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)

Sympathoadrenal system function may be altered following intrauterine growth retardation (IUGR). We tested the hypothesis that the growth-retarded newborn rat pup has increased basal sympathoadrenal activity under normoxic conditions and a blunted sympathoadrenal response to acute hypoxia. IUGR was established by uterine artery ligation on d 18 of gestation in Sprague-Dawley rats. Growth-retarded pups were chosen as those whose birth wt was more than 2 x SD below the mean birth wt of control pups delivered to sham-operated dams. At 24 +/- 12 h of age cardiac sympathetic neuronal activity (CSNA) was determined by 3H-norepinephrine tracer and alpha-methyltyrosine techniques. Adrenal medullary catecholamine synthesis (CAT SYN) was measured by 14C-tyrosine precursor methods, and adrenal catecholamine release (CAT REL) was determined using alpha-methyl-tyrosine. IUGR and control pups were studied over a 120-min period of normoxia or hypoxia (FiO2 = 0.09). Under normoxic conditions, the IUGR pups had increased CSNA and increased adrenal CAT SYN and CAT REL compared to controls. Adrenal CAT REL in normoxic IUGR pups was selective for epinephrine. In response to acute hypoxia, control pups had increased CSNA and increased adrenal CAT SYN and CAT REL compared to normoxic controls, with the proportion of norepinephrine and epinephrine released mimicking the ratio of the two amines in the adrenal. In contrast, in hypoxic IUGR pups CSNA and adrenal CAT SYN did not increase, and norepinephrine alone was released from the adrenal medulla.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neonatal sympathoadrenal response to acute hypoxia: impairment after experimental intrauterine growth retardation. 271 62

The primary structure of the growth hormone (GH) receptor in rabbits and humans determined by complementary DNA cloning revealed a single membrane-spanning protein of approximately 620 amino acids. A binding protein (bp) specific for GH has been identified in the serum of a number of species. In rabbits and man, a single 4.5-kb transcript has been identified that encodes the full-length receptor. In rats and mice, however, a smaller transcript produced by alternative splicing has been reported which is specific for the GHbp. Recently, the X-ray crystallographic structure of GH and its receptor have clearly shown the formation of an unusual homodimer, consisting of one molecule of GH and two molecules of hGHbp. Formation of the GH dimer is a necessary prerequisite for biological activity. The transcriptional activity of wild-type and mutant forms of GH receptor has been determined by co-transfecting the promoter of a GH-responsive gene, coupled to CAT along with the receptor cDNA. A 25-amino acid region near the transmembrane domain has been shown to be important for functional activity, although 8 amino acids (known as Box 1), rich in prolines, is essential. Alanine scanning mutagenesis has revealed that individual substitution of each residue is without effect, while the replacement of the last 2 or all 4 of the prolines abolishes activity. Finally, GH has been shown to induce rapid tyrosine phosphorylation of several proteins in cells expressing the receptor, one of which has recently been identified as the kinase JAK2 and another as MAP kinase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The GH receptor and signal transduction. 786 67

Reactive oxygen species are autocrine and paracrine modulators of cell behavior. Hydrogen peroxide, a cellular oxidant, has been shown to stimulate mesangial cell proliferation. In the present study we analyzed the H2O2-induced early signaling events. Immunofluorescence analysis revealed a H2O2 induced dose-dependent increase in tyrosine phosphorylation. Short treatment (2 or 5 min) with 5 mM H2O2 induced a mitogenic response and a significant (P < 0.01) increase in the number of cells compared to non-treated controls. Proteins extracted from H2O2 (0.1 to 10 mM) treated cells were separated on SDS-PAGE and subjected to immunoblot analysis with anti-phosphotyrosine. A dose-dependent induction of tyrosine phosphorylation of 180 kDa, 120 kDa and 60 kDa proteins was observed within 1 to 10 minutes. By sequentially using immunoprecipitation and immunoblotting the 180 kDa tyrosine phosphorylated band was shown to represent both PDGF alpha- and beta-receptors. The tyrosine phosphorylated 60 kDa protein was identified as the cytoplasmic protein tyrosine kinase pp60c-src. The c-src phosphorylation was associated with an inhibition of c-src kinase activity, suggesting phosphorylation of tyrosine 527 in the c-src regulatory domain. Pretreatment with catalase completely abrogated the H2O2-induced PDGF receptor and c-src tyrosine phosphorylation. These data support the notion that the activation of a signaling pathway involving the PDGF receptors and c-src contributes to the mitogenic effects of reactive oxygen species.
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PMID:Oxidative stress induces tyrosine phosphorylation of PDGF alpha-and beta-receptors and pp60c-src in mesangial cells. 880 85

