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)

Estrogen plus progestin hormone therapy has been associated with increased breast proliferation, breast density, and breast cancer risk in postmenopausal women, beyond that seen with estrogen alone. The goal of this study was to evaluate progestogen effects on gene expression profiles in the breast contributing to this promotional effect. Twenty-five ovariectomized adult female cynomolgus monkeys were given the following treatments (expressed as equivalent doses for women) in a randomized crossover design: (1) placebo; (2) oral estradiol (E2, 1 mg/day); (3) E2 + micronized progesterone (P4, 200 mg/day); and (4) E2 + medroxyprogesterone acetate (MPA, 2.5 mg/day). Treatments were given for two months, and breast biopsies were taken after each treatment period. On microarray analysis E2 + MPA treatment resulted in a greater number of significantly regulated genes compared to E2 + P4 and E2 alone (P < 0.0001). Treatment with E2 alone induced modest effects on select genes related to epidermal growth factor receptor (EGFR) activity which were augmented by the addition of MPA but not P4, consistent with patterns of epithelial cell proliferation. Genes induced by E2 + MPA included the EGFR ligands EGF, TGFA, and AREG, and downstream targets such as STAT5A, STAT5B, SRC, EIF4EBP1, and MYC. Progestogens showed mixed antagonistic effects on E2-induced genes which tended to be greater for P4 than MPA. These findings suggest that a standard dose of oral E2 + MPA has a more pronounced effect on gene expression in the breast compared to E2 alone or E2 + P4 and that promotional effects of E2 + MPA may be mediated in part by increased EGFR activity.
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PMID:Transcriptional profiles of progestogen effects in the postmenopausal breast. 1840 70

In addition to humoral angiogenic factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), integrin-mediated adhesion of vascular endothelial cells to the extracellular matrix plays an important role in neovascularization. We recently found that TNIIIA2, a peptide derived from tenascin-C, induces functional activation of beta1 integrins. Here we investigated the effect of TNIIIA2 on vascular endothelial cell migration and proliferation, key processes for angiogenesis. TNIIIA2 was shown to activate beta1-integrins on human dermal microvascular endothelial cells (HDMEC). HDMEC adhered to fibronectin mainly via integrin alpha5beta1 and their haptotactic migration on that substrate was inhibited by TNIIIA2, in concomitant with a marked inhibition of Rac activation. TNIIIA2-treatment unaffected autophosphorylation of focal adhesion kinase (FAK), but induced its physical association with phospho-paxillin (Tyr118), suggesting the FAK/paxillin-dependent negative regulation of Rac activation. HDMEC proliferation on the fibronectin substrate was also inhibited by TNIIIA2-treatment, and this was accompanied either by an increase in the population of G 0/G1 cells and, conversely, a decrease in the population of S and G2/M cells or by dephosphorylation/inactivation of MAP-kinase (ERK1/2). Inhibited HDMEC migration and proliferation were both restored by pretreating the cells with a fibronectin peptide, FNIII14, which is capable of inactivating beta1-integrins. The chorioallantoic membrane assay demonstrated an antiangiogenic effect of TNIIIA2 in vivo. Thus, TNIIIA2 appears to negatively regulate angiogenesis by inhibiting migration and proliferation of endothelial cells. The ability to activate beta1-integrins may be responsible for the antiangiogenic effect of TNIIIA2, although it cannot be excluded the possibility that an additional mechanism(s) may play a role.
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PMID:Inhibition of angiogenesis by a tenascin-c peptide which is capable of activating beta1-integrins. 1845 35

Progesterone (P) and prolactin (PRL) fulfill crucial roles during growth and differentiation of the mammary epithelium, and each has been implicated in the pathogenesis of mammary cancer. We previously identified that these hormones synergistically stimulate the proliferation of mouse mammary epithelial cells in vivo, although the mechanism(s) underlying their cooperative effect are unknown. We now report a novel pathway by which P and PRL synergize to activate transcription from the long terminal repeat (LTR) of the mouse mammary tumor virus-LTR (MMTV-LTR) in T47D breast cancer cells. Using serial 5' and 3' deletions of the MMTV-LTR, in addition to selective mutations, we identified that a previously uncharacterized inverted palindrome on the distal enhancer (-941/-930), in addition to a signal transducer and activator of transcription 5 site, was essential for the synergistic activation of transcription by P and PRL. Notably, hormone synergy occurred via a mechanism that was independent of the P receptor DNA-binding elements found in the proximal MMTV-LTR hormone-response element. The palindrome specifically recruited a protein complex (herein termed mammary gland-specific complex) that was almost exclusive to normal and cancerous mammary cells. The synergy between P and PRL occurred via a Janus kinase 2 and c-Src/Fyn-dependent signaling cascade downstream of P and PRL receptors. Combined, our data outline a novel pathway in T47D cells that may facilitate the action(s) of P and PRL during mammary development and breast cancer.
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PMID:A 5' distal palindrome within the mouse mammary tumor virus-long terminal repeat recruits a mammary gland-specific complex and is required for a synergistic response to progesterone plus prolactin. 1852 69

