Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00082 (IL-2)
 29,198 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, the SRC-like non-receptor protein tyrosine kinase p56-LCK has been shown to physically associate with the interleukin-2 receptor (IL-2-R) complex and to undergo rapid elevations in its tyrosine kinase activity upon stimulation of T lymphocytes with IL-2. The functional significance of p56-LCK kinase activation for IL-2-mediated lymphocyte responses, however, has never been directly assessed. Using gene transfer approaches, we have achieved markedly elevated levels of p56-LCK kinase activity in the IL-2-dependent cytolytic T-cell line CTLL-2 and the helper line HT-2. CTLL-2 and HT-2 cells that were stably transfected with expression plasmids encoding either the normal human p56-LCK or a constitutively active version of the mouse p56-LCK kinase (LCK[Y505]) contained striking elevations in the levels of tyrosine phosphorylation on several proteins (34-36, 50-60, 62-68, 77-78, 104-110 kDa), as determined by immunoblot analysis using anti-phosphotyrosine antibodies. CTLL-2 and HT-2 LCK- and LCK(Y505F)-transfected cells remained dependent on IL-2 for their growth and survival in culture despite the findings that (i) IL-2 specifically stimulated elevations in the activity of the endogenous p56-LCK in untransfected CTLL-2 cells without affecting the activities of the other SRC-like kinases in these cells (p59-FYN, p62-YES) and that (ii) IL-2-mediated regulation of p56-LCK correlated with IL-2-driven proliferation of these T cells. Specifically, no elevation in the proliferation (DNA synthesis) or growth of these T cells was found at any of the concentrations of IL-2 examined (0.01-25 U/ml), relative to untransfected and control transfected cells. Furthermore, when cultured in the absence of IL-2, transfected T cells whose relative levels of p56-LCK activity were elevated by approximately 20-50-fold died with the same kinetics as control cells and underwent apoptosis, as defined by uptake of trypan blue dye and DNA fragmentation assays, respectively. Taken together, these data indicate that while IL-2 can up-regulate the enzymatic activity of p56-LCK, elevated levels of p56-LCK tyrosine kinase activity are insufficient to stimulate IL-2-mediated pathways required for T-cell growth and survival. These findings thus imply the existence of other signal-transducing molecules, besides p56-LCK, that physically participate in IL-2R complexes and that are necessary for initiation of the biochemical events ultimately responsible for IL-2's pleiotropic actions on lymphocytes.
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PMID:Gene transfer investigations of p56-LCK function in IL-2-dependent T-cell lines: implications for mechanisms of IL-2-signal transduction. 129 28

We have previously reported the establishment of an interleukin-3 (IL-3)-dependent and phenotypically myeloid cell line (TALL-103/3), obtained by culturing cells from an immature T-lymphoblastic leukemia in the presence of IL-3. These cells differentiated into a T-lymphoid cell line (TALL-103/2) upon removal of IL-3 and incubation in IL-2. Despite the different phenotype, the two cell lines remained karyotypically and genotypically identical. Here, we have analyzed the phenotypic changes and the signaling events induced by these two lymphokines in TALL-103/3 cells by switching them to temporary growth in IL-2 and returning them to IL-3. All four sublines obtained (the myeloid in IL-3 and the lymphoid in IL-2) expressed RNA for CD3, IL-2 receptor (R) alpha, and T-cell receptor (TCR)-gamma and -delta chains. However, cells cultured in IL-3 failed to express detectable levels of the IL-2R beta chain at both the protein and RNA levels, whereas cells exposed to IL-2 always expressed IL-2R beta. In parallel with the changes in IL-2R beta expression, the SRC-like protein tyrosine kinase (PTK) p56 LCK could not be detected in IL-3-dependent cells, but was abundant in the IL-2-dependent cells and underwent markedly increased autophosphorylation in response to IL-2. In contrast, p53/p56 LYN was highly expressed in IL-3-dependent cells, and greatly decreased when these cells were switched to growth in IL-2. LYN kinase autophosphorylation modestly increased in response to IL-3. None of the other kinases in the SRC family that were tested underwent increased autophosphorylation after lymphokine stimulation, indicating the specificity of IL-2 for LCK and of IL-3 for LYN. The TALL-103 cell lines provide a unique system to study the interaction between lymphokines and SRC-family PTKs in signal transduction pathways leading to hematopoietic cell differentiation.
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PMID:Phenotypic changes induced by interleukin-2 (IL-2) and IL-3 in an immature T-lymphocytic leukemia are associated with regulated expression of IL-2 receptor beta chain and of protein tyrosine kinases LCK and LYN. 137 47

