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)

We examined the relative efficacy of allogeneic versus syngeneic fibroblasts admixed with tumor cells as a vaccine to induce antitumor T-cell reactivity. Allogeneic (3T3) or syngeneic (BLK) fibroblasts transfected to secrete equivalent amounts of GM-CSF were admixed with either D5 melanoma or MCA 207 sarcoma and inoculated s.c. into the flanks of C57BL/6 mice. Vaccine-primed lymph node (LN) cells were examined for in vivo antitumor reactivity in an adoptive transfer model. At fibroblast: tumor cell ratios of < or=1, allogeneic and syngeneic granulocyte macrophage colony-stimulating factor-secreting fibroblasts enhanced T-cell reactivity to tumor cells. However, at ratios of 2.4, the adjuvant effect induced by granulocyte macrophage colony-stimulating factor was not evident. Instead, we observed increased alloreactivity of primed LN cells against 3T3 targets as assessed by cytotoxicity and cytokine release assays, which was not observed with syngeneic fibroblasts. Moreover, with increasing numbers of allogeneic fibroblasts, there was a skewing of the T-cell Vbeta repertoire. These latter cells responded to tumor stimulation with the release of greater amounts of interleukin 10, which may account for the diminished antitumor reactivity observed in vivo. Allogeneic fibroblasts transduced to secrete interleukin 2 or IFN-gamma also induced diminished tumor reactivity of primed LN cells. Syngeneic fibroblasts are superior to allogeneic fibroblasts as vehicles to deliver cytokines in tumor vaccines.
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PMID:Reduced efficacy of allogeneic versus syngeneic fibroblasts modified to secrete cytokines as a tumor vaccine adjuvant. 924 54

Leukocyte integrins are fundamentally important in modulating adhesion to extracellular matrix components and to other cells. This integrin-mediated adhesion controls leukocyte arrest and extravasation during the onset of inflammatory responses. Moreover, integrin-ligand interactions trigger signaling pathways that may influence leukocyte phenotype and function at sites of inflammation. In the current studies, we evaluated the combinatorial effects of monocyte adhesion and IFN-gamma on intracellular signaling pathways. IFN-gamma triggers a well-defined signal transduction pathway, which although not directly stimulated by monocyte adherence to fibronectin or arginine-glycine-aspartate (RGD)-coated substrata, was enhanced significantly in these matrix-adherent cells. Compared with monocytes in suspension or adherent on plastic surfaces, monocytes adherent to fibronectin or RGD exhibited a greater than threefold increase in steady state levels of IFN-gamma-induced mRNA for the high affinity Fc gammaRI receptor. By electrophoretic mobility shift assays, this increase in mRNA was associated with a 5- to 10-fold increase in the STAT1-containing DNA-binding complex that binds to Fc gammaRI promoter elements. Furthermore, the tyrosine phosphorylation of STAT1 and the tyrosine kinases JAK1 and JAK2 was enhanced significantly in RGD-adherent monocytes compared with control cells. These results suggest a novel mechanism by which integrin-mediated cell adhesion can modulate the magnitude of cytokine-induced signal transduction pathways, thereby amplifying cellular events leading to monocyte activation and inflammation.
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PMID:Human monocyte binding to fibronectin enhances IFN-gamma-induced early signaling events. 927 34

