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

The IL-2 receptor (IL-2R) consists of three subunits, the IL-2R alpha, IL-2R beta, and IL-2R gamma chains, the last of which is also used in the receptors for IL-4, IL-7, IL-9, IL-13, and IL-15. The IL-2-induced proliferative signals emanate from the cytoplasmic domains of IL-2R beta and IL-2R gamma, but the nature and function of the signaling molecules that transmit these signals are not fully understood. Here we summarize our current understanding of the mechanisms by which IL-2R transmit signals by using multiple protein kinases. In fact, at least four protein tyrosine kinases (PTKs) are physically associated with IL-2R: p56lck (and its members), Syk PTK, and the Janus kinases, Jak1 and Jak3. cDNA expression studies revealed that the activation of these PTKs is critical for IL-2-induced proliferative signal transmission. Our findings indicate that a unique property of the IL-2R cytoplasmic domains is to recruit a variety of signaling molecules, which may suggest a mechanism by which these PTKs and other signaling molecules function in concert.
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PMID:IL-2 signaling involves recruitment and activation of multiple protein tyrosine kinases by the IL-2 receptor. 748 66

Janus tyrosine kinase (JAK) has recently been linked to signal transduction by cytokine receptors of the hematopoietin family. We have recently described a 116-kDa tyrosine kinase (p116) present in interleukin-2 (IL-2) receptor complexes in human YT cells that showed functional characteristics of a JAK kinase. These included receptor association, rapid and transient tyrosine phosphorylation kinetics in response to ligand, and in vitro autophosphorylating tyrosine kinase activity (Kirken, R. A., Rui, H., Evans, G. A., and Farrar, W. L. (1993) J. Biol. Chem. 268, 22765-22770). Here we extend these observations by demonstrating structural homologies between IL-2-modulated p116 and prolactin-modulated JAK2 in the rat T cell line Nb2. These include similar net charge as determined by nonequilibrium pH gradient electrofocusing and related primary structure based upon phosphopeptide mapping of V8 protease-digested hyperphosphorylated proteins. This putative JAK kinase underwent marked tyrosine phosphorylation in response to IL-2, IL-4, and IL-7, lymphoid growth factors that use the common IL-2 receptor gamma-chain, but not in response to prolactin. Furthermore, polyclonal antisera to JAK1, JAK2, or tyrosine kinase 2 did not recognize either rat or human p116. However, we identified the IL-2-modulated p116 as the recently cloned novel leukocyte Janus kinase, L-JAK, using an antiserum to a peptide corresponding to the COOH terminus of human L-JAK.
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PMID:Identification of interleukin-2 receptor-associated tyrosine kinase p116 as novel leukocyte-specific Janus kinase. 751 51

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

Interleukin-2 (IL-2) signaling requires the dimerization of the IL-2 receptor beta.(IL-2R beta) and common gamma (gamma c) chains. Mutations of gamma c can result in X-linked severe combined immunodeficiency (XSCID). IL-2, IL-4, IL-7 (whose receptors are known to contain gamma c), and IL-9 (whose receptor is shown here to contain gamma c) induced the tyrosine phosphorylation and activation of the Janus family tyrosine kinases Jak1 and Jak3. Jak1 and Jak3 associated with IL-2R beta and gamma c, respectively; IL-2 induced Jak3-IL-2R beta and increased Jak3-gamma c associations. Truncations of gamma c, and a gamma c, point mutation causing moderate X-linked combined immunodeficiency (XCID), decreased gamma c-Jak3 association. Thus, gamma c mutations in at least some XSCID and XCID patients prevent normal Jak3 activation, suggesting that mutations of Jak3 may result in an XSCID-like phenotype.
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PMID:Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. 797 58

X-SCID, the most common form of human SCID, is due to mutations in the common gamma chain gene (gamma-c) that encodes an essential component of the cytokine receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. Activation of the Janus family tyrosine kinases Jak1 and Jak3 is necessary for appropriate signalling through the IL-2 receptor (IL-2R). Neither Jak1 nor Jak3 was phosphorylated after IL-2 stimulation of an Epstein-Barr virus-transformed cell line (LCL) from an X-SCID patient with a gamma-c null mutation. However, we now show that appropriate IL-2R function can be restored in an X-SCID LCL by transduction of a wild-type gamma-c gene. A retroviral vector, G1gamma-cSvNa, was constructed and produced in the PG13 packaging line. Transduced X-SCID LCL expressed the G1gamma-cSvNa transcript. IL-2 stimulation of the transduced cell line resulted in appropriate tyrosine phosphorylation of both Jak1 and Jak3. Thus, retroviral-mediated transduction of normal gamma-c can reconstitute downstream signalling through the IL-2R in X-SCID cell lines, suggesting that gene therapy may be a treatment for this disease.
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PMID:Correction of interleukin-2 receptor function in X-SCID lymphoblastoid cells by retrovirally mediated transfer of the gamma-c gene. 860 23

