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)

Activation of the multicomponent interleukin-2 receptor (IL-2R) complex leads to a rapid increase in tyrosine phosphorylation of a number of cellular proteins including the IL-2R beta and IL-2R gamma chains of the IL-2R and the RAF-1 serine threonine kinase. In addition, phosphatidylinositol 3-kinase (PI-3K) protein and activity can be immunoprecipitated with anti-phosphotyrosine and anti-IL-2R beta antibodies from IL-2-activated but not resting T lymphocytes. We have demonstrated that the SH2 (SRC homology 2) domains of the 85 kDa subunit of PI-3K are sufficient to mediate binding of the PI-3K complex to tyrosine phosphorylated, but not non-phosphorylated IL-2R beta, suggesting that tyrosine phosphorylation is an integral component of the activation of PI-3K by the IL-2R. Since none of the members of the IL-2R complex contains an intrinsic tyrosine kinase domain, IL-2-induced tyrosine phosphorylation must be the consequence of activation of intracellular tyrosine kinases. SRC family members including lck, lyn and fyn have been demonstrated to associate with IL-2R beta through binding of the kinase domain to the acidic domain of IL-2R beta. However, we have demonstrated that the serine rich (SD) region of the cytosolic domain of IL-2R beta is also required for association of a tyrosine kinase with the IL-2R complex and that IL-2 can induce proliferation and tyrosine phosphorylation in cell lines which lack the known SRC family kinases expressed by T lymphocytes. Thus members of other kinase families besides SRC may also be involved in mediating IL-2 signal transduction. Biochemical studies and studies of cells expressing mutant IL-2 receptors indicate that IL-2-induced tyrosine kinase activation initiates a complex signaling cascade. The cascade includes SRC family kinase members such as lck, fyn, and lyn, activation of Raf-1 and PI-3K, and ras, and increased expression of the fos, fra-1, and jun protooncogenes. In addition, ligation of the IL-2R leads to rapid increases in myc expression and more delayed increases in the expression of the cdc2 and cdk2 kinases and the cyclins through a tyrosine phosphorylation independent pathway. Whether other biochemical processes initiated by IL-2R ligation, including activation of the MAP2, p70S6 and p90RSK serine threonine kinases, activation of NF-kappa B, and increased expression of Raf-1, Pim-1, bcl-2, IL-2R alpha and IL-2R beta, are consequences of the IL-2-induced tyrosine kinase cascade remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transmembrane signaling by the interleukin-2 receptor: progress and conundrums. 826 Jun 51

AP-1 is a transcriptional activator composed of homo- and heterodimers of Jun and Fos proteins. It is involved in activation of genes, such as collagenase, stromelysin, IL-2 and TGF beta 1, by tumour promoters, growth factors and cytokines. AP-1 activity is also elevated in response to transforming oncogenes and is required for cell proliferation. AP-1 activity is subject to complex regulation both transcriptionally and post-transcriptionally. Transcriptional control of jun and fos gene expression determines the amount and composition of the AP-1 complex. The jun and fos genes are regulated both positively and negatively and are highly inducible in response to extracellular stimuli. Post translational control is also important. Both cJun and cFos are subject to regulated phosphorylation. In the case of cJun, phosphorylation of sites near the DNA-binding domain inhibits DNA-binding, while dephosphorylation reverses this inhibition. Phosphorylation of cJun on sites within the N-terminal activation domain increases its ability to activate transcription. The protein kinase phosphorylating these sites is stimulated by cytokines and growth factors. Another mechanism modulating AP-1 activity is transcriptional interference by members of the nuclear receptor family and is relevant for the pathophysiology of rheumatoid arthritis (RA). In RA, chronic inflammation leads to increased AP-1 activity in T cells,macrophages and synoviocytes as a response to secretion of cytokines such as IL-1 and TNF alpha. While the IL-2 gene plays a major role in T cell activation, another AP-1 target gene encodes an enzyme, collagenase, responsible for destruction of bone and tendon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Various modes of gene regulation by nuclear receptors for steroid and thyroid hormones. 831 34

