a monophasic rise in cyclic AMP that peaks at 15 s and a depletion of cyclic AMP-dependent protein kinase that plateaus at 30-60 s. The previously observed linear relationship between the attenuation in the monophasic rise in cyclic AMP and the quantity of mediator release in the presence of incremental concentrations of the adenosine analogue 2',5',-dideoxyadenosine, DDA, which is known to inhibit adenylate cyclase, indicated a direct relationship between receptor perturbation, transmembrane activation of adenylate cyclase, and granule secretion. The role of cyclic AMP as a second messenger in this sequence is now apparent from the linear relationship between net percent mediator release and net percent activation of cyclic AMP-dependent protein kinase isoenzyme when IgE-dependent activation of adenylate cyclase is suppressed by incremental quantities of DDA. There was a comparable percent activation of both types I and II mast cell cyclic AMP-dependent protein kinase isoenzymes with anti-IgE-induced activation and secretion, and there was a parallel suppression of the activation of both isoenzymes in the presence of DDA. Although these studies firmly link the activation of cytoplasmic cyclic AMP-dependent protein kinase to the IgE receptor-initiated transmembrane activation of adenylate cyclase. they do not discriminate among the functions of the two isoenzymes.
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PMID:Mast cell mediator release as a function of cyclic AMP-dependent protein kinase activation. 627 Feb 26

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 non-histone chromosomal protein HMG-I(Y) participates in repression of transcription directed by a promoter which confers interleukin 4 (IL-4)-inducible activation in transfected B cell lines. Metabolic labeling, phosphoamino acid analyses, and in vitro phosphorylation studies demonstrate that IL-4 induces serine phosphorylation of HMG-I(Y) in B lymphocytes. Phosphopeptide mapping shows that the predominant site of phosphorylation contains a casein kinase II consensus motif. The immunosuppressive agent rapamycin has been shown preferentially to inhibit IgE production by IL-4-treated human B cells. It is shown here that rapamycin inhibits both activation of the human germ line epsilon promoter by IL-4 and IL-4-inducible phosphorylation of HMG-I(Y). These findings demonstrate a rapamycin-sensitive pathway that transduces signals from the IL-4 receptor to nuclear factors that regulate inducible transcription. The affinity of normal nuclear HMG-I(Y) for DNA is increased by dephosphorylation in vitro, whereas in vitro kinase reactions using casein kinase II decrease recombinant HMG-I(Y) binding to DNA. These data further suggest a novel mechanism in which phosphorylation triggered by IL-4 or other cytokines could regulate the effects of HMG-I(Y) on gene transcription.
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PMID:Interleukin 4-inducible phosphorylation of HMG-I(Y) is inhibited by rapamycin. 755 28

Crosslinking of the IgE receptor on rat basophilic leukemia (RBL) cells using the multivalent antigen DNP-BSA leads to a rapid and sustained increase in the filamentous actin content of the cells. Stimulation of RBL cells through the adenosine receptor also induces a very rapid polymerization of actin, which peaks in 45-60 s and is equivalent in magnitude to the F-actin response elicited through stimulation of the IgE receptor. However, in contrast to the IgE mediated response, which remains elevated for over 30 min, the F-actin increase induced by the adenosine analogue 5'-(N-ethylcarboxamido)-adenosine (NECA) is relatively transient and returns to baseline values within 5-10 min. While previous work has shown that the polymerization of actin in RBL cells stimulated through the IgE receptor is mediated by protein kinase C (PKC), protein kinase inhibitors have no effect on the F-actin response activated through the adenosine receptor. In contrast, pretreatment of the cells with pertussis toxin completely inhibits the F-actin response to NECA but has relatively little effect on the response induced through the IgE receptor. Stimulation of RBL cells through either receptor causes increased production of phosphatidylinositol mono-phosphate (PIP) and phosphatidylinositol bis-phosphate (PIP2), which correlates with the F-actin response. Production of PIP and PIP2 may be important downstream signals since these polyphosphoinositides are able to regulate the interaction of gelsolin and profilin with actin. Thus the polymerization of actin can be triggered through either the adenosine receptor or the IgE receptor, but different upstream signaling pathways are being used. The IgE mediated response requires the activation of PKC while stimulation through the adenosine receptor is PKC independent but involves a G protein.
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PMID:Polymerization of actin in RBL-2H3 cells can be triggered through either the IgE receptor or the adenosine receptor but different signaling pathways are used. 804 23

