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: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Germ line C transcripts can be induced by IL-4 in the human B cell line, BL-2. Utilizing a IFN-gamma activation site-like DNA sequence element located upstream of the I epsilon exon, we demonstrated by gel mobility shift assays that IL-4 induced a binding activity in the cytosol and nucleus of BL-2 cells. This factor was designated IL-4 NAF (IL-4-induced nuclear-activating factors) and was identified as a tyrosine phosphoprotein, which translocates from the cytosol to the nucleus upon IL-4 treatment. Because these are the characteristics of a signal transducer and activator of transcription (Stat) protein, we determined whether antibodies to Stat proteins will interfere with gel mobility shift and found that antibodies to IL-4 Stat, also known as Stat6, but not antibodies to other Stat proteins, interfere with the formation of the IL-4 NAF complex. Congruous with the involvement of a Stat protein, IL-4 induced robust Janus kinase 3 (JAK3) activity in BL-2 cells. Cotransfection of JAK3 with IL-4 Stat into COS-7 cells produced an intracellular activity which bound the same IFN-gamma activation site-like sequence and comigrated with IL-4 NAF in electrophoretic mobility shift assay. These results show that IL-4 NAF is IL-4 Stat, which is activated by JAK3 in response to IL-4 receptor engagement.
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PMID:Interleukin 4 activates a signal transducer and activator of transcription (Stat) protein which interacts with an interferon-gamma activation site-like sequence upstream of the I epsilon exon in a human B cell line. Evidence for the involvement of Janus kinase 3 and interleukin-4 Stat. 763 85

Interleukin (IL)-4 and IL-9 regulate the proliferation of T lymphocytes through interactions with their receptors. Previous studies have shown that unknown tyrosine kinases are involved in the proliferative signaling triggered by IL-4 and IL-9. Here we show that IL-4 and IL-9 induce overlapping (170, 130, and 125 kilodalton (kDa)) and distinct (45 and 88/90 kDa, respectively) protein tyrosine phosphorylation in T lymphocytes. We further identify the 170-kDa tyrosine-phosphorylated protein as 4PS/insulin receptor substrate-1-like (IRS-1L) protein and 130-kDa protein as JAK1 kinase. Furthermore, we demonstrate for the first time that JAK1 forms complexes with the IL-4 receptor and 4PS/IRS-1L protein following ligand-receptor interaction. In addition, we demonstrate that IL-9, but not IL-4, induced tyrosine phosphorylation of Stat 91 transcriptional factor. The overlapping and distinct protein tyrosine phosphorylation and activation of the same JAK1 kinase in T lymphocytes strongly suggests that IL-4 and IL-9 share the common signal transduction pathways and that the specificity for each cytokine could be achieved through the unique tyrosine-phosphorylated proteins triggered by individual cytokines.
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PMID:JAK1 kinase forms complexes with interleukin-4 receptor and 4PS/insulin receptor substrate-1-like protein and is activated by interleukin-4 and interleukin-9 in T lymphocytes. 792 91

We have reported that human ovarian-carcinoma cell lines express high-affinity IL-4 receptor. Since IL-4R has been hypothesized to share a chain with IL-13R, we investigated whether ovarian cancer cells express IL-13 receptor. In the present study, we report that the ovarian-carcinoma cell lines IGROV-1 and PA-1 express varying numbers of high-affinity IL-13 receptors. Furthermore, IL-13 inhibited the binding of IL-4 on both ovarian-carcinoma cell lines, while IL-4 did not inhibit IL-13 binding on IGROV-1 cell line. IL-13 and IL-4 induced the phosphorylation of JAK1, JAK2 and Tyk2 Janus kinases in PA-1 cells. In contrast, JAK3 tyrosine kinase was expressed in PA-1 cells, but IL-4 or IL-13 did not augment its phosphorylation. In IGROV-1 cells, Tyk2 was constitutively phosphorylated and this phosphorylation was augmented by IL-4 or IL-13. JAK1 and JAK2 but not JAK3 were expressed but only JAK2 was faintly phosphorylated in response to either IL-13 or IL-4 respectively. IRS (insulin-receptor substrate)-1 and IRS-2 were also phosphorylated constitutively in both ovarian cancer cell lines examined, but only the phosphorylation of IRS-1 was augmented in response to IL-4 or IL-13. STAT6 was phosphorylated and activated in response to IL-4 and IL-13 in all cell lines examined. Our results demonstrate that ovarian cancer cell lines may express 2 types of IL-13R and the IL-13- or IL-4-induced signaling patterns may be slightly different in each type of receptor.
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PMID:Human ovarian-carcinoma cell lines express IL-4 and IL-13 receptors: comparison between IL-4- and IL-13-induced signal transduction. 900 65

