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)

Conditioned medium (CM) from cultures of cytotoxic activated macrophages causes inhibition of mitochondrial respiration, DNA synthesis, and aconitase activity in murine EMT-6 mammary adenocarcinoma cells by an L-arginine dependent effector mechanism. CM induces cytotoxicity and nitrite synthesis in EMT-6 cells in a dose dependent manner. We have identified the soluble factors in CM that induce cytotoxicity and synthesis of inorganic nitrogen oxides from L-arginine by EMT-6 cells. Using functional inhibition experiments, the activity of lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma) in CM was investigated. The LPS inhibitor polymyxin B and TNF alpha antibody produced a modest decrease in nitrite production, while IFN gamma antibody markedly inhibited both nitrite production and cytostasis. Simultaneous treatment with polymyxin B, TNF alpha antibody, and IFN gamma antibody reduced EMT-6 cell nitrite production by 81%, and cytostasis by 74%. By Western blot, IFN gamma and TNF alpha were shown to be present in CM. When CM was subjected to hydrophobic interaction chromatography, a single peak of activity was eluted, and Western blot showed that the active fractions contained IFN gamma. Furthermore, IFN gamma antibody neutralized the activity in these chromatographic fractions. We conclude that induction of inorganic nitrogen oxide synthesis from L-arginine by the synergistic combination of IFN gamma, TNF alpha, and LPS accounts for most of the biologic activity of CM, and that IFN gamma is the major priming factor.
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PMID:Activated macrophage conditioned medium: identification of the soluble factors inducing cytotoxicity and the L-arginine dependent effector mechanism. 190 65

Both the growth hormone (GH) and interferon gamma (IFN gamma) receptors are members of the cytokine receptor family that activate tyrosine phosphorylation despite the lack of a tyrosine kinase domain. Recently, the Janus kinase (JAK) family of tyrosine kinases have been shown to play an integral role in intracellular signaling by the cytokine receptors. We demonstrate that, in the human IM-9 lymphocyte, both JAK1 and JAK2 are tyrosine-phosphorylated in response to IFN gamma, whereas only JAK2 is tyrosine-phosphorylated in response to GH. Furthermore, dimerization of the GH receptor appears to be necessary for GH stimulated tyrosine phosphorylation of JAK2. We provide two lines of evidence that the JAK2 kinases can be regulated independently by GH and IFN gamma in IM-9 cells: 1) desensitization of JAK2 to GH stimulation does not affect the IFN gamma stimulated tyrosine phosphorylation of JAK2; and 2) JAK2 tyrosine phosphorylation by GH and IFN gamma is additive to that seen with either hormone alone. Furthermore, we demonstrate that although IFN gamma activates the tyrosine phosphorylation of the p91 signal transducer and activator of transcription (STAT1) in IM-9 cells, GH does not. GH does activate the tyrosine phosphorylation of a 93-kDa protein that appears to be distinct from STAT1.
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PMID:Differential tyrosine phosphorylation of JAK1, JAK2, and STAT1 by growth hormone and interferon-gamma in IM-9 cells. 752 56

The Janus family of kinases (JAKs) has been shown to be involved in the signal transduction of a number of cytokine receptors. Recently, we have cloned a novel JAK family member, JAK3, that is expressed in natural killer and activated T cells and is coupled functionally and physically to the interleukin 2 (IL-2) receptor in these cells. Here we report that JAK3 was expressed at low but detectable levels in human monocytes. In contrast, JAK3 expression was strongly induced during activation by interferon gamma (IFN-gamma) or lipopolysaccharide. Moreover, JAK3 became tyrosine phosphorylated in response to IL-2, IL-4, and IL-7 but not response to IFN-gamma or granulocyte/macrophage colony-stimulating factor. Together, these findings suggest that JAK3 is functionally important in activated monocytes and cells of the myeloid lineage and is involved in signaling responses of cytokines that use the common gamma-chain of the IL-2 receptor.
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PMID:Regulation of JAK3 expression in human monocytes: phosphorylation in response to interleukins 2, 4, and 7. 753 38