In this study, we have developed several Chinese Hamster ovary (CHO) cell clones stably expressing various deletion mutant forms of the rabbit prolactin receptor (rbPRL-R) to better define the domains of the receptor involved in JAK2 kinase interaction, STAT5 activation, and to assess the role of tyrosine phosphorylation of the PRL-R in signal transduction. We observed that the box 1 region of the receptor was critical for productive interaction with JAK2 and its tyrosine phosphorylation after PRL stimulation. However, this region appeared to require the presence of additional cytoplasmic domain region(s), such as box 2, to exert its complete effect. In addition, we found that a mutant form lacking the 141 C-terminal residues lost the capacity to be tyrosine phosphorylated in response to PRL but remained able to activate JAK2 kinase and STAT5 transcription factor, indicating that it contained the minimal sequence required for STAT5 activation. The absence of tyrosine phosphorylation of this C-terminal rbPRL-R mutant upon PRL stimulation indicated that the phosphorylation of the PRL-R normally occured in the last 141 animo acids (aa) containing three tyrosines and was not absolutely necessary for induction of these early events in PRL signal transduction. Transfectant cell lines expressing wild type (WT) PRL-R and this C-terminal mutant form were able to induce CAT activity upon PRL stimulation when transiently transfected with the ovine-beta-lactoglobulin promoter, containing STAT5 recognition sites, fused to the CAT reporter gene. The comparison between transcriptional activity of these two receptor forms leads to the conclusion that the C-terminal region of the rbPRL-R, containing the physiological sites for tyrosine phosphorylation, is probably responsible for an amplification of the PRL signal to milk protein genes.
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PMID:Prolactin signal transduction to milk protein genes: carboxy-terminal part of the prolactin receptor and its tyrosine phosphorylation are not obligatory for JAK2 and STAT5 activation. 909 11

Reactive oxygen species (ROS) initiate multiple pathological and physiological cellular responses, including tyrosine phosphorylation of proteins. In this study, we investigated the effects of ROS on cell-extracellular matrix interactions utilizing the floating three-dimensional collagen gel assay. Exposure of mesangial cells grown in three-dimensional culture to H2O2, 3-amino-1,2,4-triazole (a catalase inhibitor), or puromycin is associated with gel reorganization accompanied by tyrosine phosphorylation of multiple proteins, including focal adhesion kinase (FAK). Neutrophils cocultured with mesangial cells in three-dimensional culture also induce mesangial cell-collagen gel reorganization and initiate tyrosine phosphorylation of a similar set of proteins. Collectively, these results show that ROS of either endogenous or exogenous origin can modulate mesangial cell-extracellular matrix interactions through initiation of a phosphotyrosine kinase signaling cascade. Consequently, ROS may play a role as signaling molecules that regulate mesangial cell-extracellular matrix interactions in both physiological and pathological conditions.
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PMID:ROS stimulate reorganization of mesangial cell-collagen gels by tyrosine kinase signaling. 995 Sep 59

We have previously reported the isolation of the JAK1 gene from the round-spotted pufferfish. In the present study, we cloned and characterized genomic sequences encoding pufferfish JAK2, JAK3, and TYK2, which are other members of JAK family. To our knowledge, this is the first report to demonstrate the existence of four JAK genes in fish. All pufferfish JAK genes except JAK1 are composed of 24 exons; JAK1 has an additional exon. A comparison of the exon-intron organization of these genes revealed that the splice sites of JAK genes are nearly identical. In addition, all pufferfish JAK genes have one intron in the 5' untranslated region. Taken together, these data suggest that the pufferfish JAK genes may have evolved from a common ancestor. By 5' rapid amplification of cDNA ends and sequence analysis, we deduced the promoter regions for all JAK genes and found they do not contain typical TATA or CCAAT boxes but rather numerous other potential binding sites for transcription factors. Interestingly, the TYK2 gene is linked to CDC37 in a head-to-tail manner with a small intergenic region of 292 bp. Within this region, there are two potential binding sites for transcriptional factors such as c-Myb and NF-IL6. The putative promoter regions of all JAK genes were tested either in a carp CF cell line or in zebrafish embryos using CAT or lacZ as reporter genes. Both assays confirmed the transcriptional activities of these promoters in vitro and in vivo.
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PMID:Complete genomic organization and promoter analysis of the round-spotted pufferfish JAK1, JAK2, JAK3, and TYK2 genes. 1094 33

