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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) potently stimulates natural killer (NK) cell proliferation and cytotoxic function. However, the molecular mechanisms by which IL-2 delivers activation signals from the IL-2 receptor to the NK cell interior are incompletely understood. Previous studies demonstrated that IL-2 stimulation induced the tyrosine phosphorylation of multiple proteins in NK cells, together with a prominent reduction in the electrophoretic mobility of p56lck. The present studies indicate that IL-2 induces a rapid (< or = 1 min) increase in the catalytic activity of p56lck, as measured by increases in protein tyrosine kinase activity in vitro. Furthermore, in response to IL-2, p56lck itself undergoes complex alterations in serine and tyrosine phosphorylation. Cyanogen bromide cleavage maps indicate that IL-2 stimulates a pronounced increase in the phosphorylation of the NH2-terminal region of p56lck containing multiple known sites of serine phosphorylation. In addition, IL-2 induced a marked increase in the phosphorylation of a COOH-terminal peptide containing the regulatory Tyr-505 residue of p56lck. These results suggest that p56lck serves as a substrate for both protein serine and tyrosine kinases activated during stimulation of this cell type with IL-2. Furthermore, these results indicate that the pleiotropic effects of IL-2 on NK cell physiology are initiated and regulated by a complex and multitiered interaction of different protein kinases including p56lck.
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PMID:Interleukin-2 signal transduction in human NK cells: multisite phosphorylation and activation of the tyrosine kinase p56lck. 138 59

The present study was performed to localize in the IL-2 molecule the active site responsible for interaction with the IL-2 receptor. To predict the receptor binding site on the IL-2 molecule, a computer programme based on the hypothesis that the active site will contain parts of the protein molecule having a high tendency to form a bend was utilized. The tendency to form a bend was evaluated by assessing the probability of beta-turn occurrence; the highest probability was found in the tetrapeptide Asn-Pro-Lys-Leu, occupying the positions 33-36 of the IL-2 molecule. Accordingly, the hexadecapeptide H-Cys-Nle-Gly-Ile-Asn-Asn-Tyr-Lys-Asn-Pro-Lys-Leu-Thr-Arg-Met-Leu-NH2 that spans over the predicted tetrapeptide Asn-Pro-Lys-Leu and comprises the region 27-40 from the IL-2 amino acid sequence was synthesized. This synthetic (I-16) peptide was found to selectively inhibit the IL-2-dependent uptake of 3H-TDR by CTLL cells, apparently by competing with IL-2 for the IL-2 receptor. The synthetic I-16 hexadecapeptide was conjugated to carrier (BSA) protein and used for immunization of rabbits. Resulting I-16 antibodies were capable of binding specifically to the I-16 hexadecapeptide in indirect ELISA test; they reacted substantially with IL-2-producing but not with IL-2-non-producing Jurkat cells in indirect cell membrane immunofluorescence, and inhibited activation of killer spleen cells with human recombinant IL-2 as detected by 51Cr microcytotoxicity assay. Taken together, these results suggest that at least one of the receptor contact sites of the IL-2 is localized within the N-terminal part of the molecule in the region defined by amino acids 27-40 and coded for by the exon 1 and 2.
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PMID:Localization of a receptor binding site on the IL-2 molecule. 244 71

To locate functional domains of the interleukin-2 (IL-2) protein, a cDNA clone encoding biologically active human IL-2 was mutagenized using synthetic oligonucleotides to incorporate defined amino acid substitutions and deletions in the mature protein. The IL-2 analogs were then produced in Escherichia coli and assayed for the ability to induce proliferation of IL-2-dependent cells and the ability to compete for binding to the IL-2 receptor. Our analysis of over 50 different mutations demonstrated that the integrity of at least three regions of the IL-2 molecule is required for full biological activity: the NH2 terminus (residues 1-20), the COOH terminus (residues 121-133), and 2 of the 3 cysteine residues (58 and 105). Deletion of the NH2-terminal 20 amino acids or the COOH-terminal 10 amino acids resulted in the loss of greater than 99% of bioactivity and binding. Amino acid substitutions at specific positions in these regions also resulted in proteins which retained less than 1% activity. The NH2 terminus and an adjacent internal region were recognized by neutralizing anti-IL-2 antibodies. In combination with the results from epitope competition analysis with neutralizing antibodies, these data are consistent with the IL-2 protein being folded such that the NH2 terminus, the COOH terminus, and the internal 30- to 60-region are juxtaposed to form the binding site recognized by the IL-2 receptor.
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PMID:Structure-function analysis of human interleukin-2. Identification of amino acid residues required for biological activity. 310 42

