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)

Despite the recent advances in knowledge of the molecular mechanism by which interleukin-4 (IL-4) induces IgE production, little is known about the signal transduction pathway that leads to this event. This study investigated the signal transduction mechanism responsible for IL-4-induced expression of germ-line C epsilon transcripts with use of a human Burkitt lymphoma B-cell line, DND39, which is known to express germ-line C epsilon transcripts in response to IL-4. On stimulation with IL-4, the generation of inositol triphosphate was observed in the cells. In addition, this generation was associated with activation of phospholipase C-gamma 1 (PLC-gamma 1). Although herbimycin A, a potent inhibitor of tryosine kinase, inhibited IL-4-induced activation of PLC-gamma 1 and generation of inositol triphosphate, direct phosphorylation of PCL-gamma 1 was not determined. Nevertheless, IL-4 stimulation could induce activation of FYN but not LYN kinase, suggesting that additional molecule(s) might link FYN kinase to PLC-gamma 1. Interestingly, herbimycin A almost completely inhibited IL-4-induced expression of germ-line C epsilon transcripts when present during the entire culture period. These results indicate that the induction of germ-line C epsilon transcripts in IL-4-stimulated DND39 cells is essentially dependent on the activation of tyrosine kinase, possibly FYN kinase.
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PMID:Possible role of tyrosine kinase activity in interleukin 4-induced expression of germ-line C epsilon transcripts in a human Burkitt lymphoma B-cell line, DND39. 808 70

We have previously reported on the expression of interleukin-4 receptors (IL-4R) on many human epithelial cancer cells; however, the binding characteristics, structure, function, and signal transduction through the IL-4R in cancer cells is not known. IL-4 binding characteristics were determined in human colon carcinoma cell lines by a 125I-IL-4 binding assay, which demonstrated that the HT-29 and WiDr colon cancer cell lines expressed high affinity IL-4R (Kd = 200 pM). Cross-linking experiments revealed a major band of 140 kDa and a broad band at 70 kDa. While the common gamma chain of IL-2R is associated with IL-4R in immune cells and is similar in size to the 70-kDa protein, this chain was not expressed in these colon cancer cells. Interestingly, IL-13, which has many functions similar to IL-4, inhibited 125I-IL-4 binding to both the 140- and 70-kDa molecules. Next, we investigated the mechanism of IL-4-induced signal transduction in colon cancer cells. After stimulation with IL-4, a 170-kDa band was primarily phosphorylated within 1 min of exposure and was identified as insulin receptor substrate-1. In addition, by immunoprecipitation assay, three other phosphorylated bands were identified as JAK1, JAK2, and Tyk2 tyrosine kinases. The phosphorylation of JAK1 and JAK2 was induced by IL-4 stimulation; however, Tyk2 was constitutively phosphorylated, and IL-4 treatment further augmented this phosphorylation. The kinetics and in vitro kinase assays demonstrated that JAK1, JAK2, and Tyk2 were phosphorylated within minutes and that JAK1 and JAK2 were activated after IL-4 exposure. Contrary to observations in immune cells. JAK3 mRNA was neither detected in colon cancer cells nor did IL-4 treatment cause phosphorylation of JAK3. These data indicate that in colon carcinoma cells JAK1, JAK2, Tyk2, and insulin receptor substrate-1 are phosphorylated after IL-4 stimulation. In addition, as is the case in lymphoid cells, IL-4 activated and phosphorylated signal transducers and activators of transcription (IL-4-STAT or STAT-6) protein in both colon cancer cell lines. These results indicate that the IL-4R complex is composed of different subunits in different tissues and shares a component with the IL-13R complex. In addition, we demonstrate for the first time that like its family members (e.g. IL-3 and GM-CSF), IL-4 can phosphorylate and activate JAK-2 kinase.
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PMID:Receptors for interleukin (IL)-4 do not associate with the common gamma chain, and IL-4 induces the phosphorylation of JAK2 tyrosine kinase in human colon carcinoma cells. 853 May 27