In rheumatoid arthritis and other inflammatory diseases we and others have found that gamma delta T cells express activation antigens, suggesting that they are involved in the pathogenesis of these disorders. In this study we have stimulated peripheral blood mononuclear cells from normal donors with recombinant interleukin-2 (rIL-2) to see whether such a stimulus alone could activate gamma delta T cells. Short-term exposure (24-96 h) to rIL-2 selectively stimulated the gamma delta but not the alpha beta T cells to express activation antigens (CD69, CD25 and HLA-DR). Long-term culture (2 weeks) in rIL-2-containing medium caused a selective increase in the proportion of the gamma delta T cells and a corresponding reduction of the fraction of alpha beta T cells. Limiting dilution analysis revealed that approximately 1/60 of the gamma delta T cells responded to IL-2 in contrast to only 1/250 of the alpha beta T cells. Comparison of the expression of the IL-2 receptor (IL-2R) alpha and beta chains showed that there was a similar expression of the alpha chain on gamma delta and alpha beta T cells whereas the relative density of the beta chain was more than twice as high on gamma delta T cells. Both the IL-2-induced proliferation of gamma delta T cells and the expression of activation antigens on these cells could be inhibited by an anti-IL-2R beta monoclonal antibody (mAb) but not by an anti-IL-2R alpha mAb. Expression of CD69 on gamma delta T cells was dependent neither on the presence of B cells, monocytes, nor alpha beta T cells. Finally, we found that the IL-2-induced expression of CD69 was inhibited by activation of cAMP-dependent protein kinase and by inhibition of the Src-family of the tyrosine protein kinase, but not by inhibition of protein kinase C or by activation of the CD45 associated tyrosine phosphatase. The ability of gamma delta T cells to be activated by IL-2 is a feature which they have in common with natural killer cells. Moreover, it may be possible that the expression of activation antigens on gamma delta T cells in inflammatory diseases is an epiphenomenon secondary to IL-2 produced by activated alpha beta T cells.
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PMID:Selective activation of resting human gamma delta T lymphocytes by interleukin-2. 837 Mar 91

IFN-alpha influences the recirculation and growth of normal and malignant B lymphocytes, although the mechanisms involved are not currently known. Lymphocyte recirculation is fundamentally dependent on cell-to-cell interactions that are mediated by cell surface adhesion molecules. In this report, we examined the relationship between the effect of IFN-alpha on cell-to-cell adhesion processes and induction of the Leu-13 cell surface protein in established human Daudi B lymphoid cell lines that are either sensitive or resistant to the antiproliferative activity of IFN-alpha. IFN-alpha directly triggered homotypic adhesion of IFN-sensitive Daudi B cells in a time- and dose-dependent manner. In contrast, IFN-alpha had no effect on the cell-to-cell adhesion of IFN-resistant Daudi B cells. The capacity of IFN-alpha to trigger homotypic aggregation correlated directly with the level of induction of the cell surface protein Leu-13 and could be potentiated by anti-Leu-13 mAb. Other cytokines also known to influence the proliferation, differentiation, or recirculation of B lymphocytes such as IFN-gamma, IL-2, IL-4, IL-6, TNF-alpha, and low molecular weight B cell growth factor did not induce either Leu-13 expression or homotypic aggregation of Daudi B cells. The adhesion pathway triggered by the IFN-inducible protein Leu-13 required metabolic energy and an intact cytoskeleton but was not dependent on: 1) new protein synthesis; 2) protein kinase C, protein kinase A, or tyrosine kinase activities; or 3) the function of known adhesion molecules including LFA-1, ICAM-1, CD44, or VLA-4. Taken together, these studies demonstrate a fundamental role for IFN-alpha and the IFN-inducible protein Leu-13 in regulating a novel homotypic adhesion pathway in B lymphocytes, and provide insight into the possible mechanisms by which IFN-alpha regulates biologic processes including recirculation.
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PMID:IFN-alpha induces homotypic adhesion and Leu-13 expression in human B lymphoid cells. 842 37

The mechanism of interleukin-1 (IL-1) signaling is unknown. Tumor necrosis factor-alpha uses a signal transduction pathway that involves sphingomyelin hydrolysis to ceramide and stimulation of a ceramide-activated protein kinase. In intact EL4 thymoma cells, IL-1 beta similarly stimulated a rapid decrease of sphingomyelin and an elevation of ceramide, and enhanced ceramide-activated protein kinase activity. This cascade was also activated by IL-1 beta in a cell-free system, demonstrating tight coupling to the receptor. Exogenous sphingomyelinase, but not phospholipases A2, C, or D, in combination with phorbol ester replaced IL-1 beta to stimulate IL-2 secretion. Thus, IL-1 beta signals through the sphingomyelin pathway.
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PMID:Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1 beta. 842 75

