Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-2 (IL-2) stimulates proliferation of T lymphocytes and is involved in the activation of both natural killer and lymphokine-activated killer precursor cells. The intracellular messengers which mediate IL-2-dependent events have not yet been identified. IL-2 receptor is not a protein-tyrosine kinase. Activation of a cellular protein-tyrosine kinase and direct association of a protein-tyrosine kinase activity with the IL-2 receptor occurs within minutes of IL-2 stimulation. We investigated the activation of phosphatidylinositol 3-kinase (PI 3-kinase) in IL-2-mediated signal transduction using the IL-2-dependent murine T-cell line, CTLL-2, and human phytohemagglutinin-stimulated peripheral blood lymphocytes (phytohemagglutinin blasts). Within a minute following stimulation of these cells with IL-2, PI 3-kinase activity could be detected in antiphosphotyrosine (anti-P-Tyr) antibody immunoprecipitates. IL-2 triggered a direct association of PI 3-kinase with the IL-2 receptor as detected in immunoprecipitates using anti-IL-2 receptor beta chain antibody. In vivo labeled CTLL-2 cells have a time-dependent increase in D-3-phosphorylated polyphosphoinositides following stimulation with IL-2. This is the first group of second messengers identified in IL-2-mediated signal transduction.
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PMID:Interleukin-2 receptor regulates activation of phosphatidylinositol 3-kinase. 171 78

The intracellular portion of the IL-2 receptor (IL-2R) signal transducing beta-chain contains a distinct region, designated "serine-rich," which encompasses sequences required for IL-2-mediated cell growth. Although the receptor does not possess intrinsic protein-tyrosine kinase activity, IL-2 binding induces activation of intracellular protein-tyrosine kinases. Activation of many protein-tyrosine kinases leads to activation of phosphatidylinositol 3-kinase (PI 3-kinase). IL-2 binding also induces activation of PI 3-kinase. To study the interaction of PI 3-kinase with the IL-2 receptor beta-chain we analyzed PI 3-kinase activity in cells which express the wild type and mutant beta-chain. IL-2 mediated an increase in association with PI 3-kinase activity and protein in immunoprecipitates from cells expressing mitogenically competent receptors. PI 3-kinase products also increased in response to IL-2 in these cells. Deletion of the beta-chain serine-rich region abolished IL-2-mediated mitogenesis and cells expressing this mutant failed to activate PI 3-kinase. The interaction of the IL-2 receptor with an intracellular tyrosine kinase, lck, has been mapped to the acidic-rich region of the beta-chain. Cells which express the beta-chain lacking the acidic-rich region grow in the presence of IL-2 and had IL-2-dependent activation of PI 3-kinase. Activation of PI 3-kinase in response to IL-2 was not abolished by treatment of cells with rapamicin and occurred only in cells which express mitogenically competent receptors. The results presented in this study suggest that IL-2-mediated PI 3-kinase activation occurs by a mechanism distinct from interaction with the lck protein-tyrosine kinase.
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PMID:Serine-rich region of the IL-2 receptor beta-chain is required for activation of phosphatidylinositol 3-kinase. 802 55

Glucocorticoids (GC) are potent immunosuppressive agents that interfere with interleukin-2 (IL-2)-dependent proliferation and IL-2 receptor signal transduction in T lymphocytes through complex mechanisms. Here we report that the basal activity, and IL-2- and phorbol ester-dependent activation of the p70/p85 S6 kinases (referred to collectively as pp70S6k) are inhibited by the glucocorticoid dexamethasone (Dex) in CTLL-20 cells. This Dex-induced inhibition is time- and dose-dependent, appears to be the consequence of pp70S6k dephosphorylation, and requires ongoing transcription. Attempts to establish a link between Dex action and those of known pp70S6k-regulating agents such as phosphatidylinositol 3-kinase, protein kinase A-stimulating agents, calyculin A-inhibited protein phosphatases, and rapamycin have been negative. Additional results with NIH3T3 cells suggest the existence of a T cell-specific blockade of pp70S6k by Dex. Implications are 2-fold: 1) pp70S6k inactivation may account for at least part of the immunosuppressive effects of GC in vivo, and 2) GC inactivation of pp70S6k is exerted through a novel, distinct mechanism that does not appear to be linked to any other known pp70S6k regulatory process.
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PMID:Inhibition of p70/p85 S6 kinase activities in T cells by dexamethasone. 888 45

