Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokine interleukin 6 (IL-6), a major mediator of immune and acute phase responses of the liver, has been implicated in the termination of pregnancy once expressed in the uterus. This study was undertaken to investigate the expression and regulation of genes encoding IL-6 and IL-6 receptor (IL-6R) in rat decidual tissue. Total RNA obtained from rat decidual tissue on different days of pseudopregnancy was analyzed by RT-PCR using specific primers for IL-6, IL-6R, and 130-kDa glycoprotein (gp130). Ribosomal L19 primers served as an internal control. IL-6R and gp130 were found to be expressed in the decidua throughout development, while no messenger RNA (mRNA) for IL-6 was detected. Interestingly, within several hours of culture, decidual explants acquired the ability to express IL-6. The apparent ability of decidual cells to express IL-6 and its lack of expression in vivo led us to examine whether the IL-6 gene is actively inhibited. Primary decidual cells were cultured in the presence of estradiol, progesterone, or PRL. Progesterone showed no effect, whereas estradiol and PRL reduced the level of IL-6 mRNA expression. To examine the mechanism by which these hormones inhibit IL-6 expression, we used a simian virus 40-transformed decidual cell line (GG-AD), which expresses only estrogen receptor-beta (ERbeta). Like primary decidual cells in culture, GG-AD cells express IL-6, IL-6R, and gp130 mRNA. When cultured in the presence of estradiol (0-100 ng/ml), mRNA for IL-6 and its receptor components were down-regulated in a dose-dependent manner. Estradiol also caused a dose-dependent decrease in IL-6 protein secretion into the culture medium. The inhibitory effect of estradiol on IL-6 mRNA expression was reversed by the antiestrogen ICI-164,384. Similar inhibition of IL-6 and gp130 mRNA expression was observed with PRL treatment. However, PRL had no effect on IL-6R mRNA levels. PRL inhibition of IL-6 expression was totally reversed by tyrphostin AG490, a JAK2 inhibitor. In summary, the results of this investigation indicate that IL-6 expression, which is detrimental to the maintenance of pregnancy, is inhibited in the rat decidual tissue. This inhibition is induced by PRL and estradiol, which down-regulate not only IL-6 expression, but also the expression of IL-6 receptor and signaling proteins. The results also suggest that PRL signaling to the IL-6 gene is mediated through the long form of PRL receptor and involves JAK2 activation, whereas that of estradiol can be transduced by estrogen receptor-beta.
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PMID:The expression of interleukin-6 (IL-6), IL-6 receptor, and gp130-kilodalton glycoprotein in the rat decidua and a decidual cell line: regulation by 17beta-estradiol and prolactin. 1049 97

Growth hormone (GH) resistance/insensitivity (GHIS) is the finding of elevated GH levels associated with a reduction in the biologic actions of GH. It may be congenital or acquired. In congenital GHIS, over 30 mutations in the GH receptor (GHR) have been described. Dimerization of the GHR activates phosphorylation cascades involving MAP kinases and the Janus kinase, JAK2. This in turn activates the STAT (Signal transducers and activators of transcription) proteins, which translocate to the nucleus. A soluble form of the GHR circulates as a GH binding protein (GHBP), and is derived from the proteolytic cleavage of the extracellular domain of the GHR. The majority of GHR mutations resulting in GHIS are though to affect GH binding, hence the finding of low levels of GHBP in many patients. However, a small group of patients with GHIS have been identified in whom there are normal or high levels of GHBP. Mutations in these patients include, among others, a splice-site mutation that results in the skipping of exon 9. The resultant protein is a truncated GHR that lacks 97% of the intracellular domain of the normal receptor. Patients heterozygous for this mutation have GHIS. In vitro studies have shown the truncated receptor acts as a dominant-negative inhibitor of receptor signalling. The truncated receptor lacks the domains essential for internalization, and is therefore highly expressed on the cell surface. It heterodimerizes with the full-length receptor and blocks signaling. Analysis of GHIS has increased our understanding of the molecular basis for GHIS and helped elucidate the factors that regulate GHR trafficking and signalling.
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PMID:The GH receptor and GH insensitivity. 1054 5