Association of interleukin-4 receptor (IL-4R) with phosphatidylinositol 3-kinase (PI3-kinase) has been demonstrated as the proximal event of IL-4 signaling. We investigated the role of this enzyme in the IL-4 signaling pathway in a human Burkitt lymphoma B cell line, DND39, that expresses germline C epsilon transcripts in response to IL-4. Stimulation of DND39 cells with IL-4 resulted in an accumulation of PI-3-monophosphate as well as a decrease of PI-4,5-bisphosphate, which were abrogated by wortmannin, a potent inhibitor of PI3-kinase. Activation of PI3-kinase was further confirmed by the finding that IL-4 caused an increase in PI3-kinase activity coimmunoprecipitated with anti-IL-4R and with anti-JAK3 kinase antibodies. As a possible downstream event of PI3-kinase activation, the translocation of a zeta isoform of protein kinase C (PKC) from the cytosol to the membrane fraction was observed after IL-4 stimulation, and wortmannin also suppressed this translocation. Moreover, IL-4-induced expression of germline C epsilon transcription was inhibited not only by wortmannin, but also by a PKC inhibitor, K252a. These results suggest that the signaling pathway involving PI3-kinase and PKC zeta plays an important role in induction of germline C epsilon transcription in DND39 cells by IL-4.
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PMID:Evidence for a role of phosphatidylinositol 3-kinase in IL-4-induced germline C epsilon transcription. 866 Aug 9

Interleukin-4 (IL-4) exerts its effects through a heterodimeric receptor complex (IL-4R), which contains the IL-4R(alpha) and gamma(c) subunits. IL-4R(alpha) also functions with other partner subunits in several receptor types, including the IL-13 receptor. To examine the roles of the individual subunits within IL-4R complexes, we employed a chimeric system that recapitulates native IL-4R function as verified by the activation of the kinases, JAK1 and JAK3, and induction of STAT-6. When a mutant gamma(c) subunit in which the four cytoplasmic tyrosines were converted to phenylalanine was paired with the cytoplasmic domain of the IL-4R(alpha) chain, specificity within the JAK-STAT pathway was not altered. Signaling events were examined further in cells expressing the IL-4R(alpha) chimera alone without the gamma(c) chimera. Ligand-induced homodimerization of these receptors activated the IL-4 signaling program despite the absence of gamma(c), including induction of JAK1 and STAT-6, phosphorylation of the insulin-related substrate 1 and cellular proliferation. Thus, homotypic interactions of the IL-4R(alpha) subunit are sufficient for the initiation and determination of IL-4-specific signaling events, and such interactions may be integral to signaling through IL-4R complexes.
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PMID:Interleukin-4-specific signal transduction events are driven by homotypic interactions of the interleukin-4 receptor alpha subunit. 888 42

Interleukin-4 (IL-4) is an important cytokine for B and T lymphocyte function and mediates its effects via a receptor that contains gammac. B cells derived from patients with X-linked severe combined immunodeficiency (X-SCID) are deficient in gammac and provide a useful model in which to dissect the role of this subunit in IL-4-mediated signaling. We found that although IL-4 stimulation of X-SCID B cells did not result in Janus tyrosine kinase-3 (JAK3) phosphorylation, other IL-4 substrates including JAK1 and IRS-1 were phosphorylated. Additionally, we detected signal transducers and activators of transcription 6 (STAT6) tyrosine phosphorylation and DNA binding activity in X-SCID B cells with a wide range of gammac mutations. However, reconstitution of these X-SCID B cells with gammac enhanced IL-4-mediated responses including STAT6 phosphorylation and DNA binding activity and resulted in increased CD23 expression. Thus, gammac is not necessary to trigger IL-4-mediated responses in B cells, but its presence is important for optimal IL-4-signaling. These results suggest that two distinct IL-4 signaling pathways exist.
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PMID:Interleukin-4 signaling in B lymphocytes from patients with X-linked severe combined immunodeficiency. 905 29

CD40 is a member of the tumor necrosis factor receptor family and plays an important role in B-cell survival, growth, differentiation, and isotype switching. Recently, CD40 has been shown to associate with JAK3, a member of the family of Janus Kinases, which are nonreceptor protein kinases involved in intracellular signaling mediated by cytokines and growth factors. To investigate the role of JAK3 in CD40-mediated signaling, we studied the effect of CD40 stimulation on B-cell proliferation, IgE isotype switching, and upregulation of surface expression of CD23, ICAM-1, CD80, and LT-alpha in JAK3-deficient patients. Our studies show that stimulation of B cells with monoclonal antibody to CD40 in the presence of interleukin-4 (IL-4) or IL-13 resulted in similar responses in JAK3-deficient patients and normal controls. This suggests that JAK3 is not essential for CD40-mediated B-cell proliferation, isotype switching, and upregulation of CD23, ICAM-1, CD80, and LT-alpha surface expression.
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PMID:Role of JAK3 in CD40-mediated signaling. 974 83