Inflammatory mediators stimulate arginine-derived nitric oxide (NO) production in a variety of cells. The purpose of this study was to determine if the inflammatory mediators, endotoxin (LPS) and interferon gamma (IFN), stimulate arginine transport and nitric oxide production in a murine breast cancer cell line. We also investigated the effect of the nitric oxide synthase (NOS) inhibitors, omega-nitro-L-arginine methyl ester (LNAME) and aminoguanidine (AG), as well as the effect of varying the concentration of L-arginine in the cellular media, on arginine transport and NO production in these tumors cells. Confluent EMT-6 murine breast cancer cells were incubated with LPS (10 microgram/ml) and IFN (50 units/ml) in the presence or absence of the NOS inhibitors, L-NAME (2 mM) or AG (1 mM), and arginine transport (using L-[3H]arginine) and NO production (the stable end-product nitrite was assayed using the Greiss reagent) were measured at various time points. In addition, the effect of varying the concentration of L-arginine (0, 10, 100, 1000, 10,000 mM) in the cellular media on stimulated L-arginine transport and nitrite accumulation was assessed. Incubation of EMT-6 with LPS and IFN stimulated arginine transport approximately 70% over control levels at 12 hr and transport returned to basal levels at 24 hr. LPS/IFN-stimulated EMT-6 cells produced 25 microM nitrite at 24 hr and reached a plateau of 55 microM nitrite at 48 hr. The NO synthase inhibitors, L-NAME and AG, failed to inhibit basal and stimulated levels of arginine transport, but significantly inhibited nitrite accumulation, which was restored by 10 mM L-arginine. Finally, L-arginine was necessary in the media for nitrite accumulation by LPS/IFN-stimulated cells, with maximal accumulation at 1 mM L-arginine. In summary, LPS/IFN stimulate arginine transport and NO production in the EMT-6 breast cancer cell line. L-NAME and AG do not inhibit basal or stimulated arginine transport in this tumor cell line and extracellular L-arginine is required for NO synthesis in these cells. LPS/IFN stimulation of arginine transport may represent an adaptive response to provide increased substrate for enhanced tumor cell NO production.
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PMID:Inflammatory mediators stimulate arginine transport and arginine-derived nitric oxide production in a murine breast cancer cell line. 859 55

GH has been shown to activate the GH receptor (GHR)-associated tyrosine kinase JAK2 and the Src homology 2 domain-containing transcription factors Stats (signal transducers and activators of transcription) 1, 3, and 5. The present work investigates the role of GHR and JAK2 in the activation of Stats 1, 3, and 5 by GH. The ability of GH to stimulate the tyrosyl phosphorylation of these Stats was assessed in Chinese hamster ovary (CHO) cells expressing truncated and mutated GHR. GH was observed to stimulate tyrosyl phosphorylation of Stats 1, 3, and 5 in CHO cells expressing GHRs that bind JAK2 [GHR1-638 (full-length) and GHR1-454 (lacks approximately half of the cytoplasmic domain)] but not in CHO cells expressing GHR that do not bind JAK2 (GHR1-318 or GHR1-294). GH-dependent tyrosyl phosphorylation of Stat5, but not Stats 1 or 3, was reduced in CHO cells expressing GHR1-454. GH-dependent tyrosyl phosphorylation of Stats 3 and 5 was severely reduced and undetectable for Stat1 in cells expressing GHR1-454 in which tyrosines 333 and 338 (the only tyrosines phosphorylated within 1-454) are mutated to phenylalanine (GHR1-454Y333, 338F). However, GH-dependent phosphorylation of Stats 1, 3, and 5 was observed in cells expressing full-length GHR in which tyrosines 333 and 338 are mutated to phenylalanine (GHR1-638Y333, 338F) GH, whose receptor lacks previously defined Stat1- or Stat3-binding sites, was found in 3T3-F442A fibroblasts and 2fTGH-GHR cells to stimulate tyrosyl phosphorylation of JAK2 to a substantially greater extent than, and JAK1 to a similar extent as, leukemia inhibitory factor (LIF) and/or interferon gamma (IFN gamma), ligands whose receptors contains Stat3- and Stat1-binding sites and activate Stat3 and Stat1, respectively, better than GH. These findings suggest that: 1) JAK2 is required for GH-dependent phosphorylation of Stats 1, 3, and 5; 2) tyrosines 333 and/or 338 are required for maximal tyrosyl phosphorylation of Stats 1, 3, and 5; 3) Stat5 binds to a phosphorylated tyrosine(s) within amino acids 454-638 in addition to tyrosines 333 and/or 338; 4) GH stimulates tyrosyl phosphorylation of JAK1 in addition to JAK2 with JAK2 having a much greater response; 5) some Stat3 and Stat5 (and possibly Stat1) may bind to nonphosphorylated amino acids in GHR or to phosphorylated tyrosines in proteins that bind to GHR (e.g. JAK22) to be maximally activated; and 6) if JAK2, which contains Stat3-binding motifs, does serve as a docking site for some Stat proteins, Stat-JAK2 binding is likely to be more important for GH than LIF or IFN gamma in 3T3-F442A cells since GH induces 15 times more tyrosyl-phosphorylated JAK2 than LIF or IFN gamma.
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PMID:The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3, and 5 by GH. 873 83

