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

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sympatho-adrenergic activity and the renin-angiotensin system are considered critical regulators of obesity and hypertension. The novel angiotensin II type 1 receptor-associated protein (ATRAP) has been demonstrated to modulate angiotensin II signalling in smooth muscle cells and cardiomyocytes. Adipose tissue expresses important renin angiotensin system components and contributes to cardiometabolic disease. However, ATRAP expression and regulation in adipocytes are unknown. We investigated expression of this novel modulator of angiotensin signalling and its regulation by beta-adrenergic receptors. We found ATRAP to be expressed in differentiated brown and white adipocytes. Stimulation of beta-adrenoceptors strongly suppressed ATRAP expression. We hypothesised a role for JAK/STAT signalling elements. Indeed, beta3-adrenergic stimulation robustly stimulated both STAT1 and STAT3 phosphorylation in a time- and dose-dependent manner. This effect was abrogated by inhibition of PKA and JAK2 signalling. Moreover, inhibition of JAK/STAT and PKA signalling reversed the beta3-adrenergic suppression of ATRAP expression. This study provides the first evidence for expression and adrenergic regulation of the angiotensin II signalling modulator ATRAP in adipocytes. Further, it indicates a novel regulatory link between beta-adrenergic and JAK/STAT signalling.
...
PMID:Expression of ATRAP in adipocytes and negative regulation by beta-adrenergic stimulation of JAK/STAT. 1823 61

Pertussis toxin (PTX) is an ancillary adjuvant used to elicit experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis. One mechanism whereby PTX potentiates EAE is to increase blood-brain barrier (BBB) permeability. To elucidate further the mechanism of action of PTX on the BBB, we investigated the genomic and proteomic responses of isolated mouse brain endothelial cells (MBEC) following intoxication. Among approximately 14,000 mouse genes tracked by cDNA microarray, 34 showed altered expression in response to PTX. More than one-third of these genes have roles in angiogenesis. Accordingly, we show that intoxication of MBEC induces tube formation in vitro and angiogenesis in vivo. The global effect of PTX on signaling protein levels and phosphorylation in MBEC was investigated by using Kinex antibody microarrays. In total, 113 of 372 pan-specific and 58 of 258 phospho-site-specific antibodies revealed changes >or=25% following intoxication. Increased STAT1 Tyr-701 and Ser-727 phosphorylation; reduced phosphorylation of the activating phospho-sites in Erk1, Erk2, and MAPKAPK2; and decreased phosphorylation of arrestin beta1 Ser-412 and Hsp27 Ser-82 were confirmed by Kinetworks multi-immunoblotting. The importance of signal transduction pathways on PTX-induced MBEC tube formation was evaluated pharmacologically. Inhibition of phospholipase C, MEK1, and p38 MAP kinase had little effect, whereas inhibition of cAMP-dependent protein kinase, protein kinase C, and phosphatidylinositol 3-kinase partially blocked tube formation. Taken together, these findings are consistent with the concept that PTX may lead to increased BBB permeability by altering endothelial plasticity and angiogenesis.
...
PMID:Pertussis toxin induces angiogenesis in brain microvascular endothelial cells. 1850 Jul 52

Excessive neuroinflammation contributes to many neurological disorders and is poorly controlled therapeutically. The signal transducer and activator of transcription (STAT) family of transcription factors has a central role in inflammatory reactions, being stimulated by multiple cytokines and interferons and regulating the expression of many proteins involved in inflammation. We found that STAT3 activation is highly dependent on glycogen synthase kinase-3 (GSK3). Inhibitors of GSK3 greatly reduced (>75%) the activating STAT3 tyrosine phosphorylation in mouse primary astrocytes, microglia, and macrophage-derived RAW264.7 cells induced by interferon-gamma (IFNgamma), IFNalpha, interleukin-6, or insulin. GSK3 inhibitors blocked STAT3 DNA binding activity and the expression of STAT3-induced GFAP and Bcl-3. GSK3 dependence was selective for activation of STAT3 and STAT5, whereas STAT1 and STAT6 activation were GSK3-independent. Knockdown of the two GSK3 isoforms showed STAT3 and STAT5 activation were dependent on GSK3beta, but not GSK3alpha. The regulatory mechanism involved GSK3beta binding STAT3 and promoting its association with the IFNgamma receptor-associated intracellular signaling complex responsible for activating STAT3. Furthermore, GSK3beta associated with the IFNgamma receptor and was activated by stimulation with IFNgamma. Thus, inhibitors of GSK3 reduce the activation of STAT3 and STAT5, providing a mechanism to differentially regulate STATs to modulate the inflammatory response.
...
PMID:Differential regulation of STAT family members by glycogen synthase kinase-3. 1855 May 25

