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: UNIPROT:P14784 (IL-2 receptor)
3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-9 (IL-9), a T-cell-derived cytokine, interacts with a specific receptor associated with the IL-2 receptor gamma chain. In this report, we analyze the functional domains of the human IL-9 receptor transfected into mouse lymphoid cell lines. Three different functions were examined: growth stimulation in factor-dependent pro-B Ba/F3 cells, protection against dexamethasone-induced apoptosis, and Ly-6A2 induction in BW5147 lymphoma cells. The results indicated that a single tyrosine, at position 116 in the cytoplasmic domain, was required for all three activities. In addition, we observed that human IL-9 reduced the proliferation rate of transfected BW5147 cells, an effect also dependent on the same tyrosine. This amino acid was necessary for IL-9-mediated tyrosine phosphorylation of the receptor and for STAT activation but not for IRS-2/4PS activation or for JAK1 phosphorylation, which depended on a domain closer to the plasma membrane. We also showed that JAK1 was constitutively associated with the IL-9 receptor. Activated STAT complexes induced by IL-9 were found to contain STAT1, STAT3, and STAT5 transcription factors. Moreover, sequence homologies between human IL-9 receptor tyrosine 116 and tyrosines (of other receptors activating STAT3 and STAT5 were observed. Taken together, these data indicate that a single tyrosine of the IL-9 receptor, required for activation of three different STAT proteins, is necessary for distinct activities of this cytokine, including proliferative responses.
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PMID:A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9. 875 28

Mutation of the gamma c chain common to interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors has been shown to be responsible for the X chromosome-linked severe combined immune deficiency (SCIDX1). Human SCIDX1 patients are characterized by an absence of T and natural killer cell differentiation. We report the case of a SCIDX1 patient who first had few detectable peripheral T cells, then developed, after haploidentical T-depleted bone marrow transplantation (BMT), up to 2,000/microL autologous T cells. These T cells have persisted over 8 years after BMT and were able to proliferate in the presence of mitogens and of some antigens, although to a lesser extent than control T cells. A stop mutation was identified which predicts that the major part of the cytoplasmic tail of gamma c is truncated. This mutation does not affect high-affinity IL-2 binding, but it partly decreases IL-2 endocytosis and prevents the downmodulation of the IL-2-receptor beta chain and the tyrosine phosphorylation of Jak 3 protein in response to IL-2. This report raises questions concerning the role of the gamma c chain in IL-2 receptor endocytosis and in T-cell development and differentiation.
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PMID:T-lymphocyte differentiation and proliferation in the absence of the cytoplasmic tail of the common cytokine receptor gamma c chain in a severe combined immune deficiency X1 patient. 878 27

In previous study, we observed that the purified substance Salmonella typhimurium-derived inhibitor of T-cell proliferation (STI) had an immunosuppressive effect, demonstrated as the suppression of mitogenic lectin-induced proliferation of murine spleen cells. In the present study, we confirmed the immunosuppressive effect of STI, which suppressed the proliferation of murine splenic T-lymphocytes activated with the anti-CD3 antibody (Ab) and phorbol 12-myristate-13 acetate (PMA) and this phenomenon was accompanied by augmentation of interferon-gamma (IFN-gamma) secretion and inhibition of interleukin-2 (IL-2) secretion. Furthermore, the augmentation of IFN-gamma secretion caused IL-2 receptor alpha chain (IL-2R alpha) over expression on T-cells. However, the addition of an anti-IFN-gamma Ab and recombinant IL-2 (rIL-2) did not reverse the suppressed T-cell proliferation, although the level of IL-2R alpha expression on T-cells recovered to around normal. Furthermore, Western blotting using an anti-phosphotyrosine Ab showed that IL-2R-mediated tyrosine phosphorylation of protein substrates in T-cells was inhibited by incubation with STI for 48 h and this inhibition was not reversed by adding the anti-IFN-gamma Ab and rIL-2. These results suggest that STI-induced suppression of T-cell proliferation involves a defect in IL-2R function and/or IL-2 signaling pathway in T-cells.
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PMID:A purified protein from Salmonella typhimurium inhibits proliferation of murine splenic anti-CD3 antibody-activated T-lymphocytes. 880 47