Interleukin 4 (IL-4) and Interleukin 13 (IL-13) have been shown to have numerous similar effects on human B cells; however, the mechanism of signal transduction is not known. We have examined IL-4- and IL-13-induced signal transduction in Epstein-Barr virus (EBV)-immortalized B cells. We demonstrate that Janus kinase 3 (JAK3) and Tyk2 but not JAK1 and JAK2 tyrosine kinases were constitutively phosphorylated in three EBV B cell lines. The phosphorylation level of Tyk2 was augmented at a low level in response to IL-13 and IL-4 in two of three cell lines; however, IL-13 did not induce or augment phosphorylation of the other JAK kinases. On the other hand, IL-4 further augmented phosphorylation of JAK3 and induced the phosphorylation of JAK1 kinases. IL-4 receptor p140 protein was also constitutively phosphorylated in two of three EBV B cell lines examined and both IL-4 and IL-13 further augmented its phosphorylation. Insulin receptor substrate (IRS)-1 or IRS-2 proteins were not constitutively phosphorylated nor did IL-13 and IL-4 induce phosphorylation of these proteins. In contrast to JAKs, IL-4-specific signal transducer and activator of transcription (STAT6) was not constitutively phosphorylated or activated in these cell lines, but both IL-4 and IL-13 induced their phosphorylation and activation. These findings suggest that in EBV-immortalized B cells JAK3 and Tyk2 proteins were constitutively phosphorylated but STAT6 protein was not constitutively phosphorylated. In addition, despite major similarities in biological effects between IL-4 and IL-13, phosphorylation patterns of JAK kinases in response to IL-13 in EBV-immortalized B cells appear to be different from those of IL-4.
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PMID:Comparison of IL-13- and IL-4-induced signaling in EBV-immortalized human B cells. 901 86

The cytokines interleukin (IL)-4 and IL-13 play a critical role in inducing Cepsilon germline transcripts and IgE isotype switching in human B cells. The IL-4 receptor (IL-4R) in B cells is composed of two chains, the IL-4-binding IL-4Ralpha chain, which is shared with the IL-13R, and the IL-2Rgamma (gammac) chain, which is shared with IL-7R, IL-9R, and IL-15R. IL-4 induces Cepsilon germline transcripts and IgE isotype switching in B cells from patients with gammac chain deficiency. Induction of Cepsilon germline transcripts by IL-4 in B cells that lack the gammac chain may involve signaling via the IL-13R. Alternatively, the IL-4Ralpha chain may transduce intracellular signals that lead to Cepsilon gene transcription independently of its association with other chains. We show that ligand-induced homodimerization of chimeric surface receptors consisting of the extracellular and transmembrane domains of the erythropoietin receptor and of the intracellular domain of IL-4Ralpha induces Janus kinase 1 (Jak1) activation, STAT6 activation, and Cepsilon germline transcripts in human B cell line BJAB. Disruption of the Jak1-binding proline-rich Box1 region of IL-4Ralpha abolished signaling by this chimeric receptor. Furthermore, B cells transfected with a chimeric CD8alpha/IL-4Ralpha receptor, which is expressed on the cell surface as a homodimer, constitutively expressed Cepsilon germline transcripts. These results suggest that homodimerization of the IL-4Ralpha chain is sufficient to transduce Jak1-dependent intracellular signals that lead to IgE isotype switching.
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PMID:Homodimerization of the human interleukin 4 receptor alpha chain induces Cepsilon germline transcripts in B cells in the absence of the interleukin 2 receptor gamma chain. 915 66