IL-2 is one of the principal growth factors regulating the proliferation of T lymphocytes. Although two independent IL-2-binding molecules have been molecularly cloned and shown to participate in the formation of a high affinity receptor complex, their primary structures do not suggest a specific mechanism for IL-2 growth signal transduction across the cell membrane. Neither IL-2 receptor subunit contains an intrinsic kinase domain; nevertheless, tyrosine phosphorylation of various intracellular substrates is one of the first biochemical changes observed following activation of the IL-2 receptor (IL-2R). Both serine/threonine and tyrosine kinases can be co-precipitated as part of the IL-2R complex suggesting that the IL-2 signalling may involve the activation of non-covalently associated intracellular kinases. However, controversy exists as to which kinases are involved in IL-2 signal transduction; in particular, which kinase(s) mediates the first or proximal event(s) in the signalling process. Activation of the IL-2R leads to serine and threonine phosphorylation of the SRC tyrosine kinase family member, LCK, and an increase in LCK tyrosine kinase activity. Furthermore, LCK can be co-immunoprecipitated with the beta chain of the IL-2R indicating its association with the receptor complex. IL-2 has also been reported to increase FYN kinase activity and to alter its association with the 85 kDa subunit of phosphatidylinositol-3 kinase thus suggesting a role for FYN in IL-2 signal transduction. However, in this report, we now demonstrate that neither LCK nor FYN are obligatory for IL-2-induced growth of HTLV-I-infected human T cells. Lack of expression of LCK or FYN in the HTLV-I-infected T cell lines was demonstrated by a combination of Northern blotting, polymerase chain reaction, Western blotting, and in vitro kinase activity. Despite the absence of LCK or FYN, IL-2 induced similar patterns of rapid tyrosine phosphorylation. Similar results were observed in cell lines lacking expression of the LYN, FGR, HCK, and LTK tyrosine kinases. Thus, none of these tyrosine kinases alone appears to be required for growth signalling through the IL-2R in the HTLV-I-infected T cell lines analyzed. The findings raise the possibility that an, as yet, unidentified tyrosine kinase is involved. Alternatively, this biological signalling system may exhibit remarkable redundancy whereby several different tyrosine kinases may be capable of associating with the IL-2R complex and mediating intracellular signalling.
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PMID:Neither the LCK nor the FYN kinases are obligatory for IL-2-mediated signal transduction in HTLV-I-infected human T cells. 147 76

Unlike many other growth factor receptors, the known subunits of the receptors for the Interleukins IL-2 and IL-3 lack intrinsic tyrosine kinase activity, and yet increases in the phosphorylation of proteins on tyrosines is a rapid event in hematolymphoid cells following stimulation with these lymphokines. Here we show that IL-2 and IL-3 regulate the activity of specific members of the SRC-family of non-receptor protein tyrosine kinases (PTKs). In IL-2-dependent T-cell lines, IL-2 induced rapid and transient increases in the activity of the p56-LCK kinase without influencing the activities of other SRC-like PTKs (p59-FYN, p62-YES) in these T-lymphocytes. In contrast to IL-2's effects on p56-LCK in T-cells, studies of an IL-2-responsive cell line of the B-cell lineage that lacks p56-LCK revealed that IL-2 specifically regulates the activity of the p53/56-LYN kinase. Thus, some flexibility exists in the ability of various SRC-like PTKs to functionally couple to IL-2 signalling pathways. In several IL-3-dependent myeloid-committed leukemic cell lines, IL-3 was found to specifically regulate the activity of the p53/56-LYN kinase without affecting the activities of other SRC-like PTKs (p59/64-HCK, p59-FYN, p62-YES) in these hematopoietic cells. This finding that p53/56-LYN can be regulated by both IL-2 in B-lineage cells and IL-3 in myeloid-committed cells demonstrates that the same SRC-family PTK can participate in signal transduction events mediated via two independent receptor systems. Taken together, our findings imply that the specific combinations of lymphokine receptors and SRC-like PTKs available for coupling with those receptors are coordinately controlled during the differentiation of hematopoietic cells.
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PMID:Regulation of SRC-family protein tyrosine kinases by interleukins, IL-2, and IL-3. 160 36