In this investigation, we show that the gene encoding p48, a subunit of transcription factor ISGF3, is transcriptionally induced by interferon gamma (IFN-gamma). We have identified a novel IFN-gamma-activated response element in the p48 gene promoter. This motif, notated as gamma-activated transcriptional element (GATE), has no significant resemblance to either pIRE (palindromic IFN-response element) or GAS (the IFN-gamma-activated sequence) but has partial homology to ISRE (IFN-stimulated response element). When fused to a neutral promoter, GATE, a 24-bp element, induced the expression of reporter genes following IFN-gamma treatment. In murine RAW cells, two IFN-gamma-inducible factors (GIF) bind to GATE. Binding of these factors to GATE is inhibited by cycloheximide and staurosporine. Although p48 gene induction is dependent on STAT1 and JAK1, activated STAT1 does not bind to GATE. Thus, GIFs appear to be novel trans-acting factors in the IFN-signaling pathway.
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PMID:Interferon gamma-induced transcription of the murine ISGF3gamma (p48) gene is mediated by novel factors. 899 Jan 68

The selective induction of effector functions of a T-cell clone (DB14), specific to pigeon cytochrome c 43-58 (p 43-58) and restricted to I-Ab, was analyzed using a professional antigen-presenting cell, B hybridoma (Th 2.58), and various non-professional antigen-presenting cells (APC), L cells transfected with I-Ab (I-Ab L cells), a medullary thymic epithelial cell line (m-TEC) and a cortical thymic epithelial cell line (c-TEC). The m-TEC, and c-TEC expressed I-Ab upon induction with interferon gamma (IFN-gamma). When stimulated with p 43-58 in the presence of I-Ab L cells as well as Th 2.58 cells, the DB14 cells showed marked proliferation and, after 18 hr of culturing, exhibited significant cytotoxicity against the APC. By contrast, in the presence of m, c-TEC, the DB14 cells showed neither proliferation nor cytotoxicity against these TEC but exhibited considerable detachment activity towards them. Furthermore, DB14 cells became expressed activation markers CD69 or CD44) following stimulation with p 43-58 plus m-TEC or c-TEC. The addition of rIL-2 to the culture of DC14 cells, p 43-58 and m-TEC or c-TEC, restored the proliferative responses. However, it was shown that anergy was not involved in the negligible proliferative responses of DB14 cells after stimulation with p 43-58 plus m, c-TEC. The present findings indicate that differences in APC functions are present among the non-professional APC and suggest that the selective induction of T-cell functions can be achieved using the appropriate non-professional APC. The characteristic activation of T cells by TEC may be related to their functional roles in situ.
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PMID:Detachment activity but not cytotoxicity induced in a T-cell clone following antigen presentation in the presence of thymic epithelial cells. 908 68

