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

Previous studies demonstrate that p56lck, a member of the src-family of protein tyrosine kinases (PTKs), can physically associate with the interleukin-2 (IL-2) receptor beta chain (IL-2R beta) and that IL-2 receptor engagement stimulates p56lck activity. To examine the mechanisms underlying p56lck PTK activation by IL-2, we established a mouse pro-B cell line, BAF-B03, expressing both IL-2R beta (either the wild-type or mutant forms) and mouse p56lck at high levels. BAF-B03 cells expressing a mutant IL-2R beta chain lacking an 'acidic' region of the cytoplasmic domain, previously shown to be essential for association with p56lck, fail to induce p56lck PTK activation upon IL-2 stimulation. This suggests that the association of p56lck with the IL-2R beta chain, despite its low stoichiometry, is required for the activation of cellular p56lck PTK upon IL-2 stimulation. Intriguingly, BAF-B03 cells expressing an IL-2R beta chain which lacks a different cytoplasmic region, the 'serine-rich' region, also fail to activate p56lck in response to IL-2. Hence, physical association of p56lck with the IL-2R beta chain is not by itself sufficient to permit IL-2-mediated regulation of this PTK. Additional experiments suggest that one result of PTK activation is the accumulation of c-fos and c-jun transcripts.
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PMID:Association of p56lck with IL-2 receptor beta chain is critical for the IL-2-induced activation of p56lck. 844 Feb 63

We isolated a cDNA clone for the gamma chain of the mouse interleukin 2 receptor. Introduction of the mouse gamma chain cDNA clone into a mouse fibroblast cell line, L929, expressing the mouse alpha beta heterodimer IL-2 receptor converted pseudo-high affinity of the IL-2 receptor into functional high, resulting in internalization of IL-2 and induction of the c-myc, c-fos and c-jun genes. The mouse beta gamma heterodimer, however, failed to bind IL-2 unlike the human beta gamma heterodimer intermediate-affinity receptor. These results indicate that the mouse functional IL-2 receptor is a complex comprising three distinct subunits, alpha, beta and gamma chains, but the beta gamma heterodimer is not functional and different from the human heterodimer.
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PMID:Cloning of the mouse interleukin 2 receptor gamma chain: demonstration of functional differences between the mouse and human receptors. 850 26

Mouse MHC class I-specific mAbs recognizing the alpha 1/alpha 2, but not those directed against the alpha 3 domain of the molecule, inhibited RNA, protein, and DNA synthesis of splenic T cells in response to stimulation through the TCR/CD3 complex. Similar inhibition was seen with LFA-1-specific mAbs under the same stimulation conditions. The effect of class I- and LFA-1-specific mAbs reflected a decrease of both IL-2 and IFN-gamma synthesis and IL-2 receptor alpha chain induction. IL-2, IL-2 receptor alpha chain, IFN-gamma, c-fos, c-jun, and c-myc mRNAs were not detected. Activation of AP-1 (c-Fos and c-Jun proteins) and NF-kappa B transcription factors were also inhibited. Inhibition was observed both after treatment of cells in culture and after intravenous injection of Abs in mice. Although bulk phosphorylation was inhibited, early tyrosine phosphorylation and calcium ion influx were normally induced. Protein phosphatase inhibitors did not reverse this inhibition, ruling out an enhanced activation of these enzymes in the observed inhibition. Cell surface expression of one of early PKC activation marker, CD69 was also inhibited. Phorbol esters that directly activate PKC prevented inhibition. Thus, class I molecules are implicated in signal transduction involved at an early stage for T cell activation in a manner that suggests their implication in accessory signal transmission that contributes to the regulation of PKC activity.
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PMID:MHC class I molecules are implicated in costimulatory signals during TCR/CD3-induced activation. 859 31