Although transmembrane signaling defect has been recognized as one of the major functional alterations involved in immune senescence, its biochemical nature as well as its precise molecular localization are still unknown. The available data indicate that an early step in the signaling cascade may be affected during the aging process. Because protein tyrosine kinases (PTK) are ubiquitously implicated in the initiation of physiological signals, they appear as prime candidates for age-related changes. The present investigation examined the effect of age on the activity of PTK associated with CD3, CD4, CD8 or the IL-2 receptor (IL-2R) in human T lymphocytes. By comparison with cells derived from young individuals, anti-CD3-activated T lymphocytes from elderly donors were more susceptible to herbimycin A, a PTK inhibitor known to prevent signal transduction by the T cell antigen receptor. This increased sensitivity of cells from senescent organisms to PTK inhibitors is most likely related to a lesser PTK activity since a significant decrease in the tyrosine phosphorylation of particular endogenous substrates was observed as a consequence of either CD3, CD4, CD8 or IL-2R activation. However, no age-related difference in tyrosine phosphorylation could be demonstrated when T cells were activated by pervanadate, a pharmacological activator of PTK. These results suggest that the intrinsic activity of the enzymes is preserved and that the age-associated defect in PTK activation occurs as a consequence of an upstream biochemical alteration. The defect in PTK activation could be the primary cause for the dysfunction of various components of the signaling cascade observed during the course of aging.
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PMID:Age-related tyrosine-specific protein phosphorylation defect in human T lymphocytes activated through CD3, CD4, CD8 or the IL-2 receptor. 881 96

Stimulation of human CD4+ T cell lines with interleukin 2 (IL-2) induces tyrosine, serine and threonine phosphorylation of a series of proteins involved in the IL-2 receptor (IL-2R) signaling pathway. Here, we examined whether IL-2 induces changes in the activity of protein serine/threonine phosphatases in antigen specific, CD4+ human T cell lines. Using inhibitors of protein phosphatases 1 (PP1, PP2A, and PP2B, we provide evidence, that IL-2 induces a downregulation of PP activity in the cytoplasmic/membrane fraction. Thus, IL-2R ligation for 30 min triggers a 16 percent decrease in total PP2A activity (p < 0.0005, n = 17) and a seven percent decrease in PP1 activity (p < 0.00005, n = 17). Cytokine-induced downregulation of PP2A activity reaches a maximum 60 min after IL-2R ligation, and returns to baseline levels within two hours. Downregulation of PPI activity reaches a maximum after 30 min and is largely reversed one hour after IL-2 stimulation. As determined from immunoblotting experiments using a specific anti-PP1 or anti-PP2A antibody, the amount of PPI and PP2A recovered from cytosolic/membrane fraction remains unchanged after IL-2 treatment suggesting that the drop in PP1/PP2A activity might be due to a regulatory change rather than to a change in the amount of PP1 and PP2A. In conclusion, we provide evidence, for the first time, that IL-2 induces a transient downregulation of PP2A activity in T cells. In addition, our findings indicate that cytoplasmic PP1 activity is transiently downregulated following IL-2R ligation in antigen-specific, human CD4+ T cells.
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PMID:Interleukin 2 induces a transient downregulation of protein phosphatase 1 and 2A activity in human T cells. 909 29

We searched for immediate early cytokine responsive genes and isolated a novel gene, CIS (Cytokine Inducible SH2 containing protein) that is induced in hematopoietic cells by a subset of cytokines including interleukin-2 (IL-2), IL-3, and erythropoietin (EPO). The mutant IL-2 receptor that fails to activate STAT5 could not induce CIS, suggesting that STAT5 is involved in the cytokine-inducible expression of CIS. We cloned the 5'-flanking region of the CIS gene and found that about 200 bases upstream of the transcription-initiation site contain four potential STAT5 binding sites (MGF boxes). Luciferase reporter assays showed that these MGF boxes were essential for EPO-dependent promoter activity. Expression of STAT5 and the EPO receptor in HEK293 cells conferred EPO-dependent activation of the CIS promoter. These data indicate that CIS is a target of the JAK-STAT5 pathway of cytokine receptors. CIS contains an SH2 domain and binds to tyrosine-phosphorylated EPO and IL-3 receptors. In HEK293 cells expressing STAT5 and the EPO receptor, EPO-dependent tyrosine phosphorylation of STAT5, as well as EPO-dependent CIS-promoter activation, was suppressed when CIS was coexpressed. Moreover, the induction of oncostatin M, another STAT5 target, as well as the tyrosine-phosphorylation of STAT5, were partially suppressed by CIS expression in Ba/F3 cells. Thus, CIS is a feedback modulator of STAT5; its expression is induced by STAT5 and it negatively modulates STAT5 activation.
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PMID:CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. 912 17

Coupling of interleukin-2 (IL-2) to the IL-2 receptor (IL-2R) induces rapid increase in tyrosine phosphorylation of cellular substrates through activation of non-receptor protein tyrosine kinases. Here, we report that stimulation through the IL-2R induced tyrosine phosphorylation of the SH2-containing protein-tyrosine phosphatase SHP-2 in F7, a hematopoietic BAF-B03 transfectant clone expressing the IL-2Rbeta chain. The tyrosine phosphorylation of SHP-2 was specific since another protein-tyrosine phosphatase SHP-1, which is structurally homologous to SHP-2, was not tyrosine phosphorylated. The IL-2-induced tyrosine phosphorylation of SHP-2 required the acidic region within the IL-2Rbeta chain where Src-family PTKs interact. Though the serine-rich region within IL-2Rbeta chain was also required for the phosphorylation of SHP-2, Jak3 activation was dispensable. In COS-7 cells, co-expression of SHP-2 with Lyn resulted in increased tyrosine phosphorylation levels of SHP-2, whereas co-expression of SHP-2 with Fyn failed to alter the levels significantly. Considering that Lyn and Fyn are major Src-family PTKs expressed in BAF-B03 cells, our data suggest that Lyn may be principally responsible for the tyrosine phosphorylation of SHP-2 in F7 cells. Furthermore, the IL-2 stimulation also induced tyrosine phosphorylation of SHP-2 in the human IL-2-dependent T-cell line ILT-Mat. Taken together, these studies demonstrate an involvement of SHP-2 in the IL-2-mediated signaling events through the activation of specific PTKs.
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PMID:Interleukin-2 induces tyrosine phosphorylation of SHP-2 through IL-2 receptor beta chain. 912 56