Progesterone action contributes to the signaling of many growth factor pathways relevant to breast cancer tumor biology, including the insulin-like growth factor (IGF) system. Previous work has shown that insulin receptor substrate-2 (IRS-2) but not IRS-1 levels were regulated by progestin in progesterone receptor-B (PR-B) isoform expressing MCF-7 cells (C4-12 PR-B). Furthermore, type 1 IGF receptor (IGF1R) signaling via IRS-2 correlated with the increased cell migration observed in a number of breast cancer cell lines. Consequently, in this study, we examined whether the elevation of IRS-2 protein induced by progestin was sufficient to promote IGF-I-stimulated cell motility. Treatment of C4-12 PR-B cells with progestin shifted the balance of phosphorylation from IRS-1 to IRS-2 in response to IGF-I. This shift in IRS-2 activation was associated with enhanced migration in C4-12 PR-B cells pretreated with progestin, but had no effect on cell proliferation or survival. Treatment of C4-12 PR-B cells with RU486, an antiprogestin, inhibited IGF-induced cell migration. Attenuation of IRS-2 expression using small interfering RNA resulted in decreased IGF-stimulated motility. In addition, IRS-2 knockdown resulted in an abrogation of PKB/Akt phosphorylation but not mitogen-activated protein kinase. Consequently, LY294002, a phosphoinositide-3-kinase inhibitor, abolished IGF-induced cell motility in progestin-treated C4-12 PR-B cells. These data show a role for the PR in functionally promoting growth factor signaling, showing that levels of IRS proteins can determine IGF-mediated biology, PR-B signaling regulates IRS-2 expression, and that IRS-2 can mediate IGF-induced cell migration via phosphoinositide-3-kinase in breast cancer cells.
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PMID:Progesterone receptor-B regulation of insulin-like growth factor-stimulated cell migration in breast cancer cells via insulin receptor substrate-2. 1881 36

Aldosterone synthesis is primarily regulated by angiotensin II and potassium ions. In addition, endothelial cell-secreted factors have been shown to regulate mineralocorticoid release. We analyzed the pathways that mediate endothelial cell-factor-induced aldosterone release from adrenocortical cells, NCI-H295R using endothelial cell-conditioned medium (ECM). The cAMP antagonist Rp-cAMP caused a 44% decrease in the ECM-induced aldosterone release but inhibition of cAMP-dependent PKA had no effect on aldosterone release. Interestingly, inhibition of cAMP-regulated guanine nucleotide exchange factor Epac with brefeldin-A decreased the ECM-induced aldosterone release by 45%. Similarly, inhibition of p38 MAP-kinase; PI-3-kinase and PKB significantly reduced the ECM-induced aldosterone release whereas inhibition of ERK1/2 and PKC did not decrease aldosterone release. These results provide evidence for the existence of a cAMP-dependent but PKA-independent pathway in mediating the ECM-induced aldosterone release and the significant influence of more than one signaling mechanism.
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PMID:Endothelial factors mediate aldosterone release via PKA-independent pathways. 1907 32

A new biological paradigm, Systems Biology, has emerged with the completion of the Human Genome Project. The Human Genome Project has advanced the view that biological information operates on multiple hierarchical levels and is processed in complex networks. In this paradigm, cumulative knowledge will be used to build models, providing positive externalities to researchers who can use this knowledge to generate new products. As systems biology is likely to become the dominant paradigm in biology, central to the development of medically viable products is ensuring accessibility to systems-based knowledge for multiple researchers. In this paper, we have selected seven systems based on their biological significance including: the Akt (Protein Kinase B), BCR-ABL, GPCR (G-Protein-Coupled Receptor), JAK/STAT (Janus Kinase/Signal Transducers and Activators of Transcription), MAP Kinase, NF-kappaB (Nuclear Factor Kappa B), and Phospholipase C signaling pathways. For each system we provide a complete list of patents, including categorization and institutional ownership; we also review specific patents for each system from the perspective of type of assignee, breadth of claims, and focus-namely whether the focus of the patent is on upstream knowledge regarding the signaling pathway or downstream on pharmaceutical or biological drug development, screening assays, or diagnostics.
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PMID:Recent patents on cell signaling systems. 1907 31