The expression of various proto-oncogenes in primary culture of lymphocytes from peripheral blood of bovine with chronic lymphocytic leukemia (CLL) was studied. Cellular proto-oncogenes encode proteins that propagate growth, differentiation or apoptosis signals from cell membrane to nucleus. The proliferation and differentiation of normal eukaryotic cells are precisely controlled. Tumor cells usually are characterized both by the continuous growth signal and by the block of cell differentiation. We have previously reported that along with spontaneous proliferation, bovine CLL lymphocytes continuously differentiate and enter apoptosis in vitro. CLL cells with an autocrine growth mechanism and at the same time undergoing spontaneous differentiation and apoptosis in vitro provide a new model system to investigate the possible involvement of various proto-oncogenes in the regulation of cellular proliferation, differentiation and apoptosis. Northern blot analysis revealed simultaneous expression of a number of proto-oncogenes in CLL cells. Transcripts of c-fos, c-myc, c-myb, A-raf, c-raf1, hck, IL-2 receptor alpha-chain (IL-2R alpha) were found in lymphocytes at the peak of their proliferative activity in culture. Kinetics studies demonstrated that CLL cells constitutively express transcripts of so-called immediate response nuclear proto-oncogenes c-myc, c-fos as well as cytoplasmic proto-oncogenes hck and c-raf1, i.e., genes coding for tyrosine and serine-threonine protein kinases, respectively. Expression level did not change significantly during all stages of CLL cells in culture. The results show that continuous expression of c-myc mRNA does not prevent CLL cell differentiation and may be associated with apoptotic cell death.
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PMID:Proto-oncogene expression in bovine peripheral blood leukemic lymphocytes during their spontaneous proliferation, differentiation and apoptosis in vitro. 959 70

Interleukin 2 (IL-2)- and IL-4-mediated stimulation of survival and growth, reflected by the induction of bcl2 and c-myc, respectively, depends on the integrity of the membrane-proximal region (S-region) in the IL-2 receptor beta-chain (IL-2R beta) and the haematopoietin homology box1-containing region of the IL-4 receptor alpha-chain (IL-4R alpha). In contrast to IL-4, IL-2 induces the expression of c-fos and c-jun family genes, mediated by the acidic region (A-region) within the cytoplasmic domain of IL-2R beta. A highly acidic motif is also present in IL-4R alpha, and evidence in favour and against its importance has been published. The authors have constructed chimeric receptors between IL-2R beta and IL-4R alpha by substitution of either the S-region or the A-region of IL-2R beta with sequences derived from IL-4R alpha. These chimeras were stably transfected into BA/F3 cells and assayed for the capacity to restore functions of IL-2 beta, such as growth mediation by IL-2 and the induction of proto-oncogenes (c-myc, c-junB and c-fos). Replacement of both the S- and A-region of IL-2R beta with IL-4R alpha derived regions of similar size and cytoplasmic location supported growth-stimulation by IL-2 as well as proto-oncogene induction. In contrast, all IL-2R functions were lost by exchange of the S-region with the corresponding part of IL-4R alpha. Induction of c-junB and c-fos RNA as an indicator of A-region function, however, was maintained in an IL-2R beta chimera containing the acidic box-bearing region of IL-4R alpha. These data indicate a functional role of the acidic region in the IL-4R alpha-chain.
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PMID:Function of the human interleukin 4 receptor (IL-4R)-derived acidic motif revealed by cytoplasmic domain chimeras of the IL-4R alpha chain and the IL-2R beta chain. 961 70

The pituitary gland expresses cytokines and their receptors. IL-2 receptor transcripts and protein products are co-localized in ACTH-, PRL-, and GH-producing cells (double immunofluorescence). IL-2 and IL-6 (1-1000 IU/ml) are involved in the autocrine/paracrine regulation of normal and tumor (GH3 mammosomatotroph cell line and adenoma cell cultures) anterior pituitary hormone-producing cell growth (cell number, DNA synthesis, c-fos mRNA expression and autoradiography combined with hormone staining). IL-1 regulates the growth of normal pituitary cells but does not act on GH3 cells. IL-1ra, which blocks this action, is expressed in tumoral pituitary (mainly GH- and ACTH-) cells. In ACTH- cells, IL-1 enhances glucocorticoid feedback, stimulating glucocorticoid response element transcriptional activity. Cytokines, through specific functional receptors, act as inter/auto-cellular factors that regulate not only the function but also the growth of anterior pituitary cells.
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PMID:Cytokine expression and molecular mechanisms of their auto/paracrine regulation of anterior pituitary function and growth. 962 79

In this review we discuss several molecules that are attractive candidates as transducing molecules involved in signaling processes. IL-2 receptor signaling is a complex process involving a large number of molecules: Ras, Rho, PI3 kinase, PKC, Akt, transcription factors NF-AT, and NF-kappaB and some target genes such as bcl-2, c-myc, c-jun and c-fos. Ras and Rho have been defined as dual molecules because Ras- and Rho-initiated signals can either promote or inhibit apoptosis. Several studies have contributed to the delineation of a signaling pathway structured in three independent channels designated channels 1, 2, and 3. These three channels serve as major landmarks: Lck-c-fos/c-jun (channel 1), Syk-myc (channel 2), and a pathway leading to actin organization/bcl-2 expression (channel 3). The detailed hierarchical organization of these three channels is presented throughout the review and the model is depicted in the figure.
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PMID:IL-2-induced cellular events. 963 10