Theileria parva is an obligate, intracellular, parasitic protozoan that causes East Coast fever, an acute leukemia-like disease of cattle. T. parva and the related parasite, Theileria annulata, are unique among protozoa in that their intralymphocytic stages induce transformation of bovid lymphocytes. Comparison of in vitro protein kinase activities between uninfected IL-2-dependent T lymphoblasts and T. parva-infected lymphocytes revealed a 4.7- to 12-fold increase in total phosphorylation and the induction of a group of Theileria infection-specific phosphoproteins. The enzyme that phosphorylates these substrates is a serine/threonine kinase with substrate and effector specificities of casein kinase (CK) II. Northern blot analyses revealed a 3.9- to 6.0-fold increase in CKII alpha mRNA in the infected cells relative to the controls. Furthermore, a marked increase of CKII antigen was observed on Western blots of materials prepared from the infected cell lines. The antibovine CKII antibody used in these studies immunoprecipitated a protein kinase that phosphorylated casein in a reaction that was inhibited by low (nM) quantities of heparin. Our data show marked increases of bovine CKII at the transcriptional, translational and functional levels in T. parva-infected lymphocytes, relative to quiescent cells or IL-2-dependent parental lymphoblasts. Bovine CKII thus appears to be constitutively activated in these cells and we propose that this kinase may be an important element in the signal-transducing pathways activated by Theileria in bovid lymphocytes and perhaps in some leukemic cells.
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PMID:Evidence for the induction of casein kinase II in bovine lymphocytes transformed by the intracellular protozoan parasite Theileria parva. 846 9

The experiments reported herein have characterized the signaling pathway leading to stimulation of type I protein kinase A isozyme (PKA-I) activity during the early events of Ag receptor-mediated T cell activation. Inhibitor studies demonstrated that receptor-initiated activation of nonreceptor protein tyrosine kinases, phosphorylation and activation of phospholipase C-gamma 1, and activation of protein kinase C occur temporally and precede PKA-I activation. Bypass of both the TCR/CD3 complex and IL-1R and direct activation of protein kinase C by a phorbol ester can also activate PKA-I. To confirm that PKA-I activation via the TCR/CD3 complex and IL-1R requires antecedent protein tyrosine kinase-catalyzed phosphorylation of phospholipase C-gamma 1, we used wild-type and CD45-deficient (mutant J45.01) Jurkat T cell lines. Unlike wild-type Jurkat T cells, the absence of CD45 tyrosine phosphatase resulted in the failure of receptor-mediated activation of PKA-I activity and of IL-2 mRNA transcription in the mutant J45.01 Jurkat cell line. In conclusion, our data support the concept that a signal derived from ligand binding to both the TCR/CD3 complex and IL-1R receptor mediates rapid activation of the PKA-I isozyme in primary T lymphocytes by sequential activation of an intracellular pathway comprised of CD45 phosphatase/protein tyrosine kinase/polyphosphoinositide/Ca2+/protein kinase C pathway rather than via the conventional surface receptor/stimulatory G protein system.
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PMID:Activation of type I protein kinase A during receptor-mediated human T lymphocyte activation. 854 99

We have studied pim-1 proto-oncogene expression in human T cell responses to Ag receptor-generated signals. The pim-1 gene encodes a serine/threonine protein kinase that is expressed primarily in cells of hematopoietic lineage and is implicated in the intracellular signaling processes accompanying lymphocyte activation. We show here that pim-1 mRNA expression is rapidly induced after receptor cross-linking with anti-CD3 Abs. We examined the linkage of pim-1 expression to known signaling pathways generated through the T cell Ag receptor. pim-1 mRNA was not substantially induced after elevation of intracellular free Ca2+. In contrast, PMA, which directly activates PKC, induced rapid pim-1 expression. Further, anti-CD3- or PMA-induced pim-1 expression was markedly reduced by various PKC inhibitors and by deficiency of the PKC epsilon isoform in a mutant T cell line. Thus, T cell Ag receptor-linked pim-1 expression appears to be coupled to the PKC component of transmembrane signaling. Because the activation of protein kinase C has been shown to activate Raf-1 kinase activity, the involvement of Raf-1 in pim-1 expression was also investigated using a human T cell line stably transfected with an inducible Raf expression vector. Although the overexpression of activated Raf was shown to cause a substantial increase in IL-2 expression, no discernible effects on pim-1 were apparent. In addition, we examined transcriptional and post-transcriptional mechanisms involved in PKC-mediated pim-1 expression and observed that both transcriptional and post-transcriptional mechanisms are coordinately involved in the up-regulation of the pim-1 proto-oncogene.
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PMID:pim-1 proto-oncogene expression in anti-CD3-mediated T cell activation is associated with protein kinase C activation and is independent of Raf-1. 854 5