IL-2 binding to its high-affinity receptor regulates signaling events that control both lymphocyte cell survival and cell cycle progression. Although many studies have examined the mechanisms by which IL-2 regulates cell growth, few studies have dissected the pathways involved in promoting cell survival or the coupling of these pathways to the receptor. In the present study, using the pre-B cell line Baf-B03 transfected with a truncated form of the IL-2 receptor (IL-2R) beta chain, we demonstrate that IL-2-dependent cell survival requires only the N-terminal 350 amino acids of the IL-2Rbeta chain. IL-2-dependent survival of cells expressing the truncated receptor correlates with increases in receptor-associated phosphatidylinositol 3-kinase (PI3K) activity and expression of Bcl-X(L), but not with changes in c-Myc expression or proliferation. Inhibition of the PI3K pathway in these cells, but not in cells expressing the wild-type receptor, has a marked effect on the capacity of IL-2 to prevent cell death and diminishes the Bcl-X(L) response. The requirement for IL-2-induced PI3K activity in suppressing the onset of apoptotic cell death is discussed.
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PMID:An IL-2 receptor beta subdomain that controls Bcl-X(L) expression and cell survival. 1022 82

In recent times 3-phosphoinositides have emerged as important regulators of cell metabolism, survival, and proliferation. During the last year, the phospholipid phosphatidylinositol 3, 5-bisphosphate (PtdIns3,5P2) was identified in yeast, fibroblasts, SV40-transformed kidney (COS-7) cells, and platelets. The discovery of this novel phospholipid has increased the complexity of the metabolism relating to the generation of biologically active inositol-containing lipids. We describe here the identification of PtdIns3,5P2 in the CTLL-2 mouse T-lymphocyte cell line using two in vivo radiolabeling protocols. Treatment of the cells with UV radiation led to an increase in the cellular content of PtdIns3,5P2. In contrast, preincubation of the cells with wortmannin or treatment with hypertonic medium (high concentration sorbitol) led to the opposite effect. Herein we demonstrate that interleukin-2 (IL-2), the growth factor required for CTLL-2 cell proliferation, was able to increase the level of PtdIns3,5P2 with similar kinetics to that of the formation of phosphatidylinositol 3,4-bisphosphate (PtdIns3, 4P2). An increase in this novel 3-phosphorylated lipid in response to IL-2 seems to be a general property of this cytokine because a similar result was obtained when the pre-B cell line BaF/3 expressing the high affinity IL-2 receptor was used. Using a constitutively active regulatory subunit of type I phosphatidylinositol 3-kinase and cells expressing a deletion of the serine-rich domain of the IL-2 receptor beta chain, which is required for IL-2-stimulated type I phosphatidylinositol 3-kinase activation, we demonstrate that IL-2-induced generation of PtdIns3, 5P2 is related to the activation of this enzyme. The results show for the first time the identification of PtdIns3,5P2 in both T- and B-lymphocytes and indicate its positive regulation by the mitogen IL-2.
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PMID:The identification of phosphatidylinositol 3,5-bisphosphate in T-lymphocytes and its regulation by interleukin-2. 1037 47