T cell development and function in complex ganglioside-lacking (GM2/GD2 synthase gene-disrupted) mice were analyzed. GM1, asialo-GM1, and GD1b were representative gangliosides expressed on T cells of the wild type mice and completely deleted on those of the mutant mice. The sizes and cell numbers of the mutant mice spleen and thymus were significantly reduced. Spleen cells from the mutant mice showed clearly reduced proliferation compared with the wild type when stimulated by interleukin 2 (IL-2) but not when treated with concanavalin A or anti-CD3 cross-linking. Expression levels of IL-2 receptor alpha, beta, and gamma were almost equivalent, and up-regulation of alpha chain after T cell activation was also similar between the mutant and wild type mice. Activation of JAK1, JAK3, and SAT5 after IL-2 treatment was reduced, and c-fos expression was delayed and reduced in the mutant spleen cells, suggesting that the IL-2 signal was attenuated in the mutant mice probably due to the modulation of IL-2 receptors by the lack of complex gangliosides.
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PMID:Attenuation of interleukin 2 signal in the spleen cells of complex ganglioside-lacking mice. 1031 76

ERYTHROPOIETIN (EPO): Erythropoietin (EPO) is a hormone that promotes the proliferation and differentiation of erythroid progenitor cells and regulates the number of erythrocytes in peripheral blood. EPO is produced mainly by the kidneys, and transcription of the EPO gene is promoted by a reduction in the oxygen concentration in the blood. The existence of EPO was suggested near the end of the 19th century by the discovery that hypoxia increases the production of red blood cells. EPO was identified as a serum factor in the 1950s, and in 1970 Miyake and coworkers succeeded in purifying it by using the urine of patients with aplastic anemia as a starting material. The human EPO gene was cloned in 1985 using a partial amino acid sequence from this purified EPO, and it is well known that recombinant EPO is currently used as a drug to treat anemia associated with chronic renal failure and other illnesses. ACTION OF EPO: When human bone marrow cells are cultured in a semisolid medium containing EPO, they form small erythroblast colonies in five to seven days, and by day 10 large erythroblast colonies appear that resemble fireworks ("burst" colonies). The original cells in the former colonies are called colony forming units-erythroid (CFU-E) or late-stage erythroblast progenitor cells and in the latter colonies they are called burst forming units-erythroid (BFU-E) or early-stage erythroblast progenitor cells. As shown in Figure 1, red blood cells are produced through differentiation from stem cells to BFU-E, CFU-E, and erythroblasts. Although EPO acts on both BFU-E and CFU-E cells, CFU-E cells show greater sensitivity to EPO, and other factors such as stem cell factor (SCF), interleukin (IL)-3, IL-4, and granulocyte macrophage colony-stimulating factor (GM-CSF) must be present together with EPO for BFU-E cell proliferation. In erythroblasts beyond the CFU-E stage, sensitivity to EPO decreases as the cells mature. THE EPO RECEPTOR AND THE CYTOKINE RECEPTOR FAMILY: The EPO receptor gene was cloned by D'Andrea and coworkers in 1989 from murine erythroleukemia cells [1]. It became clear that the EPO receptor belongs to the cytokine receptor family that comprises receptors for the various interleukins, GM-CSF, granulocyte colony-stimulating factor (G-CSF), growth hormone and prolactin. The special characteristic of this family of receptors is that they are switched on (i.e., the receptor is activated) and transduce signals to the interior of the cell by the formation of homo- or hetero-oligomers (dimers or trimers). Moreover, hetero-oligomers of these receptors share a common receptor subunit. As shown in Figure 2, the IL-3, IL-5 and GM-CSF receptors have a common &bgr; subunit, and their ligand specificity is determined by the &agr; subunit. In the same manner, the IL-6, LIF and oncostatin M (OSM) receptors all share gp130, which is the &bgr; subunit of the IL-6 receptor. The IL-2, IL-4 and IL-7 receptors all share the &ggr; subunit of the IL-2 receptor. All the above receptors are activated by the formation of hetero-oligomers, but the G-CSF receptor, EPO receptor, and growth hormone receptor are activated by the formation of homodimers of the same types of molecules [2]. We can see that groups of cytokines such as the interleukins that affect a relatively wide range of cells and have redundant biological activity create this redundancy through the common use of a single receptor subunit. On the other hand, EPO and G-CSF act with high specificity on a relatively limited range of cells, so it was probably unnecessary for their receptors to share one of the subunits. EPO RECEPTOR AND JAK2 KINASE: The signal for cellular proliferation and differentiation into erythroblasts is thought to originate at the EPO receptor. The cytoplasmic domain of the EPO receptor can be divided into two major regions. Roughly half of the cytoplasmic domain, the part lying nearest the plasma membrane, is