The extracellular matrix (ECM) is composed of a number of macromolecules that promote cell adhesion, cell migration, and differentiation. Receptors for these molecules have been identified and belong to a superfamily of cell surface proteins, collectively known as the integrins. In this study, we show that the matrix protein fibronectin (FN) acts synergistically with immobilized anti-CD3 antibody to promote proliferation of total human peripheral blood lymphocytes (HPBL) in the absence of exogenous IL-2. Proliferation was inhibited by both the alpha 5 beta 1 and alpha 4 beta 1 recognition peptides. ARG-GLY-ASP (RGD), and GLU-ILE-LEU-ASP-VAL-PRO-SER-THR (EILDVPST), respectively. Expression of CD25 (IL-2 receptor) was significantly higher on cells cultured on anti-CD3 and FN, indicative of T-cell activation. Additionally, cells cultured on immobilized anti-CD3 and FN for 3 days showed increased adhesion to FN and increased forward light scatter/side scatter profile. Synthesis of both IL-1 and to a lesser extent IL-2 was elevated in supernatants from cultures containing both anti-CD3 and FN. These data are consistent with published reports which demonstrate that ECM proteins can act as costimulants of lymphocyte proliferation. Finally, our results show that cells cultured on anti-CD3 antibody and FN have an activated phenotype and that cytokines may be involved in this process.
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PMID:Fibronectin augments anti-CD3-mediated IL-2 receptor (CD25) expression on human peripheral blood lymphocytes. 182 61

A great deal of information has emerged over the past decade regarding the gene structures and corresponding protein products of the cellular and transformation-associated forms of the ABL tyrosine kinase family. Many reports have also detailed the biological effects of these proteins (particularly the viral ABL forms) on a broad range of cell types. However, in spite of all these research efforts, the precise role of the ABL gene in normal and neoplastic growth remains to be determined. To elucidate the mechanism of action of normal and altered ABL proteins, it is imperative to identify their relevant cellular substrates and establish the role of the ABL target proteins in transformation and normal cellular growth. The availability of temperature-sensitive ABL proteins, coupled with the use of sensitive anti-phosphotyrosine antibodies, should be useful in this respect. Purification of enzymatically active, intact forms of the ABL proteins produced in insect cells by employing baculovirus expression vectors should permit direct comparison of the biochemical properties and tertiary structures of the various members of the ABL protein kinase family. Such studies will aid in understanding the nature of the alteration of ABL which results in the activation of its transforming potential. Furthermore, the availability of purified ABL proteins should permit examination of interactions of ABL with other growth-regulatory proteins, such as growth factor receptors. It has been shown that transformation-associated ABL proteins interact with the IL-3, IL-2 and GM-CSF growth-factor pathways. These and other components of the cellular signalling pathways are potential ABL targets. The elucidation of ABL function by a variety of approaches such as those described above will ultimately aid in the development of far-reaching therapeutic treatments for at least two forms of human leukaemia: Ph positive CML and Ph positive ALL.
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PMID:Role of the ABL oncogene tyrosine kinase activity in human leukaemia. 333 51