The monoclonal antibody (mAb) AA4 recognizes two alpha-galactosyl derivatives of the GD1b ganglioside on rat mast cells and on the rat basophilic leukemia RBL-2H3 cultured cell line. Here we demonstrate that mAb AA4 coprecipitated both protein tyrosine and serine kinases. In contrast, a monoclonal antibody to the GD3 ganglioside did not coprecipitate any kinase activity. In kinase assays of mAb AA4 immunoprecipitates there were phosphorylated proteins of 71-80, 53/56, and 41/42 kDa. All proteins were phosphorylated on tyrosine, whereas the 71-80- and 41/42-kDa proteins were also phosphorylated on serine residues. The precipitation of these proteins by mAb AA4 correlated with the presence of the alpha-galactosyl derivatives of GD1b. The 53/56-kDa proteins were identified as the Src-related tyrosine kinase p53/56lyn. The presence of p53/56lyn in the mAb AA4 immunoprecipitates was specific and was observed when several different detergents were used. The same 71-80-kDa tyrosine-phosphorylated proteins were immunoprecipitated by mAb AA4 and anti-Lyn antibodies and may play a role in the interaction of p53/56lyn with the gangliosides. Although there is a weak association of the high affinity IgE receptor with these gangliosides, the coprecipitation of p53/56lyn with mAb AA4 was not secondary to the association of this kinase with receptor. These complexes of gangliosides and several proteins that include p53/56lyn, a serine kinase, and the high affinity IgE receptor could play an important role in receptor-mediated signal transduction.
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PMID:Src family tyrosine kinase p53/56lyn, a serine kinase and Fc epsilon RI associate with alpha-galactosyl derivatives of ganglioside GD1b in rat basophilic leukemia RBL-2H3 cells. 810 8

We have previously shown that macrophage-secreted prostaglandins of the E series (PGE) and other agents which increase cAMP inhibit IgM production and proliferation of murine B lymphocytes. In this study, we show that PGE2 inhibits B cell activation events including enlargement, class II MHC hyperexpression, and the expression of the low-affinity receptor for IgE, Fc epsilon RII/CD23 (35-50%) in a cAMP-dependent manner. PGE action is mimicked by other cAMP-inducing agents and is inhibited by RpcAMP (a nonhydrolyzable cAMP analog which is a competitive inhibitor of cAMP-dependent protein kinase A). PGE2 could inhibit enlargement and upregulation of activation Ag even if preincubated with cells and then washed out prior to B cell stimulation. This change in B cell phenotype was abrogated if the reversible protein synthesis inhibitor cycloheximide was included during B cell incubation with PGE2. To identify the newly synthesized cAMP- and PGE-inducible regulatory proteins (PIRP), two-dimensional gel electrophoresis of lysates of B lymphocytes treated +/- PGE2 was performed. This report is the first to identify putative PIRP proteins. The roles of PIRP in PGE regulation of B cell activation and class switching are discussed.
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PMID:Prostaglandin E2 inhibits B lymphocyte activation by a cAMP-dependent mechanism: PGE-inducible regulatory proteins. 813 Dec 4

The B cell surface antigen receptor, surface IgM (sIgM), is involved in B cell activation and proliferation. CD40 is involved in regulating IgE production and B cell survival. Cross-linking of B cell sIgM activates the Ras/Raf/p42erk2 pathway. In contrast, ligation of CD40 by antibody or soluble gp39 (CD40 ligand) leads to activation of the c-Jun kinase (JNK)/stress-activated protein kinase pathway. JNK/stress-activated protein kinase activation correlated with the stimulation of MEK kinase activity. CD40 does not activate the p42erk2 pathway, and sIgM fails to regulate the JNK/stress-activated protein kinase pathway in B cells. Thus, two important cell surface receptors involved in controlling specific B cell response differentially regulate sequential protein kinase pathways involving different members of the mitogen-activated protein kinase family. Anti-CD40 also rescued B cell apoptosis induced by anti-IgM. CD40 ligation did not affect the sIgM stimulation of p42erk2 activity. Conversely, sIgM ligation did not influence CD40 stimulation of JNK/stress-activated protein kinase. These results suggest that independent, parallel protein kinase response pathways are involved in the integration of sIgM and CD40 control of B cell phenotype and function.
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PMID:Selective activation of c-Jun kinase mitogen-activated protein kinase by CD40 on human B cells. 853 May 26