In the present study, we have investigated the involvement of the cyclic adenosine monophosphate (cAMP)-dependent signaling pathway on interleukin-4 (IL-4) gene expression in freshly isolated human T lymphocytes. 2'-0-dibutyryl cAMP (db-cAMP) and prostaglandin E2 (PGE2) were used to directly and indirectly activate the protein kinase A pathway. Northern analysis showed that concanavalin A (Con A)-, anti-CD3 (alpha CD3)-, or anti-CD3 plus anti-CD28 (alpha CD3/alpha CD28)-induced accumulation of IL-4 mRNA was inhibited by db-cAMP (10(-3) mol/L). Db-cAMP showed a steep dose-dependent inhibition; concentrations < or = 10(-4) mol/L did not affect IL-4 mRNA accumulation. In contrast, GM-CSF mRNA expression showed a wider dose-dependent range; 10(-5) mol/L db-cAMP still affected GM-CSF accumulation. PGE2 inhibited the Con A- and alpha CD3/alpha CD28-induced accumulation of IL-4 mRNA in a dose-dependent fashion. Con A-induced IL-4 mRNA was inhibited by 10(-4) to 10(-7) mol/L PGE2; alpha CD3/alpha CD28-induced IL-4 mRNA was inhibited by 10(-5) to 10(-8) mol/L PGE2. Nuclear run-on experiments showed that the inhibitory effects of db-cAMP and PGE2 were accomplished at transcriptional level in Con A-activated T cells, whereas changes at transcriptional and posttranscriptional level were involved in alpha CD3/alpha CD28-activated T lymphocytes. In contrast to Con A and alpha CD3/alpha CD28 activation, phorbol myristate acetate plus A23187-induced IL-4 mRNA expression was insensitive to the inhibitory effect of db-cAMP and PGE2. Moreover, it appeared that the sensitivity for cAMP-mediated downregulation could not be blocked by stimulation T lymphocytes with alpha CD3/alpha CD28 in the presence of IL-2, IL-7, IL-10, IL-12, or a combination of these cytokines. Finally, it was shown that, in accordance with the mRNA studies, db-cAMP and PGE2 suppressed the IL-4 secretion in Con A- and alpha CD3/alpha CD28-activated T cells. In conclusion, these data show that IL-4 expression is negatively regulated by the protein kinase A-dependent signaling pathway by transcriptional and posttranscriptional mechanisms that depend on costimulatory signals.
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PMID:Interleukin-4 gene expression in activated human T lymphocytes is regulated by the cyclic adenosine monophosphate-dependent signaling pathway. 855 92

TCR engagement stimulates the activation of the protein kinase Raf-1. Active Raf-1 phosphorylates and activates the mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase kinase 1 (MEK1), which in turn phosphorylates and activates the MAP kinases/extracellular signal regulated kinases, ERK1 and ERK2. Raf-1 activity promotes IL-2 production in activated T lymphocytes. Therefore, we sought to determine whether MEK1 and ERK activities also stimulate IL-2 gene transcription. Expression of constitutively active Raf-1 or MEK1 in Jurkat T cells enhanced the stimulation of IL-2 promoter-driven transcription stimulated by a calcium ionophore and PMA, and together with a calcium ionophore the expression of each protein was sufficient to stimulate NF-AT activity. Expression of MEK1-interfering mutants inhibited the stimulation of IL-2 promoter-driven transcription and blocked the ability of constitutively active Ras and Raf-1 to costimulate NF-AT activity with a calcium ionophore. Expression of the MAP kinase-specific phosphatase, MKP-1, which blocks ERK activation, inhibited IL-2 promoter and NF-AT-driven transcription stimulated by a calcium ionophore and PMA, and in addition, MKP-1 neutralized the transcriptional enhancement caused by active Raf-1 and MEK1 expression. We conclude that the MAP kinase signal transduction pathway consisting of Raf-1, MEK1, and ERK1 and ERK2 functions in the stimulation IL-2 gene transcription in activated T lymphocytes.
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PMID:MEK1 and the extracellular signal-regulated kinases are required for the stimulation of IL-2 gene transcription in T cells. 855 75


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