OK-432, a streptococcal preparation, is known to have strong BRM functions and is expected to produce clinical improvement and prolongation of survival in treated cancer patients. In order to clarify the immunopharmacological mechanisms involved with its clinical effectiveness, intrapleural injection of OK-432 was attempted in patients with malignant pleural effusion due to metastasis from lung cancer. About 70-80% of patients thus treated showed clinical improvements with reduction or disappearance of effusion and effusion tumor cells within a week after the therapy. The clinical response was accompanied by an abrogation or reduction of suppressor macrophages and a stimulatory increase of effective cytotoxic cells resulting in an increase of NK and ATK activity. These in vivo effects observed in the OK-432-treated patients were reproducible in vitro by incubating normal or effusion lymphocytes with tumor-associated macrophages. OK-432 was also shown to reduce the locomotor inhibitory activity of macrophages toward LGL, and to augment the production of various sorts of cytokines, such as IL-1 and MCF by macrophages and IL-2 and NKCF by lymphocytes, all of them being exerted upon activation of the anti-tumor immunological mechanism.
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PMID:[Effective mechanisms of BRM, with special reference to induction of autologous tumor cell-killing (ATK) activity by OK-432]. 348 24

C57BL/6J nu/nu mice respond to the type 2 TI antigen DAGG-Ficoll, but not to the TD antigen SRC. A comparable difference can also be seen in vitro, but only at high spleen cell density and in the presence of selected batches of FBS. At low spleen cell density and in the absence of FBS, the DAGG-Ficoll-induced B cell response is strictly dependent on soluble helper factors or cloned specific helper T cells. The B cell response so induced requires that the T cell-depleted spleen cells be compatible in the I-A subregion of the H-2 complex. These helper factors, induced by antigen in an I-A-restricted T cell-macrophage interaction, provide helper for T cell-depleted spleen cells irrespective of their H-2 haplotype. Under conventional culture conditions, the stringent requirement for helper factors in the in vitro response to DAGG-Ficoll is obscured by FBS. In vitro culture of low numbers of spleen cells, in serum-free medium instead of FBS, provides a sensitive assay for helper factors. We have compared the helper activity for a B cell response to SRC or DAGG-Ficoll as provided by antigen-induced supernatants of various individual EA-specific T cell clones. There was a remarkable and consistent heterogeneity among individual T cell clones: their helper activity in the response to TI and TD antigens did not correlate, nor was there any correlation between helper activity and antigen-induced TCGF (interleukin 2) activity.
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PMID:T cell control of the antibody response to the T-independent antigen, DAGG-Ficoll. 617 69

The signaling molecules insulin receptor substrate (IRS)-1 and the newly described IRS-2 (4PS) molecule are major insulin and interleukin 4 (IL-4)-dependent phosphoproteins. We report here that IL-2, IL-7, and IL-15, as well as IL-4, rapidly stimulate the tyrosine phosphorylation of IRS-1 and IRS-2 in human peripheral blood T cells, NK cells, and in lymphoid cell lines. In addition, we show that the Janus kinases, JAK1 and JAK3, associate with IRS-1 and IRS-2 in T cells. Coexpression studies demonstrate that these kinases can tyrosine-phosphorylate IRS-2, suggesting a possible mechanism by which cytokine receptors may induce the tyrosine phosphorylation of IRS-1 and IRS-2. We further demonstrate that the p85 subunit of phosphoinositol 3-kinase associates with IRS-1 in response to IL-2 and IL-4 in T cells. Therefore, these data indicate that IRS-1 and IRS-2 may have important roles in T lymphocyte activation not only in response to IL-4, but also in response to IL-2, IL-7, and IL-15.
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PMID:Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. 749 65

Interleukin (IL-12) has many effects on the function of natural killer and T cells, and is important in the control of cell-mediated immunity. IL-2 and IL-12 display many similar activities, yet each also induces a distinct set of responses. A human IL-12 receptor subunit has recently been cloned and, like the IL-2R beta and IL-2R gamma, is a member of the hematopoietic receptor superfamily; however, the molecular mechanisms of IL-12 action are unknown. In this report we show that IL-12 and IL-2 induce tyrosine phosphorylation of distinct members of the Janus (JAK) family of protein tyrosine kinases in human T lymphocytes. IL-12, but not IL-2, stimulates the tyrosine phosphorylation of TYK2 and JAK2, whereas JAK1 and JAK3, which are phosphorylated in response to IL-2, are not phosphorylated after IL-12 treatment. The use of distinct but related JAK family tyrosine kinases by IL-12 and IL-2 may provide a biochemical basis for their different biological activities.
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PMID:Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. 752 75


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