In addition to a role in response to insulin and insulin-like growth factors, insulin receptor substrate 1 (IRS-1) is phosphorylated in response to IL-4, the interferons (IFNs) and oncostatin M (OSM). Here mutant cell lines lacking JAK1, JAK2, or Tyk2 were used to determine the role(s) of the Janus kinase (JAK) family of protein-tyrosine kinases in IRS-1 phophorylation. 32D cells, which do not express IRS proteins, were analyzed for any requirement for these proteins in response to the IFNs. For the mutant human fibrosarcoma cell lines, phosphorylation of IRS-1 through the insulin-like growth factor receptor is independent of JAK1, JAK2, or Tyk2. In contrast, phosphorylation of IRS-1 mediated by the Type I IFNs, IL-4, and OSM is JAK-dependent. For the alphabeta-IFNs, activation of IRS-1 is dependent on JAK1 and Tyk2, consistent with the interdependence of these kinases in the IFN-alphabeta response. Neither IRS-1 nor IRS-2 was detectably activated by IFN-gamma. Consistent with this, activation of neither IRS proteins appears to be an absolute requirement for an antiproliferative or an antiviral response to the IFNs. For IL-4 and OSM phosphorylation of IRS-1 in the human fibrosarcoma cells is largely dependent on JAK1 but can also be mediated through Tyk2 or JAK2. Activation of phosphatidylinositol 3'-kinase in response to IL-4 and OSM, at least, was also JAK-dependent. The JAKs are, therefore, required not only for STAT activation but also for the activation, through a variety of different types of cytokine receptor, of an additional signaling pathway(s) through IRS-1 and phosphatidylinositol 3'-kinase.
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PMID:Janus kinase-dependent activation of insulin receptor substrate 1 in response to interleukin-4, oncostatin M, and the interferons. 930 69

We have used a human salivary gland cell line (HSG) as a possible in vitro model to evaluate the effects of IFN-gamma on human salivary gland epithelium (Wu et al., 1994, 1996, 1997). In the present study, we examined the JAK-STAT signal-transduction pathway in IFN-gamma-treated HSG cells. We demonstrate that JAK2 and Stat1 are phosphorylated at tyrosine residues in a time- and concentration-dependent manner following exposure to IFN-gamma. In addition, we show that activation of this signalling pathway is decreased by the addition of a blocking antibody to the IFN-gamma receptor. The same maneuver is also able to reduce by approximately 50-70% the surface expression of two IFN-gamma-induced immunoregulatory molecules: HLA-DR and ICAM-1. These results demonstrate that the JAK2 and Stat1 signalling pathway is active in salivary-derived epithelial cells and may contribute to their immunopathologic destruction.
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PMID:Interferon-gamma-induced JAK2 and STAT1 signalling in a human salivary gland cell line. 932 55

Selective activation among several effector functions of a T cell clone, DB14, specific for pigeon cytochrome c 43-58 (p43-58) and restricted to I-Ab/d was induced by antigen (Ag) presentation with nonprofessional Ag-presenting cells (APC), cortical thymic epithelial cells (c-TEC) (B7-1- CD40-), whereas full activation of the DB14 was induced with another nonprofessional APC, I-Ab L cell (B7-1+ CD40+). In the present study, to elucidate the mechanism underlying the selective activation of DB14 cells by c-TEC, we established c-TEC transfected with human CD40 alone (huCD40-c-TEC) or both human CD40 and murine B7-1 (huCD40/mB7-1-c-TEC), and compared the APC functions with those of the original c-TEC and I-Ab L cell. IFN-gamma production but not the proliferative response of DB14 was elevated by Ag presentation with huCD40-c-TEC as compared with unmanipulated c-TEC. On the other hand, upon stimulation with Ag plus huCD40/mB7-1-c-TEC both a significant proliferative response and IFN-gamma production were induced in DB14. However, the level of these responses did not reach that induced in the presence of I-Ab L cell. A similar pattern of APC functions was demonstrated with the other B7-independent T cell clone, PAB3, or T cell hybridomas (DBhy22 and BD7-5) which are basically independent of costimulation for the activation. The present finding along with our previous report that several structural differences of I-Ab molecules are present between c-TEC and I-Ab L cell suggests that the distinct APC activity of c-TEC is attributable not only to a lack of B7-1 and CD40 but also to inefficient presentation of MHC-peptide complex on the c-TEC.
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PMID:Selective antigen presenting activity of cortical thymic epithelial cells against CD4+ T cells associated with both lack of costimulatory molecules and inefficient presentation of MHC-peptide ligands. 939 3