Activation of inhibitory nonadrenergic noncholinergic (NANC) nerves in the rat duodenum cause relaxations, which are reduced by nitric oxide synthase (NOS) inhibitors indicating that this response involves a nitrergic neurotransmission. The precise nature of the nitrergic neurotransmitter is still controversial since nitric oxide (NO) scavengers and superoxide generators, even in the presence of superoxide dismutase inhibitors, failed to inhibit nitrergic neurotransmission mediated relaxations. In order to understand the role of NOS in nitrergic neurotransmission and considering that N-OH-arginine (OH-L-Arg), L-citrulline, NO, S-nitrosoglutathione (GSNO) and hydroxylamine (NH2OH) can be formed in cells during the N(G)-oxidation of L-arginine catalyzed by NOS we explored whether any of these products could exhibit biological properties comparable to those of the nitrergic neurotransmitter. After establishing which of them was able to relax the rat duodenum, the pharmacological profile of such effect was determined employing oxyhemoglobin (OxyHb), pyrogallol (PYR), hydroquinone (HQ), hydroxocobalamin (HC) or carboxy-PTIO (C-PTIO) and compared with that of nerve mediated relaxations. NO, GSNO and NH2OH, but not OH-L-ARG and L-citrulline, caused concentration-dependent relaxations that were not affected by tetrodotoxin or L-NOARG. OxyHb almost abolished NO-induced relaxations but decreased only marginally the magnitude of nerve-, NH2OH- and SNG-induced relaxations. PYR, HQ and C-PTIO reduced significantly GSNO- and NO- induced relaxations but did not affect those induced by NH2OH or nerve activation. In contrast, HC abolished NO-induced relaxations while it did not affect those induced by GSNO, NH2OH and nerve activation. The catalase inhibitor 1,2,4 aminotriazole failed to affect nerve and NH2OH induced relaxations. These findings indicate that among the products that can be formed during NOS catalyzed L-arginine N(G)-oxidation, only NH2OH caused relaxations that exhibited a pharmacological profile similar to those induced by the nitrergic neurotransmitter. Furthermore, if NH2OH is the actual neurotransmitter it appears to be acting either directly or by a catalase independent release of NO.
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PMID:Pharmacological profile of nitrergic nerve-, nitric oxide-, nitrosoglutathione- and hydroxylamine-induced relaxations of the rat duodenum. 1120 85

Epidemiological studies demonstrate an association between increased human morbidity and mortality with exposure to air pollution particulate matter. We hypothesized that such effects may be associated with the ability of the particles to mediate generation of reactive oxygen species (ROS), either directly, via interaction with ambient oxygen or indirectly through initiation of an oxidative burst in phagocytes. To test this hypothesis, we determined 8-oxo-dG formation as a measure of direct generation of ROS, in response to particulate exposures to 2'-deoxyguanosine (dG), free and in calf thymus DNA in aerated solutions as the target molecule and cell culture, to assess the relationship between induction of oxidative damage, particulate metal content and metal bioreactivity. The HPLC-ECD technique was employed for separation and quantification of 8-oxo-dG, the most widely recognized marker of DNA oxidation. Particles used in this study include: Arizona desert dust (AZDD), coal fly ash (CFA and ECFA), oil fly ash (OFA and ROFA), and ambient air [SRM 1649 and Dusseldorf (DUSS), Germany]. The major difference between these particles is the concentration of water-soluble metals. The fly ash particulates OFA and ROFA showed a significant dose-dependent increase in dG hydroxylation to 8-oxo-dG formation over the control dG (p < 0.05), with yields 0.03 and 1.25% at the highest particulate concentration (1 mg/mL). Metal ion chelators and DMSO, a hydroxyl radical scavenger, inhibited this hydroxylation. In contrast, desert dust, coal fly ash and urban air particles induced 8-oxo-dG with yields ranging from 0.003 to 0.006%, respectively, with levels unaffected by pretreatment of the particles with metal ion chelators or addition of DMSO to the incubation mixture. When calf thymus DNA was used as a substrate, all the particles induced 8-oxo-dG in a pattern similar to that observed for dG hydroxylation, but with relatively less yield. Treatment of the particles with metal ion chelator before reacting with DNA or addition of catalase in the incubation mixture, suppressed 8-oxo-dG formation significantly (p < 0.05) in oil-derived fly ash particles only. To determine whether the oxidative responses of these particulates as shown in cell-free systems were consistent with responses using a more biologically relevant environment, human airway epithelial cells were treated with the particulates and induction of 8-oxo-dG was determined. All particles induced 8-oxo-dG in the DNA of cells above culture control, except CFA. Cells exposed to 10-400 mg/mL of ROFA for 2 h induced a dose-dependent increase in 8-oxo-dG formation. Treatment of ROFA with metal ion chelator attenuated these effects. Overall, damage enhancement by particulates in dG, calf thymus, and cellular DNA as determined by 8-oxo-dG formation under aerobic conditions is consistent with the concentration of water-soluble, not the total metal content of the particle.
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PMID:Air pollution particles mediated oxidative DNA base damage in a cell free system and in human airway epithelial cells in relation to particulate metal content and bioreactivity. 1145 35

Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have been reported to exert anti-inflammatory activities in macrophages by competition for transcriptional coactivators with some transcriptional factors, including NF-kappaB. In the present study the influence of PPARgamma activators on IFN-gamma-elicited macrophage stimulation and signaling cascades was investigated. The results show that IFN-gamma-induced inducible NO synthase (iNOS) gene transcription, iNOS protein induction, and NO production are more sensitive to inhibition by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) than by the other two PPARgamma agonists, GW1929 and ciglitazone. Delayed addition of 15dPGJ(2) for 2 h resulted in reduced inhibition, suggesting action by 15dPGJ(2) on the upstream signaling cascades. Immunoblotting, DNA binding, and reporter gene assays consistently revealed the inhibitory ability of 15dPGJ(2), but not GW1929 or ciglitazone, on IFN-gamma-elicited signaling cascades, including tyrosine phosphorylation of Janus tyrosine protein kinase 2 and STAT1, DNA binding, and IFN regulatory factor-1 trans-activation of STAT1. These effects of 15dPGJ(2) were not abrogated by the PPARgamma antagonist, bisphenol A diglycidyl ether, indicating the PPARgamma-independent actions. 15dPGJ(2) also attenuated IL-6-induced tyrosine phosphorylation of STAT1 and STAT3 in Hep3B hepatoma cells. Consistent with the inhibitory effect of reactive oxygen species on STAT1 signaling, STAT1 inhibition by 15dPGJ(2) was abrogated by N-acetylcysteine, glutathione, superoxide dismutase, and catalase. Furthermore, 15dPGJ(2)-induced inhibition of STAT1 phosphorylation and NO production still occurred in the presence of peroxovanadate, ruling out the action mechanism of 15dPGJ(2) on tyrosine phosphatase. Taken together, for the first time in this study we demonstrate that 15dPGJ(2) can inhibit cytokine-stimulated Janus kinase 2-STAT signaling through a PPARgamma-independent, reactive oxygen species-dependent mechanism. These data provide a novel molecular mechanism of iNOS inhibition by 15dPGJ(2) and confirm its physiological role in anti-inflammation.
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PMID:Inhibition of IFN-gamma-mediated inducible nitric oxide synthase induction by the peroxisome proliferator-activated receptor gamma agonist, 15-deoxy-delta 12,14-prostaglandin J2, involves inhibition of the upstream Janus kinase/STAT1 signaling pathway. 1284 70

Leptin is recognized as a profibrogenic hormone in the liver, but the mechanisms involved have not been clarified. The tissue inhibitor of metalloproteinase (TIMP)-1, which acts through inhibition of collagen degradation, is synthesized by activated hepatic stellate cells (HSC) in response to fibrogenic substances. The capacity of leptin to induce TIMP-1 and its signaling molecules were investigated in a human HSC cell line, LX-2. Leptin stimulated TIMP-1 protein, mRNA, and promoter activity. JAK1 and -2, as well as STAT3 and -5, were activated. After leptin, there was increased expression of tyrosine 1141-phosphorylated leptin receptor, which may contribute to STAT3 activation. AG 490, a JAK inhibitor, blocked JAK phosphorylation with concomitant inhibition of STAT activation, TIMP-1 mRNA expression, and promoter activity. Leptin also induced an oxidative stress, which was inhibited by AG 490, indicating a JAK mediation process. ERK1/2 MAPK and p38 were activated, which was prevented by catalase, indicating an H2O2-dependent mechanism. Catalase treatment resulted in total suppression of TIMP-1 mRNA expression and promoter activity. SB203580, a p38 inhibitor, prevented p38 activation and reduced TIMP-1 message half-life with down-regulation of TIMP-1 mRNA. These changes were reproduced by overexpression of the dominant negative p38alpha and p38beta mutants. PD098059, an ERK1/2 inhibitor, opposed ERK1/2 activation and TIMP-1 promoter activity, leading to TIMP-1 mRNA down-regulation. Thus, leptin has a direct action on liver fibrogenesis by stimulating TIMP-1 production in activated HSC. This process appears to be mediated by the JAK/STAT pathway via the leptin receptor long form and the H2O2-dependent p38 and ERK1/2 pathways via activated JAK.
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PMID:Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: respective roles of the JAK/STAT and JAK-mediated H2O2-dependant MAPK pathways. 1462 4


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