required for generating the signals for proliferation and differentiation such as the induction of globin synthesis [3, 4]. The remaining half is not required for this signaling, and, conversely, it acts to dampen the signals. It is known that a tyrosine kinase called JAK2 associates with the region near the plasma membrane, undergoes autophosphorylation, and phosphorylates the EPO receptor, and a transcription factor called a STAT [5]. It is thought that JAK2 plays an important role in promoting cellular proliferation. The STAT is activated by the phosphorylation, and it then translocates to the nucleus, recognizes a specific base sequence in the promoter region of its target gene, and initiates transcription. At present, we know that the STAT whose activation is mediated by the EPO receptor is STAT5, and the target genes are CIS [6], which has an SH2 domain (a molecular structure that recognizes a phosphorylated tyrosine) and OSM [7], which is a pleiotropic cytokine. However, activation of STAT5 and activation of the target genes are not unique to the EPO receptor, and they also occur with the IL-2 and IL-3 receptors. Moreover, the JAK2 substrate that is directly linked to cellular proliferation is still unknown. At present, studies are under way to determine the transcription factors specific to EPO and their target genes, as well as the substrates of JAK2. RECEPTOR PHOSPHORYLATION AND CESSATION OF THE SIGNAL: On the other hand, tyrosine phosphorylation of the receptor is necessary at the cytoplasmic tail region far from the plasma membrane, and the signal transduction pathway that originates with this phosphorylated tyrosine and is mediated by proteins with SH2 domains becomes activated. First, a GTP/GDP exchange factor called SOS, which is mediated by Shc and Grb2, migrates to the plasma membrane and converts a ras protein to its GTP form. The activated ras protein then activates the Raf-MAP kinase kinase-MAP kinase cascade, and ultimately initiates the transcription of oncogenes such as c-fos and c-jun. An enzyme called PI3 kinase binds to the tyrosine phosphorylation site of the receptor and a second messenger is born. It is known that this pathway is a requirement for DNA synthesis in certain types of fibroblasts. However, these signal transduction pathways are not unique to the EPO receptor, and they are also activated by most growth factor receptors, so they are not necessarily required for EPO-induced proliferation. Conversely, the tyrosine phosphatase SH-PTP1 (also called HCP) that has an SH2 domain and is specific to blood cells associates with the tyrosine phosphorylation site of the receptor and promotes the dephosphorylation of JAK2. In other words, the role of SH-PTP1 is to stop generation of the signal [8]. Therefore, in mutations lacking this cytoplasmic tail region of the receptor far from the plasma membrane, the receptors do not undergo tyrosine phosphorylation, JAK2 activation continues for a longer period of time, and thus the signal is generated more efficiently. In fact, in one patient with a mild case of familial erythrocytosis a mutation was discovered in which the C-terminus of the EPO receptor was missing 70 amino acids [9]. This was a dominant genetic trait, and the patient's erythroblasts showed an increased sensitivity to EPO. In this family the impairment was not severe enough to be called an illness, and in fact it is said that this patient was proficient enough athletically to compete for a gold medal at the Olympics. More specifically, the reason that athletes undergo training at high altitudes is to boost EPO production because of the lower oxygen partial pressure, and this brings about the desired effect of sustained athletic capability due to a resultant increase in red blood cells. However, the same effect has occurred naturally in this athlete thanks to accelerated receptor capability.
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PMID:Physician Education: The Erythropoietin Receptor and Signal Transduction. 1038 12

Most of the data accumulated to date on the immunoregulatory effects of prostaglandins (PG) on T cell activation stem from the archetypal inhibitory effect of PGE(2). In this study we provide instead, the first evidence that exogenous PGB(2), a catabolic metabolite of PGE(2), synergizes with signals delivered by T cell receptor (TCR) engagement to induce interleukin-2 (IL-2) production and IL-2 receptor (IL-2R) alpha-expression in Jurkat cells. Accordingly, PGB(2) enhances the proliferation of anti-CD3-activated peripheral blood lymphocytes (PBL). In terms of cellular signaling, we present evidence that PGB(2) activates tyrosine kinase activities and efficiently increases c-fos mRNA expression and nuclear factor-kappa B (NF-kappa B) translocation to the nucleus. Owing to these features, PGB(2) appears as a new lipid mediator capable of delivering an ancillary signal leading to T lymphocyte activation.
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PMID:Prostaglandin B(2) delivers a co-stimulatory signal leading to T cell activation. 1090 9


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