Previous studies have shown that different agonists increase tyrosine phosphorylation of the focal adhesion related proteins p125(FAK), p130(Cas), and paxillin in different cell types and that tyrosine phosphorylation depends on the integrity of the actin cytoskeleton. Because phosphoinositides are important for the maintenance of the cytoskeleton, the role of phosphoinositides in the tyrosine phosphorylation of these proteins in response to occupancy of m3 muscarinic and CCK(A) receptors has been investigated in pancreatic acini. Addition of carbachol or CCK-8 to pancreatic acini resulted in rapid increases in the tyrosine phosphorylation of p125(FAK), p130(Cas), and paxillin. Pretreatment of pancreatic acini with LY294002 or wortmannin resulted in a concentration-dependent inhibition of tyrosine phosphorylation of p125(FAK), p130(Cas), and paxillin stimulated by carbachol or CCK-8. Carbachol- or CCK-8-stimulated tyrosine phosphorylation of these proteins was not inhibited by rapamycin, PD 98059 or SB 203580, and thus it was dissociated from the activation of p70 S6 or MAP kinases. These results indicate that m3 muscarinic and CCK(A) receptor-mediated increase in p125(FAK), p130(Cas), and paxillin tyrosine phosphorylation in pancreatic acini depends on the ability of these cells to synthesise phosphoinositides.
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PMID:A role for phosphoinositides in tyrosine phosphorylation of p125 focal adhesion kinase in rat pancreatic acini. 1070 24

Since the effects of progesterone are mediated mainly via estrogen-dependent progesterone receptor (PR), the expression of the effects of progesterone may be masked or overridden by the influence of estrogen under conditions in which priming with estrogens is required. We have established a PR-positive but estrogen receptor-alpha (ER-alpha) negative breast cancer cell model by transfecting PR cDNA into ER-alpha- and PR-negative MDA-MB-231 cells in order that the functions of progesterone can be studied independently of estrogens. We have demonstrated using this model that progesterone markedly inhibited cell growth. We have also discovered that progesterone induced remarkable changes in cell morphology and specific adhesion structures. Progesterone-treated cells became considerably more flattened and well spread than vehicle-treated control cells. This was associated with a striking increase of stress fibers, both in number and diameter, and increased focal contacts as shown by the staining of focal adhesion proteins paxillin and talin. There were also distinct increases in tyrosine phosphorylation of focal adhesion protein paxillin and focal adhesion kinase in association with increased focal adhesion. The staining of tyrosine-phosphorylated proteins was concentrated at focal adhesions in progesterone-treated cells. More interestingly, monoclonal antibody (Ab) to beta1 integrin was able to inhibit progesterone-induced cell spreading and formation of actin cytoskeleton. To our knowledge, this is the first report describing a direct effect of progesterone in inducing spreading and adhesion of breast cancer cells, and beta1-integrin appeared to play an essential role in the effect. It is known that the initial step of tumor metastasis is the breakaway of tumor cells from primary tumor mass when they lose the ability to attach. Hence, progesterone-induced cell spreading and adhesion may have significant implications in tumor metastasis.
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PMID:Progesterone induces focal adhesion in breast cancer cells MDA-MB-231 transfected with progesterone receptor complementary DNA. 1070 53

Drug resistance remains a serious limiting factor in the treatment of acute myeloid leukaemia (AML) either at initial presentation or following primary or subsequent relapses. Using specific kinase inhibitors, this study has investigated the contribution of the Ras/PI3-kinase regulated survival pathways to drug resistance and suppression of apoptosis in a cell line derived from AML (HL60). Inhibition of the Raf/MAP-kinase (ERK) pathway with a specific MAP-kinase inhibitor, apigenin did not sensitise HL60 cells to drug-induced apoptosis, indicating a lack of involvement in chemoresistance. In contrast, the PI3-kinase inhibitors, LY294002 and wortmannin, did induce a significant increase in apoptosis in combination with cytotoxic drugs. The contribution of downstream mediators of PI3-kinase, p70S6-kinase and PKB/Akt were then investigated. While inhibition of p70S6-kinase with rapamycin did not increase drug-induced apoptosis, PI3-kinase inhibition resulted in notable dephosphorylation of PKB, suggesting that the PI3-kinase/PKB survival pathway may play a major role in chemoresistance in AML. This pathway has been reported to mediate heterodimer interactions with the proapoptotic regulator, Bad. In contrast to previous studies, we found no evidence of Bad binding to anti-apoptotic Bcl-2, Bcl-XL or McI-1, or of alterations in Bax heterodimers. This suggests that alternative targets of PI3-kinase/PKB, distinct from the Bcl-2 family may be responsible for contributing to survival factor-mediated drug resistance in AML.
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PMID:Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals. 1076 45