IFNgamma is strongly related to mast cell-associated diseases. There are many reports that IFNgamma inhibits mast cell degranulation. However, inflammatory cytokine production in mast cells stimulated with IFNgamma has not yet been clearly investigated. Therefore, we aimed to investigate the signaling pathways of cytokine production in mast cells stimulated with IFNgamma. Human mast cell line (HMC)-1 or mouse bone marrow-derived mast cells (BMMCs) were stimulated with IFNgamma (100 units) for time periods indicated. Expressions of proteins and mRNAs of cytokines were determined by ELISA and RT-PCR, respectively, activities of MAP kinases, PKC, JAK1/2, and STAT1 on tyrosine 701 and serine 727 by immunoblotting, the DNA-binding activity of the transcription factors by electrophoretic mobility shift assay. IFNgamma-stimulated mast cells showed increase in expressions of proteins and mRNAs of inflammatory cytokines, phosphorylations of MAP kinases, PKCalpha and betaI, JAK1/2, and STAT1 on tyrosine 701 and serine 727. JAK inhibitor or PKC inhibitors inhibited the phosphorylations of p38 kinase, STAT1 on serine 727, and activities of NF-kappaB and AP-1 compared to IFNgamma stimulation alone. These data suggest that IFNgamma-stimulated mast cells induce productions of inflammatory cytokines through PKC/p38/NF-kappaB and AP-1 pathways, not through classical JAK/STAT1 pathway, in both mast cells.
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PMID:Cytokine production through PKC/p38 signaling pathways, not through JAK/STAT1 pathway, in mast cells stimulated with IFNgamma. 1923 Dec 33

The immunomodulatory properties of growth hormone (GH) are well recognized. Enhanced production of NO and cytokines by macrophages on treatment with GH was reported by us recently. The present investigation elucidates the signaling mechanism(s) by which GH activates macrophages in vitro. It is observed that GH induces the phosphorylation (activation) of JAK2, PI3K, PKC and MAP kinases. Studies with pharmacological inhibitors of various signaling molecules also indicated that GH-induced proinflammatory responses in macrophages are mediated by JAK2/PI3K/PKC/ERK1/2, JAK2/JNK and JAK/STAT signaling cascades. It was further observed that GH induced the enhanced expression/phosphorylation of transcription factors c-fos, c-jun, Elk-1 and Stat1. It is also demonstrated that GH-induced ERK1/2 cascade regulates the production of TNF-alpha and IL-1beta in macrophages, whereas JNK cascade mediated the production of TNF-alpha, IFN-gamma and IL-12. These results suggest that JAK2 plays a central role in mediating proinflammatory responses of macrophages on GH treatment.
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PMID:Growth hormone-induced production of cytokines in murine peritoneal macrophages in vitro: role of JAK/STAT, PI3K, PKC and MAP kinases. 1925 Jun 98

The cellular effects of the toxic metal cadmium (Cd) are manifold. A large proportion of the cellular reactions affected by ionic Cd(2+) are mediated by cellular signaling cascades. The aim of this review is to provide a principal understanding of the known physiological signaling cascades, which are recruited by Cd(2+), and to highlight the fact that Cd(2+), similarly to other toxic metals, disrupts physiological signal transduction. In principle, second messengers are generated at the time of receptor activation, are short-lived, and act specifically in space and time through non-covalent binding on effectors to transiently alter their activity. Signaling dysregulation induced by Cd(2+) is reflected by a permanent disruption of transducing modules, resulting in low and/or elevated and constant levels of second messengers, which overwhelm the control mechanisms of signaling. This disturbs physiological cellular functions, gene transcription and regulation and may result in cell death and/or stress-induced adaptation and survival as well as carcinogenesis. The impact of Cd(2+) on Ca(2+)-, cAMP-, NO-, ROS-, MAP-kinase-, PKB/Akt-, nuclear factor-kappa B-, and developmental signaling is critically discussed. The hierarchical as well as cooperative and integrative character of signaling cascades activated by Cd(2+) is illustrated in the kidney proximal tubule, a major target of Cd(2+) toxicity. This review also aspires to pinpoint new avenues of research that may contribute to a more differentiated view of the complex mechanisms underlying Cd(2+) toxicity in target tissues and eventually lead to rationales and strategies for prevention and therapy of Cd(2+) toxicity.
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PMID:Cadmium and cellular signaling cascades: to be or not to be? 1937 14

We have recently reported that the activation of focal adhesion kinase (FAK) and its downstream targets upon pathogen challenge regulate phagocytosis in medfly haemocytes. The goal of this study was to further explore the signalling pathway underlying the process of phagocytosis. In particular, in this report, we used flow cytometry, RNA interference, enzyme-linked immunosorbent assay, Western blot and immunoprecipitation analysis to demonstrate the haemocyte surface receptor, through which the extracellular signals in response to bacteria are transmitted intracellularly. The presented data demonstrate the expression of a beta integrin subunit in the surface of medfly haemocytes that transmits signals upon pathogen triggering to FAK and its downstream targets, Src, MAP kinases and Elk-1-like protein, for the engulfment of pathogen. Interestingly LPS is not internalized through integrins.
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PMID:A beta integrin subunit regulates bacterial phagocytosis in medfly haemocytes. 1942 87


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