T lymphocytes, essential for the generation of a normal immune response, require the presence of the lymphokine interleukin-2 (IL-2) in order to proliferate. Cells that respond to IL-2 possess a surface receptor glycoprotein specific for this lymphokine. We have recently purified and chemically characterized the IL-2 receptor from both phytohaemagglutinin-activated human T cells and the human T-cell lymphoma HUT-102 (ref. 5). From the NH2-terminal protein sequence obtained in that study, we have now used synthetic oligonucleotides to probe a complementary DNA library, prepared from HUT-102 messenger RNA, for the presence of cDNA clones that might code for the IL-2 receptor. Two cDNA clones were isolated which had closely related DNA sequences. Interestingly, only one coded for an active receptor when transfected into COS-7 cells. This clone contained a 216-base pair (bp) insert that was not present in the other clone. The insert was flanked by an 8-bp direct repeat reminiscent of a transposable element, and appeared to code for a region of marked structural homology to the NH2-terminal region of the receptor molecule.
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PMID:Cloning, sequence and expression of human interleukin-2 receptor. 609 20

Signal transduction of cytokine receptors is mediated by the JAK family of tyrosine kinases. Recently, the kinase partners for the interleukin (IL)-2 receptor have been identified as JAK1 and JAK3. In this study, we report the identification of splice variants that may modulate JAK3 signaling. Three splice variants were isolated from different mRNA sources: breast (B), spleen (S), and activated monocytes (M). Sequence analysis revealed that the splice variants contain identical NH2-terminal regions but diverge at the COOH termini. Analyses of expression of the JAK3 splice isoforms by reverse transcriptase-polymerase chain reaction on a panel of cell lines show splice preferences in different cell lines: the S-form is more commonly seen in hematopoietic lines, whereas the B- and M-forms are detected in cells both of hematopoietic and epithelial origins. Antibodies raised against peptides to the B-form splice variant confirmed that the 125-kDa JAK3B protein product is found abundantly in hematopoietic as well as epithelial cells, including primary breast cancers. The lack of subdomain XI in the tyrosine kinase core of the B-form JAK3 protein suggests that it is a defective kinase. This is supported by the lack of detected autokinase activity of the B-form JAK3. Intriguingly, both the S and B splice isoforms of JAK3 appear to co-immunoprecipitate with the IL-2 receptor from HUT-78 cell lysates. This and the presence of multiple COOH-terminal splice variants coexpressed in the same cells suggest that the JAK3 splice isoforms are functional in JAK3 signaling and may enrich the complexity of the intracellular responses functional in IL-2 or cytokine signaling.
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PMID:A kinase-deficient splice variant of the human JAK3 is expressed in hematopoietic and epithelial cancer cells. 755 33

When T cells become infected by the parasite Theileria parva, they acquire a transformed phenotype and no longer require antigen-specific stimulation or exogenous growth factors. This is accompanied by constitutive interleukin 2 (IL-2) and IL-2 receptor expression. Transformation can be reversed entirely by elimination of the parasites using the specific drug BW720c. Extracellular signal-regulated kinase and jun NH2-terminal kinase (JNK) are members of the mitogen-activated protein kinase family, which play a central role in the regulation of cellular differentiation and proliferation and also participate in the regulation of IL-2 and IL-2 receptor gene expression. T. parva was found to induce an unorthodox pattern of mitogen-activated protein kinase expression in infected T cells. JNK-1 and JNK-2 are constitutively active in a parasite-dependent manner, but have altered properties. In contrast, extracellular signal-regulated kinase-2 is not activated even though its activation pathway is functionally intact. Different components of the T cell receptor (TCR)-dependent signal transduction pathways also were examined. The TCRzeta or CD3epsilon chains were found not to be phosphorylated and T. parva-transformed T cells were resistant to inhibitors that block the early steps of T cell activation. Compounds that inhibit the progression of T cells to proliferation, however, were inhibitory. Our data provide the first example, to our knowledge, for parasite-mediated JNK activation, and our findings strongly suggest that T. parva not only lifts the requirement for antigenic stimulation but also entirely bypasses early TCR-dependent signal transduction pathways to induce continuous proliferation.
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PMID:Jun NH2-terminal kinase is constitutively activated in T cells transformed by the intracellular parasite Theileria parva. 914