CD26 or dipeptidylpeptidase IV (DPP IV) is a cell surface protease involved in T-cell activation. Triggering or costimulation of T-cells via CD26 was shown to be dependent on the expression of the T-cell receptor (TCR) associated zeta-chain with at least one functional immune receptor tyrosine based activation motif (ITAM). Here we tested T-cell lines expressing chimeric proteins (hCD25-zeta) consisting of human IL-2 receptor-alpha chain derived extracellular sequences (hCD25) fused to mouse-specific zeta-chain segments, for their capacity to transfer CD26 mediated signals. Although these 'minimal receptor' expressing T-cell lines were capable of transmitting signals from other costimulatory molecules (e.g. CD2), crosslinking of CD26 did not induce IL-2 secretion. Co-cross-linking of hCD25 and CD26 molecules, however, resulted in the stimulation of the T-cells. Thus, although the zeta-chain is a prerequisite for CD26 mediated signaling events, the sole expression of zeta-protein as a signaling molecule is not sufficient for CD26 mediated triggering but permits CD26 induced costimulation in TCR negative cells.
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PMID:The T-cell receptor associated zeta-chain is required but not sufficient for CD26 (dipeptidylpeptidase IV) mediated signaling. 916 85

Several tyrosine kinases such as Jak1, Jak3, Lck and Syk are known to participate in IL-2-mediated intracellular signal transduction. Jak1, Lck and Syk are associated with the cytoplasmic domain of the beta chain, whereas Jak3 is associated with the cytoplasmic domain of the gamma chain, which is shared among receptors for IL-2, IL-4, IL-7 and IL-15. We first demonstrated that Jak1 is associated with the alpha chains of receptors for IL-4, IL-7 and IL-15 as well as the IL-2 receptor beta chain. Furthermore, we revealed that two proline residues in the box1 region, which is conserved in the IL-2 receptor beta chain and the alpha chains of the cytokine receptors, are essentially involved in association with Jak1. The MOLT4 transfectants with the box1 mutants of the IL-2 receptor beta chain lacking Jak1 association showed IL-2 responsiveness, in terms of activations of Jak3 and Stat5 and induction of cell growth, indicating that Jak1 is dispensable for IL-2-mediated cell growth signaling, and that Jak1 activation is not required for activation of Jak3 and Stat5 in the MOLT4 transfectants.
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PMID:Regulation of IL-2 signaling. 920 10

Interleukin-2 (IL-2) has been shown to stimulate ACTH secretion by anterior pituitary cells and has been implicated in pathophysiological processes of the pituitary and brain in several major neuropsychiatric disorders. The present study tested the hypothesis that IL-2 receptor-beta (IL-2R beta), a constitutively expressed and essential subunit for IL-2 signaling in lymphocytes, is expressed by AtT-20 pituitary cells and involved in transducing intracellular signals induced by IL-2. We isolated and sequenced three overlapping IL-2R beta cDNA clones from AtT-20 pituitary cells representing key regions of the gene protein coding sequence. These cDNA clones including conserved sequences shared by growth hormone and prolactin as well as intracytoplasmic Src and JAK family homology domains of nonreceptor protein tyrosine kinases essential for IL-2 signaling in lymphocytes. Their nucleotide sequences were 100% homologous with those expressed by lymphocytes (together they comprised 70% of the full length coding sequence). The IL-2R beta gene is constitutively expressed by AtT-20 pituitary cells, and its transcription was upregulated after CRF stimulation. Species-specific Il-2 induced intracellular signals in AtT-20 cells known to be mediated by Il-2R beta, including a transient increase in c-myc nuclear proto-oncogene transcription and the dose-dependent induction of DNA replication as measured by [3H]thymidine incorporation. The IL-2-induced DNA replication signal was not delivered by heat inactivated IL-2 and was partially blocked by a murine anti-IL-2R beta monoclonal antibody. These studies suggest that IL-2R beta may be a critical target involved in mediating the neuroimmunological actions of this prototypical cytokine in endocrine cells.
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PMID:Isolation of IL-2 receptor-beta cDNA clones from AtT-20 pituitary cells: constitutive expression and role in signal transduction. 925 80


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