The effects of pituitary and extrapituitary prolactin include cellular proliferation and differentiation. PC12 cells was used as a model to delineate respective signaling of prolactin. Prolactin acted as a mitogen for undifferentiated PC12 cells, as measured by significant increases in bromodeoxyuridine incorporation and in cell numbers, with an efficacy equal to epidermal growth factor. Both the long and short form of the prolactin receptor was expressed, yet only the long isoform was tyrosine-phosphorylated upon agonist binding. Functional prolactin receptor signaling was further demonstrated in the activation of JAK2 and phosphorylation activation of the transcription factors Stat1, -3, and -5a. Surprisingly, prolactin stimulated a sustained activation of Raf-B, without activation of the MAP kinases ERK1 or -2. Instead, in solid phase kinase assays using a glutathione S-transferase-c-Jun fusion protein (amino acids 1-79) as the substrate, a significant activation of the mitogen-activated protein Janus kinase (c-Jun N-terminal kinase; JNK) was observed. The prolactin-induced activation of JNK was prolonged and accompanied by a significant increase in c-Jun mRNA abundance and c-Jun protein synthesis. Moreover, analysis of bromodeoxyuridine incorporation at the single cell level revealed that epidermal growth factor-dependent incorporation was inhibited by PD98059 and independent of SB203580, whereas prolactin-induced incorporation was ERK and mitogen-activated protein kinase p38 independent but was abolished with JNK inhibition by 30 microm SB203580. Our studies suggest that prolactin may have a role in the growth of PC12 cells, where it stimulates concurrent mitogenic and differentiation-promoting signaling pathways.
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PMID:Prolactin-induced cell proliferation in PC12 cells depends on JNK but not ERK activation. 1080 11

The effect of insulin on glucose transport, glucose transporter 4 (Glut4) translocation, and intracellular signaling were measured in fat cells from lean and obese Zucker rats of different ages. Insulin-stimulated glucose transport was markedly reduced in adipocytes from old and obese animals. The protein content of Glut4 and insulin receptor substrates (IRS) 1 and 2 were also reduced while other proteins, including the p85 subunit of PI3-kinase, Shc and the MAP kinases (ERK1 and 2) were essentially unchanged. There was a marked impairment in the insulin stimulated tyrosine phosphorylation of IRS-1 and 2 as well as activation of PI3-kinase and PKB in cells from old and obese animals. Furthermore, insulin-stimulated translocation of both Glut4 and PKB to the plasma membrane was virtually abolished. The phosphotyrosine phosphatase inhibitor, vanadate, increased the insulin-stimulated upstream signaling including PI3-kinase and PKB activities as well as rate of glucose transport. Thus, the insulin resistance in cells from old and obese Zucker rats can be accounted for by an impaired translocation process, due to signaling defects leading to a reduced activation of PI3-kinase and PKB, as well as an attenuated Glut4 protein content.
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PMID:Insulin resistance in fat cells from obese Zucker rats--evidence for an impaired activation and translocation of protein kinase B and glucose transporter 4. 1083 89

Rat eosinophil survival was prolonged by recombinant rat IL-5 prepared by the baculovirus expression system. The IL-5-induced prolongation of eosinophil survival was dose-dependently inhibited by the protein synthesis inhibitor cycloheximide, the DNA-dependent RNA synthesis inhibitor actinomycin D, and the tyrosine kinase inhibitor herbimycin A. The MEK-1 inhibitor PD98059 inhibited IL-5-induced phosphorylation of both p44 and p42 MAP kinases, but the IL-5-induced prolongation of eosinophil survival was not inhibited. In contrast, the JAK2 inhibitor AG490 inhibited the IL-5-induced prolongation of eosinophil survival. Treatment of eosinophils with IL-5 resulted in phosphorylation of STAT5 but not STAT1, and the IL-5-induced phosphorylation of STAT5 was inhibited by AG490. These findings suggest that recombinant rat IL-5 activates JAK2 tyrosine kinase, which phosphorylates STAT5, and induces protein synthesis required for the prolongation of rat eosinophil survival.
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PMID:Analysis of the prolongation of rat eosinophil survival induced by recombinant rat interleukin-5. 1086 6

In the present study we have examined the proteins involved in the insulin signaling cascade during and after differentiation of human adipocyte precursor cells and their correlation with glucose uptake. The differentiation of human adipocytes was characterized by a two- to threefold stimulation of glucose transport in response to insulin and a marked increase protein expression for the insulin receptor, IRS-1, GLUT-4, PI 3-kinase, and PKB, with respect to undifferentiated cells. In contrast, there were small changes in the protein expression of IRS-2, and no changes in PKC zeta and MAP kinases, although basal MAP kinase activity and GLUT-1 protein were reduced during differentiation. In conclusion, there are quantitative differences in the regulation of IRS-1 and other proteins during differentiation which may contribute to more efficient insulin signaling leading to glucose uptake in mature fat cells. Alterations in this pattern may reflect or contribute to an insulin-resistant state.
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PMID:Regulation of proteins involved in insulin signaling pathways in differentiating human adipocytes. 1100

PLEASE NOTE: This draft Special Report is an evidence-based analysis of the relative effectiveness of different treatment programs and components of treatment for anorexia nervosa. It does not attempt to address the question as to whether the TEC criteria are met.
Tecnologica MAP Suppl 2000 Jun
PMID:Special report: relative effectiveness of treatment programs and components of treatment for anorexia nervosa. 1106 85


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