Although much is known about the activation, proliferation, and function of CD4(+) T cells, little is known about how they survive as resting T cells in animals. Resting T cells have a half-life in animals of more than a week; however, when they are removed from animals and placed in tissue culture their half-life falls to approximately 24 h. In this paper, we show that the survival of resting T cells in vitro is promoted by two cytokines, interleukins 4 and 7 (IL-4, IL-7). They may do this in part by maintaining levels of survival-promoting proteins such as Bcl-2 in the cells, because the levels of Bcl-2 and Bcl-Xl in resting T cells fall rapidly after the cells are isolated from animals, and are maintained by culture in IL-4. Because the IL-4 receptor is known to signal through the JAK1 and JAK3/Stat6 pathway, we tested whether Stat6 was required for IL-4- dependent T cell survival. Surprisingly, we found that IL-4 rescued T cells from apoptosis in what appeared to be a Stat6-independent manner. These results demonstrate that the survival of resting T cells is an active process that can be affected by signals delivered by cytokines and also suggest that the IL-4 receptor on resting T cells may use a novel signaling pathway to facilitate T cell viability.
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PMID:Interleukin 4 (IL-4) or IL-7 prevents the death of resting T cells: stat6 is probably not required for the effect of IL-4. 922 62

Interleukin (IL)-13 is a pleiotropic immunoregulatory cytokine that shares many, although not all, of the biological activities of IL-4. The overlapping biological properties of IL-4 and IL-13 appear to be due to the existence of shared components of the receptors, and we and others showed that the IL-4 receptor-alpha is involved in signal transduction paths activated by both. We show here that expression of the IL-13 receptor-alpha in two factor-dependent cell lines, the premyeloid FD5 and the T lymphoid CT4.S, conferred the ability to grow continuously in response to IL-13; to respond to IL-13 with tyrosine phosphorylation of JAK1, Tyk2, IL-4Ralpha, IRS-2, and STAT6; and to respond to IL-4 with tyrosine phosphorylation of Tyk2 in addition to those induced in parental cell lines. Expression of a truncated IL-13 receptor-alpha that lacked the cytoplasmic domain demonstrated that this domain was essential for IL-13-dependent growth and phosphorylation of the above substrates. Expression of this truncated IL-13 receptor also resulted in an inhibition of biochemical and biological responses to IL-4 that was exacerbated by the presence of IL-13. These dominant inhibitory effects indicate that the extracellular domain of the truncated IL-13 receptor competes with gammac for complexes of IL-4 and the IL-4 receptor-alpha, or, when itself bound to IL-13, competes with IL-4 for the IL-4 receptor-alpha.
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PMID:An interleukin (IL)-13 receptor lacking the cytoplasmic domain fails to transduce IL-13-induced signals and inhibits responses to IL-4. 927 58

The present study describes two novel cell lines, DUNATIS and SILVANUS, established from B lineage acute lymphoblastic leukemia patients. Respectively, DUNATIS and SILVANUS display an early pre-B cell and a pre-B cell phenotype. Spontaneous DNA replication of both cell lines was strongly inhibited by IL-4. This effect was directly mediated by IL-4 and exerted through the CD124 IL-4 receptor chain. Notably, IL-4 was associated with rapid cell death and reduction of cellularity in DUNATIS, whereas these parameters were considerably less pronounced and only observed after longer-term exposure of the SILVANUS cells to IL-4. In addition to these differences, although both cell lines expressed FES oncoprotein, a 100 kDa protein associated with FES was strikingly found to be tyrosine-phosphorylated in response to IL-4 exclusively in DUNATIS cells. These data demonstrate that IL-4 displays heterogenous effects on leukemic B cell precursors responsive to inhibition of DNA synthesis via IL-4 mediated engagement of the CD124 receptor chain. The present findings may be of use for appreciation of the effects of IL-4 in B lineage ALL, and the novel cell lines could represent a model for further identification of target molecules in IL-4 signalling.
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PMID:Heterogeneity of the inhibitory effects of IL-4 in two novel B lineage acute lymphoblastic leukemia cell lines. 944 37