TRAIL (TNF-related apoptosis inducing ligand), like other members of the TNF family of proteins, is able to induce apoptosis in sensitive target cells. Recently, cell-surface TRAIL has been shown to be expressed by activated human and mouse T lymphocytes, raising the possibility that TRAIL might be involved in T cell-mediated cytotoxicity and/or immune regulation. In the present study we show by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis that activated, but not resting, mouse T cells express abundant TRAIL mRNA. TRAIL transcripts were detectable within 4 h of T cell activation. A panel of pharmacologic inhibitors was used to investigate the signal transduction pathways involved in TRAIL gene induction following T lymphocyte activation. TRAIL gene expression was sensitive to the src-like protein tyrosine kinase (PTK) inhibitor herbimycin A, as well as the more general PTK inhibitor genistein, suggesting the involvement of a src family PTK. The PKC inhibitors staurosporine and calphostin C, and the phosphatidylinositol 3-kinase (PI3-K) inhibitors wortmannin and LY294002, also prevented TRAIL mRNA transcription by activated T cells, indicating a role for PKC and PI3-K. In addition, TRAIL induction was inhibited by cyclosporin A, implicating the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin. TRAIL expression was also blocked by rapamycin, which inhibits p70 S6 kinase involved in CD28 and interleukin (IL)-2 receptor signaling. However, TRAIL mRNA expression was not induced by IL-2, suggesting that TRAIL gene induction is not coupled to the IL-2 receptor. Data obtained by RT-PCR were confirmed at the protein level by immunoblotting with TRAIL-specific antibody. We conclude that TRAIL gene induction is initiated through a T cell receptor-associated signaling pathway similar to that responsible for the expression of cytokine genes such as IL-2.
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PMID:Murine TRAIL (TNF-related apoptosis inducing ligand) expression induced by T cell activation is blocked by rapamycin, cyclosporin A, and inhibitors of phosphatidylinositol 3-kinase, protein kinase C, and protein tyrosine kinases: evidence for TRAIL induction via the T cell receptor signaling pathway. 1050 2

Most, if not all, cytokines activate phosphatidylinositol 3-kinase (PI-3K). Although many cytokine receptors have direct binding sites for the p85 subunit of PI-3K, others, such as the interleukin-3 (IL-3) receptor beta common chain (betac) and the IL-2 receptor beta chain (IL-2Rbeta), lack such sites, leaving the mechanism by which they activate PI-3K unclear. Here, we show that the protooncoprotein Shc, which promotes Ras activation by recruiting the Grb2-Sos complex in response to stimulation of cytokine stimulation, also signals to the PI-3K/Akt pathway. Analysis of Y-->F and "add-back" mutants of betac shows that Y577, the Shc binding site, is the major site required for Gab2 phosphorylation in response to cytokine stimulation. When fused directly to a mutant form of IL-2Rbeta that lacks other cytoplasmic tyrosines, Shc can promote Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation. Overexpression of mutants of Grb2 with inactive SH2 or SH3 domains also blocks cytokine-stimulated Gab2 phosphorylation. The majority of cytokine-stimulated PI-3K activity associates with Gab2, and inducible expression of a Gab2 mutant unable to bind PI-3K markedly impairs IL-3-induced Akt activation and cell growth. Experiments with the chimeric receptors indicate that Shc also signals to the PI-3K/Akt pathway in response to IL-2. Our results suggest that cytokine receptors lacking direct PI-3K binding sites activate Akt via a Shc/Grb2/Gab2/PI-3K pathway, thereby regulating cell survival and/or proliferation.
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PMID:New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway. 1098 27