This study was designed to determine whether the JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) pathway is activated in cardiac hypertrophy induced in vivo by pressure overload in rats and to demonstrate whether angiotensin II is involved in the activation of the JAK/STAT pathway. Acute pressure overload was produced by constricting the abdominal aorta of Wistar rats. Immunoprecipitation-Western blot analysis revealed that pressure overload activated JAK1, JAK2, and Tyk2 as early as 5 minutes and that STAT1, STAT2, and STAT3 were tyrosine-phosphorylated rapidly after exposure to the pressure overload. Phosphorylation of STAT1 and STAT2 peaked in the early stage at 5 to 15 minutes, whereas that of STAT3 peaked in the late stage at 60 minutes. Gel mobility shift of the interferon gamma activation site/interferon alpha-stimulating response element was observed immediately after the aortic banding, whereas the band of sis-inducing element was shifted in the late stage at 60 minutes. Both cilazapril (angiotensin II-converting enzyme inhibitor) and E4177 (angiotensin II type 1 [AT1] receptor antagonist) significantly suppressed the phosphorylation of Tyk2 and partially inhibited the phosphorylation of JAK2, but neither affected JAK1. Coimmunoprecipitation of the AT1 receptor with JAK2 or Tyk2 was clearly observed at 5 minutes and peaked at 15 minutes (20-fold the control value). These results indicate that the JAK/STAT pathway is activated by acute pressure overload in rats and that angiotensin II is involved in activating Tyk2, and partially activating JAK2, via the AT1 receptor. Both angiotensin II-dependent and -independent pathways take part in activating the JAK/STAT pathway in the pressure-overloaded rat heart.
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PMID:Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. 931 43

Leukemia inhibitory factor (LIF) is a member of the interleukin-6 family of cytokines, which induces a wide range of responses in a variety of cells. The aim of this study was to investigate whether LIF induces cardiomyocyte hypertrophy and transmits signals through the JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) pathway in primary cultured neonatal rat cardiomyocytes. LIF increased protein content and [3H]phenylalanine uptake in cardiomyocytes in a dose-dependent manner. LIF (10(3) U/mL) induced rapid tyrosine phosphorylation of gp130, JAK1, JAK2, STAT1, and STAT3 but not Tyk2 or STAT2. LIF also induced autokinase activity of JAK1 in a time-dependent manner. Gel shift assays for interferon gamma activation site/interferon-stimulated responsive element and sis-inducible element (SIE) revealed that LIF induced dimerization of STAT1 and STAT3 and formation of sis-inducing factor complexes, which subsequently interacted with SIE in the promoter. Preincubation with anti-STAT1 and anti-STAT3 antibodies inhibited the binding of SIF complexes. In conclusion, LIF induces cardiac hypertrophy and directly stimulates the JAK/STAT pathway in cardiomyocytes.
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PMID:Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, activates the JAK/STAT pathway in rat cardiomyocytes. 935 38

In contrast to BALB/c mouse macrophages, the A/J macrophages after activation by interferon gamma (IFN gamma) develop an anti-MHV3 effect which correlates with the resistance to virus infection. To understand the cellular basis of this antiviral effect, we studied the possible involvement of arginine metabolism through nitric oxide (NO) and arginase induction, since these metabolic pathways have been described as implicated in antiviral activities of macrophages. The studies were performed by activating macrophages with inducers of NO (IFN gamma) and arginase (IL4 IL10). NO synthase (iNOS) and arginase inhibitors (N-methyl-arginine, NMA, and hydroxyarginine, OH-ARG) were used. The results show that in both macrophage populations, no spontaneous synthesis of NO occurred and the MHV3 enhanced the NO release induced by IFN gamma. After activation with IFN gamma, BALB/c macrophages released higher amounts of NO than the A/J macrophages. The inhibition of IFN gamma-induced NO-synthesis with NMA or with arginine free medium did not affect the virus replication. In BALB/c macrophages, IL4 or IL10, induced higher amounts of arginase than in A/J macrophages. In both macrophage populations the MHV3 infection had no influence on the arginase synthesized, and the inhibition of the arginase with OH-ARG had no influence on the virus growth. The level of MHV3 replication or inhibition was also not influenced when we used macrophages from knockout mice for the iNOS gene, and as a consequence were unable of synthesizing NO. These data indicate that NO and arginase do not participate in the anti-MHV3 state induced by IFN gamma in macrophages.
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PMID:Anti-MHV3 state induced by IFN gamma in macrophages is not related to arginine metabolism. 941 8


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