We have isolated a second human Stat5 cDNA, Stat5B, and demonstrated that the genes encoding both Stat5A and Stat5B are located at chromosome 17q11.2. Both genes were constitutively transcribed in peripheral blood lymphocytes. By using specific antisera, we demonstrated that both Stat5A and Stat5B are activated by interleukin-2 (IL-2) in peripheral blood lymphocytes, natural killer-like YT leukemia cells, and human T cell lymphotropic virus type I-transformed MT-2 T cells. In COS-7 cells, which constitutively express the Janus family tyrosine kinase Jak1, reconstitution of IL-2-induced Stat5A and Stat5B DNA binding activities was dependent on the coexpression of Jak3 along with the IL-2 receptor beta chain and the common cytokine receptor gamma-chain. This IL-2-induced Stat5 activation was dependent on the presence of either of two tyrosines (Tyr-392 or Tyr-510) in the IL-2 receptor beta chain, indicating that either of these two tyrosines can serve as a docking site. Moreover, we demonstrated that human Stat5 activation is also dependent on Tyr-694 in Stat5A and Tyr-699 in Stat5B, indicating that these tyrosines are required for dimerization. The COS-7 reconstitution system described herein provides a valuable assay for further elucidation of the IL-2-activated JAK-STAT pathway.
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PMID:Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells. 863 83

The cytokines interleukin (IL)-2 and IL-15 share many biological activities as a consequence of their utilization of the beta and gamma chains of the IL-2 receptor. However, each cytokine binds to a specific receptor alpha chain; IL-2 with low affinity and IL-15 with high affinity. Here, we demonstrate that IL-15, like IL-2, up-regulates expression of IL-2R alpha on human T and B cells, but rapidly down-regulates IL-15 high-affinity binding sites, which represent IL-15R alpha. This leads to a decreased responsiveness to IL-15 as measured by induction of Jak3 tyrosine phosphorylation. These results suggest a mechanism by which IL-15, a product of activated macrophages, may cooperate with IL-2 at the initiation of an immune response and enhance subsequent IL-2 responsiveness during T cell expansion.
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PMID:Interleukin-15 up-regulates interleukin-2 receptor alpha chain but down-regulates its own high-affinity binding sites on human T and B cells. 864 98

Ligand binding to cytokine receptors rapidly triggers tyrosine phosphorylation of Janus family tyrosine kinases (Jaks) and signal transducers and activators of transcription (Stats). Jak2 activation is mediated by PRL receptor homodimers as well as by receptors for the interleukin (IL)-3, IL-5, and granulocyte macrophage-colony stimulating factor, which share the common beta c-subunit. Otherwise, Jak1 and Jak3 are involved in IL-2 signaling through heterodimerization of the IL-2 receptor-beta (IL-2R beta) and gamma c-chains. Stat5, a member of the Stat family, confers the PRL response on milk protein genes. Here we show that chimeric PRL receptors that contain the transmembrane and cytoplasmic domains of the IL-2R beta or beta c-chains transduce in response to PRL tyrosine phosphorylation and activation of Jak1 and Jak2, respectively. Tyrosine phosphorylation of Stat5, activation of its DNA-binding activity assessed in bandshift experiments using a lactogenic hormone responsive region (LHRR) probe, and transcriptional induction of a beta-casein promoter luciferase construct in stably transfected CHO cells are observed with both chimeras upon PRL stimulation. Our results demonstrate that distinct cytoplasmic domains of these cytokine receptors elicit convergent signaling pathways and provide evidence that beta c and IL-2R beta function as a complete signal transducer. Our data strengthen previous observations that Stat5 activation is not dependent on the activation of a specific Jak kinase and also suggest that neither Jak3 nor gamma c have a specific role in this process.
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PMID:Convergence of signaling transduced by prolactin (PRL)/cytokine chimeric receptors on PRL-responsive gene transcription. 872 89

R24 is a monoclonal antibody directed against the cell surface ganglioside GD3. It can detect GD3 on the surface of a subset of T lymphocytes and can stimulate proliferation and secretion of cytokines in vitro. In the present report, we examined the effects of the R24 antibody upon antigen-specific T cell response, employing an HLA-DR7-specific T cell clonal model. As previously shown, primary stimulation of HLA-DR7-specific alloreactive T cell clones by transfectants expressing HLA-DR7 alone (t-DR7) in the absence of B7 co-stimulation resulted in anergy. Binding of cell surface GD3 on HLA-DR7-specific alloreactive T cell clones with R24 under these anergizing conditions resulted in interleukin-2 (IL-2) accumulation and prevented the induction of alloantigen-specific T cell clonal anergy. Binding of GD3 by R24 also prevented anergy under conditions where B7:CD28 interactions were blocked by CTLA4-Ig. The effect of R24 was abrogated in the presence of a combination of monoclonal antibodies for the alpha and beta chains of the IL-2 receptor (IL-2R) or a neutralizing anti-IL-2 antibody. R24 does not appear to interact directly with the IL-2R since incubation of T cell clones with R24 did not induce early activation of IL-2R associated Jak kinases, Jak1 and Jak3, as was induced following incubation with IL-2. In contrast, incubation of HLA-DR7-specific clones with t-DR7 in the presence of R24 did result in phosphorylation of IL-2R related Jak kinases after 24 h. Our data indicate that the membrane ganglioside GD3 structure recognized by R24 may play an important role in antigen-specific T cell clonal response.
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PMID:R24 anti-GD3 ganglioside antibody can induce costimulation and prevent the induction of alloantigen-specific T cell clonal anergy. 881 60

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


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