Aging in humans is associated with the decline of functional activities of the GH-insulin-like growth factor I (IGF-I) axis and the immune system. Because lymphocytes express GH-IGF-I, as well as GHRH and their respective receptors, restoration of this axis in age-advanced individuals, by the administration of GHRH, may enhance immune cell function. This hypothesis was tested by a single blind randomized placebo-controlled trial of 5 months duration, in which healthy elderly subjects (10 women, 9 men) self-administered sc nightly placebo for 4 weeks, followed by 16 weeks of [norleucine27]GHRH (1-29)-NH2 at a dose of 10 micrograms/kg. Fasting (0800 h-0900 h) blood samples were obtained for immune studies and for measurements of serum concentrations of IGF-I and soluble interleukin (IL)-2 receptor. GH pulsatility was determined in blood samples obtained at 10-min intervals for 12 h (2000 h-0800 h). Freshly isolated peripheral lymphocytes were analyzed by flow cytometric analysis for determination of lymphocyte subsets and monocytes. Mitogen stimulation responses, natural killer cell number and cytotoxicity, basal and stimulated IL-2 secretion from cultured lymphocytes, and IL-2 and IL-2R messenger RNA expression were measured. These studies were conducted at baseline, after placebo, and during GHRH analog administration at 4 and 16 weeks. Treatment with GHRH analog resulted in a significant increase (107 and 70% in men and women, respectively) in the 12-h integrated GH secretion (P < .05) and serum IGF-I levels (28%) (P < .001) in both men and women by 4 weeks and lasted 12 weeks for IGF-I and 16 weeks for GH. Activation of the immune system occurred in both sexes within 4 weeks. A 30% increase (P < .001) in lymphocytes expressing the transferrin receptor (CD71) and in monocytes (CD14) (P < .05) occurred within 4 weeks. By 16 weeks, there was a significant increase (30%) in B cells (CD20) (P < .01), in cells expressing the T cell receptor alpha/beta (20%) (P < .01), and T cell receptor gamma/delta (40%) (P < .0001). There were no changes in the number of T cells (CD3), T cell subsets (CD4, CD8), or natural killer cell (CD57) over the treatment period. The increase in B cell number was associated with enhanced responsiveness (50%) to the B cell mitogens: pokeweed mitogen (P < .01 or better) and Staphylococus aureus cells (P < .001), and a transient increase at 4 weeks in circulating IgG (P < .0001), IgM, and IgA (P < .001). T cells were functionally activated, as evidenced by a 50% increase in responsiveness to phytohemagglutinin (P < .01 or better), 70% increase in the number of lymphocytes expressing the IL-2 receptor (IL-2R) (CD25) (P < .001), and enhanced IL-2R messenger RNA expression and basal IL-2 secretion (50%) (P < .05) at 16 weeks of treatment. Furthermore, circulating soluble IL-2 receptor rose significantly (15%) (P < .05) within 4 weeks of treatment and remained elevated for the duration of the study. There were no sex differences in the immune response to GHRH analog and no adverse effects. These results indicate that GHRH analog administration has profound immune-enhancing effects and may be of therapeutic benefit in states of compromised immune function.
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PMID:Effects of [norleucine27]growth hormone-releasing hormone (GHRH) (1-29)-NH2 administration on the immune system of aging men and women. 936 May 12