We have investigated the effects of wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), on antigen-mediated signaling in the RBL-2H3 mast cell model. In RBL-2H3 cells, the cross-linking of high affinity IgE receptors (Fc epsilon R1) activates at least two cytoplasmic protein tyrosine kinases, Lyn and Syk, and stimulates secretion, membrane ruffling, spreading, pinocytosis, and the formation of actin plaques implicated in increased cell-substrate adhesion. In addition, Fc epsilon R1 cross-linking activates PI 3-kinase. It was previously shown that wortmannin causes a dose-dependent inhibition of PI 3-kinase activity and also inhibits antigen-stimulated degranulation. We report that the antigen-induced synthesis of inositol(1,4,5)P3 is also markedly inhibited by wortmannin. Consistent with evidence in other cell systems implicating phosphatidylinositol(3,4,5)P3 in ruffling, pretreatment of RBL-2H3 cells with wortmannin inhibits membrane ruffling and fluid pinocytosis in response to Fc epsilon R1 cross-linking. However, wortmannin does not inhibit antigen-induced actin polymerization, receptor internalization, or the actin-dependent processes of spreading and adhesion plaque formation that follow antigen stimulation in adherent cells. Wortmannin also fails to inhibit either of the Fc epsilon R1-coupled tyrosine kinases, Lyn or Syk, or the activation of mitogen-activated protein kinase as measured by in vitro kinase assays. Strikingly, there is substantial in vitro serine/threonine kinase activity in immunoprecipitates prepared from Fc epsilon R1-activated cells using antisera to the p85 subunit of PI 3-kinase. This activity is inhibited by pretreatment of the cells with wortmannin or by the direct addition of wortmannin to the kinase assay, suggesting that PI 3-kinase itself is capable of acting as a protein kinase. We conclude that Fc epsilon R1 cross-linking activates both lipid and protein kinase activities of PI 3-kinase and that inhibiting these activities with wortmannin results in the selective block of a subset of Fc epsilon R1-mediated signaling responses.
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PMID:Wortmannin blocks lipid and protein kinase activities associated with PI 3-kinase and inhibits a subset of responses induced by Fc epsilon R1 cross-linking. 853 12

We studied the effects of beta 2-adrenoceptor agonist on IgE production in vitro in human and in vitro and in vivo in mouse. We observed that salbutamol and fenoterol potentiate the IL-4-induced IgE production from peripheral blood mononuclear cells. This effect is associated by an enhanced mRN expression for IgE. Fenoterol also potentiated, but in a lesser extent, the IgE production from purified B lymphocytes stimulated by both IL-4 and CD40, suggesting that the activity of beta 2-adrenoceptor agonist is mediated through T lymphocyte or monocyte modulation. Fenoterol also inhibited the PHA-induced IFN-gamma production by T lymphocytes. Analogues of cAMP or activator of PKA also elicited an increase in IgE production. Moreover, the effect of fenoterol on IgE production was suppressed in the presence of PKA inhibitor. Salbutamol also potentiated the IL-4-induced IgE production from murine splenocytes activated by LPS. Furthermore, mice sensitized to ovalbumin elicited increased IgE responses after daily injection of salbutamol. This was accompanied by an increased in cytokines of Th2 subtypes. Our results showed that beta 2-adrenoceptor agonist, which are currently used in the treatment of asthma, potentiate the IgE production in vitro and in vivo.
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PMID:[Effects of beta-adrenergic compounds on IgE production]. 858 26

Aggregation of the high affinity receptor for IgE (FcepsilonRI) on the mucosal mast cell line, RBL-2H3, results in the rapid and persistent tyrosine phosphorylation of Vav. Immunoprecipitation of Vav from activated cells revealed co-immunoprecipitated phosphoproteins of molecular weights identical to the FcepsilonRI beta and gamma chains, and the former was reactive with antibody to the FcepsilonRI beta chain. Conversely, Western blots revealed the presence of p95 Vav in FcepsilonRI immunoprecipitates. The association of Vav and of Grb2 with the receptor was found to be regulated by aggregation of the receptor, and the interaction of Vav with the FcepsilonRI was localized to the gamma chain. To gain insight on the signaling pathway in which Vav participates, we investigated the in vivo associations of Vav with other molecules. A reducible chemical cross-linking agent was used to covalently maintain protein interactions under nonreducing conditions. A fraction of Vav increased in mass to form a complex of >300 kDa in molecular mass. Under reducing conditions the cross-linked Vav immunoprecipitates showed the presence of Grb2, Raf-1, and p42(mapk) (ERK2). In vitro kinase assays of Raf-1 activity associated with Vav revealed that this complex had an activity greater than that of Raf-1 derived from nonactivated cells, and aggregation of the FcepsilonRI did not modulate this activity. In contrast, aggregation of the FcepsilonRI increased the total Raf-1 activity by 2-5-fold. These results demonstrate that Vav associates constitutively with components of the mitogen-activated protein kinase pathway to form an active multimeric signaling complex whose in vivo activity and associations may be directed by aggregation of the FcepsilonRI. The findings of this study may also be relevant to other members of the immune recognition receptor family that share the T-cell antigen receptor zeta/gamma chains.
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PMID:Association of a p95 Vav-containing signaling complex with the FcepsilonRI gamma chain in the RBL-2H3 mast cell line. Evidence for a constitutive in vivo association of Vav with Grb2, Raf-1, and ERK2 in an active complex. 890 Jan 82


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