Leflunomide is an immunosuppressive drug capable of inhibiting T and B cell responses in vivo. A number of studies demonstrate that leflunomide functions both as a pyrimidine synthesis inhibitor and as a tyrosine kinase inhibitor. We previously reported that leflunomide inhibits LPS-stimulated B cell proliferation, cell cycle progression, and IgM secretion. This inhibition can be reversed by the addition of exogenous uridine, suggesting that leflunomide functions as a pyrimidine synthesis inhibitor in B cells. We report here that while the addition of uridine restored proliferation and IgM secretion to leflunomide-treated LPS-stimulated B cells, as determined by metabolic labeling and immunoprecipitation, it did not completely restore secretion of IgG Ab. We hypothesized that leflunomide inhibits LPS-induced IgG secretion by inhibiting tyrosine kinase activity required for isotype switch. We tested this hypothesis in a well-defined model of isotype switch, LPS plus IL-4 induction of IgG1. Leflunomide inhibited IgG1 secretion in this model in a dose-dependent manner. The signal transduction pathway utilized by IL-4 to induce IgG1 involves tyrosine phosphorylation of the IL-4 receptor, JAK1, JAK3, and STAT6 proteins induced by IL-4 binding to the IL-4R. Leflunomide diminished the tyrosine phosphorylation of JAK3 and STAT6 in the absence or presence of uridine. In gel mobility shift studies, STAT6 binding to the STAT6 DNA binding site in the IgG1 promoter decreased in the presence of leflunomide or leflunomide plus uridine. Taken together, these data suggest that leflunomide acts as a tyrosine kinase inhibitor to block IgG1 production.
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PMID:Inhibition of JAK3 and STAT6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgG1 production. 946 13

In hematopoietic cells, interleukin-2 receptor (IL-2R) gamma chain (termed gammac) is shown to be a component of the IL-4R system, whereas in nonhematopoietic cells, gammac is absent and it is not a component of the IL-4R system. Here, we show that the IL-13R alpha' chain (termed IL-13Ralpha') but not the IL-13R alpha chain (termed IL-13Ralpha) can substitute for gammac and, thus, IL-13Ralpha' forms a novel component of the IL-4R system. This conclusion was drawn on the basis of chemical cross-linking, immunoprecipitation, the ability of IL-13Ralpha' but not IL-13Ralpha to augment IL-4 binding affinity, and the requirement of IL-13Ralpha' for IL-4-induced STAT6 activation in Chinese hamster ovary (CHO) cells transfected with various receptor subunits. Cotransfection of IL-4 receptor p140 (termed IL-4Rbeta) with gammac or IL-13Ralpha' increased IL-4 binding affinity and allowed for STAT6 activation in response to IL-4. However, cotransfection of all three chains did not further increase IL-4 binding or alter the extent of STAT6 activation suggesting that all three chains together do not seem to participate in IL-4 function. Instead, IL-4Rbeta heterodimerizes with gammac or IL-13Ralpha' and mediates STAT6 activation. Cotransfection of IL-4Rbeta with IL-13Ralpha neither increased IL-4 binding affinity nor allowed for STAT6 activation in response to IL-4 indicating that IL-13Ralpha does not convert binding affinity nor transmit signals for IL-4. Because IL-4 phosphorylates JAK1 and JAK2 tyrosine kinases in nonhematopoietic cells, we investigated whether JAK1 and JAK2 are required for IL-4-induced STAT6 activation in various transfectants. Cotransfection experiments with different chains of IL-4R and kinase-deficient JAK1 and JAK2 mutants in CHO cells showed that JAK1 and JAK2 are required for optimal activation of STAT6 in the alpha' beta transfectant but only partially in the beta gammac transfectant. Taken together, our results show that IL-13Ralpha' is a novel functional component of the IL-4R system and that JAK1 and JAK2 mediate IL-4-induced optimal activation of STAT6 in nonhematopoietic cells.
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PMID:Interleukin-13 receptor alpha' but not alpha chain: a functional component of interleukin-4 receptors. 957 26


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