Interferon-gamma (IFNgamma) transmits its signal through a specific cell surface receptor (IFNgammaR), which consists of a primary ligand binding alpha-chain (IFNgammaR alpha) and a signaling beta-chain (IFNgammaR beta). Recent studies identified the cytokines IFNgamma, interleukin-6 (IL-6), IL-1alpha, and tumor necrosis factor-alpha in testicular cells. Therefore, we: 1) examined the expression of IFNgammaR alpha and IFNgammaR beta subunits in freshly isolated and purified rat testicular cells; 2) examined the differential regulation of receptor components by cytokines using primary cultures of Sertoli cells; 3) identified the cell signaling pathway components of testicular IFNgammaR; and 4) characterized the functional role of testicular IFNgamma using primary Sertoli cells. We demonstrated the messenger RNAs for both chains of IFNgammaR in rat testicular cells using Northern hybridization analysis. Western blot analysis and immunocytochemistry showed that both specific IFNgammaR protein subunits were present in cultured primary Leydig and Sertoli cells prepared from the testes of immature rats. The expression of both IFNgammaR component messenger RNAs in cultured Sertoli cells was increased by its specific ligand (IFNgamma), as well as IL-1alpha and tumor necrosis factor-alpha, in both a time- and dose-dependent manner. IFNgamma-activation of the Janus (JAK) tyrosine kinases, JAK1 and JAK2 proteins, indicate that IFNgammaR, expressed in the Sertoli cell, is functional. Moreover, IFNgamma modulates the expression of interferon regulatory factor (IRF)-1 and IL-1beta converting enzyme genes in Sertoli cells. Thus, our data are suggestive of a role(s) for IFN-gamma in the regulation of distinct gene expression and cell-specific sensitivity to apoptosis in the testis.
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PMID:Identification and regulation of testicular interferon-gamma (IFNgamma) receptor subunits: IFNgamma enhances interferon regulatory factor-1 and interleukin-1beta converting enzyme expression. 956 81

We previously demonstrated that the macrophage cell lines RAW 264.7 and WEHI-3 exhibit distinct patterns of gene expression in response to IFN-gamma. This difference is controlled at the transcriptional level and results from a specific inability of the less mature WEHI-3 cells to utilize either the IFN-stimulated response element or the gamma-activated sequence DNA regulatory element in response to stimulation with IFN-gamma, while other aspects of IFN-gamma gene induction remain intact. In the work described here, we examined the components of the IFN-gamma signal transduction pathway in RAW 264.7 and WEHI-3 cells to determine whether differences in pathway components or activity exist in WEHI-3 cells that could give rise to this difference in transcriptional response. Reverse transcriptase-PCR (RT-PCR) and flow cytometric analyses indicated that the levels of IFN-gamma receptor mRNA accumulation and protein expression are comparable for RAW 264.7 and WEHI-3 cells. RT-PCR and immunoblot analyses revealed that the principal components of this signaling pathway, including JAK1, JAK2, and STAT1, are present in both RAW 264.7 and WEHI-3 cells. However, analysis of STAT1 DNA-binding activity by electrophoretic mobility shift assay and of STAT1 phosphorylation by immunoblot revealed that this DNA-binding factor is active in RAW 264.7, but not in WEHI-3, cells after IFN-gamma stimulation. These results demonstrate that the components of the IFN-gamma signal transduction pathway are intact in WEHI-3 cells, but stimulation of these cells by IFN-gamma does not result in STAT1 activation.
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PMID:Analysis of the IFN-gamma-signaling pathway in macrophages at different stages of maturation. 957 37