To become competent killer cells, CD8(+) T cells require stimulation through signal transduction pathways associated with the T-cell receptor, costimulatory molecules such as CD28, and cytokine receptors such as the interleukin (IL)-2 receptor. We used wortmannin and LY294002, two inhibitors of phosphatidylinositol 3-kinase (PI3-K), to study the role of PI3-K in mouse cytotoxic T-lymphocyte (CTL) induction in response to mitogenic anti-CD3 antibody. Anti-CD3-induced CD8(+) T-cell proliferation and CTL development were inhibited dose dependently by both PI3-K inhibitors. IL-2 synthesis by anti-CD3-activated CD8(+) T cells was also diminished by PI3-K inhibition. PI3-K inhibition resulted in a modest decrease in anti-CD3-induced CD4(+) T-cell proliferation but failed to affect IL-2 expression by anti-CD3-activated CD4(+) T cells. PI3-K inhibition during CTL induction resulted in decreased levels of mRNAs coding for granzyme B, perforin, and Fas ligand. In addition, CTL induced in the presence of PI3-K inhibitors failed to conjugate normally with P815 target cells. Exogenous IL-2 did not reverse the effects of PI3-K inhibition on CD8(+) T-cell proliferation and CTL induction. These results support the conclusion that PI3-K activation is involved in T-cell receptor, CD28, and IL-2 receptor signaling of CD8(+) T cells. PI3-K is, therefore, an important component of multiple signal transduction pathways involved in CTL generation.
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PMID:Phosphatidylinositol 3-kinase inhibitors prevent mouse cytotoxic T-cell development in vitro. 1135 90

The T cell costimulatory receptor 4-1BB enhances cell cycle progression and proliferation of CD8(+) T cells in both an IL-2-dependent and -independent manner. In these studies, 4-1BB costimulation was shown to increase cyclin D2, D3, and E expression, and concomitantly down-regulate the expression of the cyclin-dependent kinase inhibitor p27(kip1). 4-1BB increases cyclin D2 transcription via mitogen-activated/extracellular signal-regulated kinase-1/2 and LY294002-sensitive phosphatidylinositol 3-kinase (PI3K) signaling pathways. In addition, 4-1BB up-regulates cyclin D2 translation via PI3K/Akt/mammalian target of rapamycin (mTOR) pathways, presumably triggered by IL-2/IL-2 receptor ligation. The enhanced cyclin D2 and D3 expression initiates up-regulation of cyclin E expression and down-regulation of p27(kip1). Our results suggest a role for cyclin D2, D3, and E, and p27(kip1) proteins in the 4-1BB-mediated cell cycle progression of CD8(+) T cells in vivo.
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PMID:4-1BB enhances CD8+ T cell expansion by regulating cell cycle progression through changes in expression of cyclins D and E and cyclin-dependent kinase inhibitor p27kip1. 1288 87

The interleukin-2 (IL-2) receptor promotes T cell proliferation in part by inducing the expression of D-type cyclins, which enable cells to progress from the G1 to S phase of the cell cycle. We previously showed that the IL-2 receptor induces expression of cyclin D2 by activating the transcription factor Stat5, which binds directly and immediately to a site upstream of the cyclin D2 promoter. We show here that subsequent transcription of the cyclin D2 gene occurs by a delayed, cycloheximide-sensitive mechanism, which implies the involvement of additional regulatory mechanisms. The transcription factor c-Myc is induced by Stat5 and is reported to bind to two E box motifs in the cyclin D2 promoter. However, in IL-2-stimulated T cells, c-Myc does not appear to be involved in cyclin D2 induction, since we found that these two E boxes are preferentially bound by USF-1 and USF-2 and, moreover, are dispensable for cyclin D2 promoter activity. Instead, we found that Stat5 activates the phosphatidylinositol 3-kinase (PI3 kinase) pathway by a delayed, cycloheximide-sensitive mechanism and that PI3 kinase activity is essential for the induction of cyclin D2 by Stat5. Chromatin immunoprecipitation experiments revealed that PI3 kinase is required for the optimal binding of RNA polymerase II to the promoters of cyclin D2 as well as other genes. Our results reveal a novel link between PI3 kinase and RNA polymerase II promoter binding activity and demonstrate discrete, coordinated roles for the PI3 kinase and Stat5 pathways in cyclin D2 transcription.
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PMID:A permissive role for phosphatidylinositol 3-kinase in the Stat5-mediated expression of cyclin D2 by the interleukin-2 receptor. 1466 Jun 77


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