The bipartite human interleukin-4 (IL-4) receptor was functionally expressed in murine pro-B cells and activated by human IL-4 to evoke intracellular signaling. Mutual association of signal transducing proteins within the receptor complex was then studied in dependence of ligand stimulation. Besides ligand-induced receptor heterodimerization and contacts of the two IL-4 receptor subunits alpha and gamma with Janus kinases JAK1 and JAK3 a prominent constitutive binding between JAK1 and signal transducer and activator of transcription STAT5 was detected. Since both these proteins become phosphorylated in response to IL-4 receptor stimulation, the influence of tyrosine phosphorylation on their mutual contact was analyzed. Association of JAK1 and STAT5 was found to occur exclusively between unphosphorylated proteins.
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PMID:Constitutive association of JAK1 and STAT5 in pro-B cells is dissolved by interleukin-4-induced tyrosine phosphorylation of both proteins. 984 80

Interleukin-4 (IL-4) plays a major role in immunoglobulin E (IgE) production. Its signal is conferred to effector cells through binding to the alpha chain of the IL-4 receptor (IL-4Ralpha). We present further evidence for polymorphisms in the IL-4Ralpha gene having an effect on IgE regulation. For two of four common polymorphisms, S503P and Q576R, we found an association with lowered total IgE concentrations (P=0.0008 if occurring together). The polymorphism S503P has not yet been described and is located within the I4R motif of the receptor. In vitro analyses using synthetic peptides of this region showed that the tyrosine kinase Janus kinase 1 (JAK1), as well as IRS-1 and IRS-2 bind to the I4R motif irrespective of the polymorphism or a tyrosine phosphorylation. In vivo immunoassays using T cells of four different groups of individuals (S503/Q576; P503/Q576; S503/R576; P503/R576) revealed that only in case of both polymorphisms the phosphorylation of IRS-1 and IRS-2, but not JAK1 was increased. We found no binding of STAT6 to the I4R synthetic peptides; however, the phosphorylation was reduced in the presence of any of the two polymorphisms, including P503 alone. We discuss possible conformational changes of the receptor leading to the observed effects on the phosphorylation status of IRS-1, IRS-2 and STAT6, in addition to previous findings that Q576R alters STAT6 binding. We conclude that P503 and R576 influence the signal transduction pathways through the IL-4Ralpha, an effect that is magnified by the presence of both polymorphisms. This could explain the observed association effects with lowered total IgE concentrations.
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PMID:The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction. 1023 17

Interleukin-4 (IL-4) is a pleiotropic cytokine, which acts on both hematopoietic and non-hematopoietic cells, through different types of receptor complexes. In this study, we report that in human B cells, IL-4 caused rapid phosphorylation of Janus kinase (JAK) 1 and JAK3 tyrosine kinases. In keratinocytes, the hematopoietic-specific receptor common gamma(c) chain is not expressed and the IL-13 receptor alpha(1) (IL-13Ralpha(1)) participates in IL-4 signal transduction. In keratinocytes, IL-4 induced JAK1 and JAK2 phosphorylation but, unlike in immune cells, IL-4 did not involve JAK3 activation for its signaling. In both cell types, IL-4 induced phosphorylation and DNA binding activation of the signal transducer and activator of transcription (STAT) 6 protein. Furthermore, IL-4 stimulation of keratinocytes also induced tyrosine phosphorylation of STAT3 which was found to bind to the phosphorylated IL-13Ralpha(1). STAT3 however did not significantly translocate to the nucleus, nor did it bind with high affinity to target DNA sequences.
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PMID:Binding of IL-4 to the IL-13Ralpha(1)/IL-4Ralpha receptor complex leads to STAT3 phosphorylation but not to its nuclear translocation. 1061 90

To determine whether the paracrine secretion of interleukin-4 (IL-4) can efficiently induce T helper type 2 (Th2) cell-dominated immune response, BLK fibroblasts were stably transfected to secrete IL-4 (750 units/10(6) cells/48 h). Their effects on T helper cell-mediated immune response were investigated in ovalbumin (OVA)-primed C57BL/6 mice, and were compared with those of free recombinant IL-4. Injection with IL-4-secreting fibroblasts (BLK/IL-4) significantly increased anti-OVA IgG1 production in OVA-primed mice. In addition, the BLK/IL-4 cells were more effective than free recombinant IL-4 in decreasing OVA-specific IFN-gamma production and in increasing OVA-specific IL-4 production by splenic CD4(+) T cells. This work suggests that IL-4-secreting fibroblasts can efficiently induce Th2 cell-dominated immune response and may be beneficial in the treatment of diseases caused by undesired Th1 cell-dominated responses.
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PMID:Injection with interleukin-4-secreting fibroblasts efficiently induces T helper type 2 cell-dominated immune response. 1081 26


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