IL-13, a cytokine similar to IL-4, is a regulator of human B cell and monocyte functions. Biologic effects of IL-13 on primary human NK and T cells have not been well defined. We demonstrate that, in primary NK cells, IL-13, but not IL-4, may induce low levels of IFN-gamma secretion. When NK cells were costimulated with IL-13 and IL-2, IL-13 generally resulted in two types of reactivity: IL-13 synergized with IL-2 to stimulate IFN-gamma production or it modestly inhibited IL-2-mediated IFN-gamma production. In both types of donors, the effect of IL-13 on IL-2-induced IFN-gamma production was in marked contrast to the strong inhibition seen with IL-4 in NK cells. Additionally, IL-13 suppresses IL-2-induced NK cytolytic and proliferative activities although less efficiently than IL-4. In T cells, IL-13 inhibits anti-CD3 mAb/IL-2- or PHA-mediated IFN-gamma production and enhances cytolytic potential. Furthermore, we demonstrate that IL-13, like IL-4, induces distinct STAT6-DNA binding complexes and tyrosine phosphorylation of STAT6 and Janus kinase 3 (JAK3) in NK and T cells. We observed that Abs directed against unique domains of STAT6 have differential effects on complexes in T cells but not in NK cells, suggesting different STAT6 isoforms. These findings show that IL-13 and IL-4 have the ability to regulate NK and T cell activation and that IL-13 is a potent regulator of STAT6 and JAK3 in these cell types.
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PMID:Differential regulation of the Janus kinase-STAT pathway and biologic function of IL-13 in primary human NK and T cells: a comparative study with IL-4. 964 27

It has been shown that interferons (IFNs) exert their signals through receptor-associated Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). However, molecular mechanism of regulation of IFN signaling has not been fully understood. We have reported novel cytokine-inducible SH2 protein (CIS) and JAK binding protein (JAB) family genes that can potentially modulate cytokine signaling. Here we report that JAB is strongly induced by IFN-gamma but not by IFN-beta in mouse myeloid leukemia M1 cells and NIH-3T3 fibroblasts. NIH-3T3 cells ectopically expressing JAB but not CIS3 lost responsiveness to the antiviral effect of IFN-beta and IFN-gamma. M1 leukemic cells stably expressing JAB were also resistant to IFN-gamma and IFN-beta-induced growth arrest. In both NIH-3T3 and M1 transformants expressing JAB, IFN-gamma did not induce tyrosine phosphorylation and DNA binding activity of STAT1. Moreover, IFN-gamma-induced activation of JAK1 and JAK2 and IFN-beta-induced JAK1 and Tyk2 activation were inhibited in NIH-3T3 JAB transformants. These results suggest that JAB inhibits IFN signaling by blocking JAK activity. We also found that IFN-resistant clones derived from LoVo cells and Daudi cells expressed high levels of JAB without stimulation. In IFN-resistant Daudi cells, IFN-induced STAT1 and JAK phosphorylation was partially reduced. Therefore, overexpression of JAB could be, at least in part, a mechanism of IFN resistance.
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PMID:A Janus kinase inhibitor, JAB, is an interferon-gamma-inducible gene and confers resistance to interferons. 971 95

To study the oncogenic role of the p210(bcr-abl) fusion protein in chronic myelogenous leukemia cells, we generated a mouse cell line that was stably transfected with and overexpressed the human p210(bcr-abl) fusion protein. We then looked for phosphorylation activation of the Janus-activated kinase (JAK) family of tyrosine-specific protein kinases by the p210(bcr-abl) fusion protein. We found that JAK1, which has been shown by others to be associated with the IFN-alpha and -gamma plasma membrane receptors, was phosphorylated to a much greater degree in cells containing the p210(bcr-abl) fusion protein than was the case in the original, untransfected cell line. In contrast, no phosphorylation of the JAK2 kinase, which is associated with the IFN-gamma but not IFN-alpha receptor, was observed either with or without p210(bcr-abl) protein. A substrate of JAK1, STAT1 (signal transducers and activators of transcription 1), was found to be phosphorylated in cells containing overexpressed p210(bcr-abl) fusion protein. These results indicate that the presence of the p210(bcr-abl) protein kinase within a cell is associated with phosphorylation of the JAK1 kinase and its substrate STAT1.
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PMID:Potential role of bcr-abl in the activation of JAK1 kinase. 981 65


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