IFN-gamma is a pleiotropic cytokine importantly involved in the development of skin inflammatory responses. Epidermal keratinocytes are extremely susceptible to IFN-gamma action, but, once transduced with the suppressors of cytokine signaling (SOCS)1 molecule, they can no longer express a number of IFN-gamma-inducible signal transducer and activator of transcription (STAT)1-dependent genes. Extracellular-signal-regulated kinase (ERK)1/2 pathway is also involved in the protection of keratinocytes from the proinflammatory effect of IFN-gamma. Here we show that, after IFN-gamma stimulation, SOCS1 inhibited IFN-gamma receptor and STAT1 phosphorylation but maintained ERK1/2 activation. SOCS1 was also necessary for the IFN-gamma-induced RAS and Raf-1 activities in keratinocytes. The enhanced ERK1/2 pathway in SOCS1-overexpressing keratinocytes was in part responsible for their inability to respond to IFN-gamma, in terms of CXCL10 and CCL2 production, and for the high production of CXCL8. Moreover, SOCS1 interacted with the RAS inhibitor p120 RasGAP and promoted its degradation after IFN-gamma stimulation. We hypothesize that SOCS1 functions as suppressor of IFN-gamma signaling, not only by inhibiting STAT1 activation but also by sustaining ERK1/2-dependent antiinflammatory pathways.
...
PMID:Suppressor of cytokine signaling 1 inhibits IFN-gamma inflammatory signaling in human keratinocytes by sustaining ERK1/2 activation. 1855 63

Poliovirus (PV) and enterovirus 71 (EV71) cause severe neurological symptoms in their infections of the central nervous system. To identify compounds with anti-PV and anti-EV71 activities that would not allow the emergence of resistant mutants, we performed drug screening by utilizing a pharmacologically active compound library targeting cellular factors with PV and EV71 pseudoviruses that encapsidated luciferase-encoding replicons. We have found that metrifudil (N-[2-methylphenyl]methyl)-adenosine) (an A2 adenosine receptor agonist), N(6)-benzyladenosine (an A1 adenosine receptor agonist) and NF449 (4,4',4'',4'''-[carbonylbis[imino-5,1,3-benzenetriyl bis(carbonyl-imino)]] tetrakis (benzene-1,3-disulfonic acid) octasodium salt) (a Gs-alpha inhibitor) have anti-EV71 activity, and that GW5074 (3-(3, 5-dibromo-4-hydroxybenzylidine-5-iodo-1,3-dihydro-indol-2-one)) (a Raf-1 inhibitor) has both anti-PV and anti-EV71 activities. EV71 mutants resistant to metrifudil, N(6)-benzyladenosine and NF449 were isolated after passages in the presence of these compounds, but mutants resistant to GW5074 were not isolated for both PV and EV71. The inhibitory effect of GW5074 was not observed in Sendai virus infection and the treatment did not induce the expression of OAS1 and STAT1 mRNA. Small interfering RNA treatment against putative cellular targets of GW5074, including Raf-1, B-Raf, Pim-1, -2, and -3, HIPK2, GAK, MST2 and ATF-3, did not consistently suppress PV replication. Moreover, downregulation of Raf-1 and B-Raf did not affect the sensitivity of RD cells to the inhibitory effect of GW5074. These results suggest that GW5074 has strong and selective inhibitory effect against the replication of PV and EV71 by inhibiting conserved targets in the infection independently of the interferon response.
...
PMID:Characterization of pharmacologically active compounds that inhibit poliovirus and enterovirus 71 infectivity. 1879 21

The BGLF4 protein kinase of Epstein-Barr virus (EBV) is a member of the conserved family of herpesvirus protein kinases which, to some extent, have a function similar to that of the cellular cyclin-dependent kinase in regulating multiple cellular and viral substrates. In a yeast two-hybrid screening assay, a splicing variant of interferon (IFN) regulatory factor 3 (IRF3) was found to interact with the BGLF4 protein. This interaction was defined further by coimmunoprecipitation in transfected cells and glutathione S-transferase (GST) pull-down in vitro. Using reporter assays, we show that BGLF4 effectively suppresses the activities of the poly(I:C)-stimulated IFN-beta promoter and IRF3-responsive element. Moreover, BGLF4 represses the poly(I:C)-stimulated expression of endogenous IFN-beta mRNA and the phosphorylation of STAT1 at Tyr701. In searching for a possible mechanism, BGLF4 was shown not to affect the dimerization, nuclear translocation, or CBP recruitment of IRF3 upon poly(I:C) treatment. Notably, BGLF4 reduces the amount of active IRF3 recruited to the IRF3-responsive element containing the IFN-beta promoter region in a chromatin immunoprecipitation assay. BGLF4 phosphorylates GST-IRF3 in vitro, but Ser339-Pro340 phosphorylation-dependent, Pin1-mediated downregulation is not responsible for the repression. Most importantly, we found that three proline-dependent phosphorylation sites at Ser123, Ser173, and Thr180, which cluster in a region between the DNA binding and IRF association domains of IRF3, contribute additively to the BGLF4-mediated repression of IRF3(5D) transactivation activity. IRF3 signaling is activated in reactivated EBV-positive NA cells, and the knockdown of BGLF4 further stimulates IRF3-responsive reporter activity. The data presented here thus suggest a novel mechanism by which herpesviral protein kinases suppress host innate immune responses and facilitate virus replication.
...
PMID:Epstein-Barr virus BGLF4 kinase suppresses the interferon regulatory factor 3 signaling pathway. 1905 84

Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation of tryptophan and is strongly induced in interferon-gamma (IFNgamma)-stimulated dendritic cells (DCs). IDO has recently been established as a key enzyme in T-cell suppression-mediated immune tolerance to tumors. STAT1 phosphorylation appears to play an important role in the control of IDO expression by IFNgamma, but the precise regulatory mechanism remains obscure. Here we present a novel mechanism of IFNgamma-induced IDO expression in bone marrow-derived dendritic cells. In addition, we demonstrate that curcumin, an active component of turmeric, significantly inhibited the induction of IDO expression and activity by IFNgamma. We found that curcumin suppressed STAT1 activation by directly inhibiting Janus-activated kinase 1/2 and protein kinase Cdelta phosphorylation in bone marrow-derived DCs, suppressing the subsequent translocation and binding of STAT1 to the GAS element of the IRF-1 promoter. Coincident with these inhibitory effects on IFNgamma-induced IDO expression, curcumin reversed IDO-mediated suppression of T-cell responses. Our results, thus, suggest that down-regulation of IDO in DCs is an important immunomodulatory property of curcumin that may be exploited therapeutically in the control of cancers.
...
PMID:Curcumin suppresses the induction of indoleamine 2,3-dioxygenase by blocking the Janus-activated kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells. 1907 17

How neuroinflammatory activities affect signaling pathways leading to blood-brain barrier (BBB) injury during HIV/AIDS are currently unknown. Our previous work demonstrated that HIV-1 exposure activates pro-inflammatory genes in human brain microvascular endothelial cells (HBMEC) and showed that these genes are linked to the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Here, we report that HIV-1 gp120 protein activated STAT1 and induced interleukin (IL)-6 and IL-8 secretion in HBMEC. IL-6, IL-8, and gp120 increased monocyte adhesion and migration across in vitro BBB models. The STAT1 inhibitor, fludarabine, prevented gp120-induced IL-6 and IL-8 secretion. Inhibitors of STAT1, mitogen activated protein kinase kinase (MEK) (PD98059), and phosphatidyl inositol 3 kinase (PI3K) (LY294002), blocked gp120-induced STAT1 activation and significantly diminished IL-8-, IL-6-, and gp120-induced monocyte adhesion and migration across in vitro BBB models. These data support the notion that STAT1 plays an important role in gp120-induced inflammation and BBB dysfunction associated with viral infection. Results also suggest crosstalk between STAT1, MEK, and PI3K pathways in gp120-induced BBB dysfunction. Inhibition of STAT1 activation could provide a unique therapeutic strategy to decrease neuroinflammation and BBB dysfunction in HIV/AIDS.
...
PMID:HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood-brain barrier: modulatory effects of STAT1 signaling. 1910 8

Suppressor of cytokine signaling 3 (SOCS3), as a key regulator of cytokine signaling, has the potential to modulate numerous cellular processes. Its involvement in inflammatory disease is well established, and there is increasing evidence for a role in breast cancer as a regulator of signal transducers and activators of transcription (STATs). Here we show that over-expression of SOCS3 markedly supresses STAT3 expression, and abrogates STAT5 phosphorylation, resulting in decreased cell proliferation in T47D breast cancer cells, and decreased proliferation and anchorage-independent growth in MCF7 cells. Using T47D cells, we elucidated the signaling pathways and transcription factors involved in SOCS3 expression in response to prolactin, a key mammotropic hormone. Quantitative real time PCR was used to examine SOCS3 mRNA expression, IP/WB was used to examine STAT phosphorylation, luciferase reporter assays, chromatin immunoprecipitation (ChIP) and gel shift assays allowed evaluation of cis-elements and trans-factors regulating SOCS3 expression. We demonstrate that prolactin-induced SOCS3 expression is STAT-dependant, predominantly involving STAT5, although STAT1 is also associated with the promoter. In addition, prolactin-induced SOCS3 promoter activation requires PKA-stimulated Sp1 binding to the GC-rich region of the promoter. Finally, we show that PRL-induced SOCS3 expression can be potentiated by co-treatment with PGE(2). This study demonstrates that SOCS3 acts as an anti-proliferative agent in breast cancer cells, and highlights the complexity of SOCS3 regulation and crosstalk.
...
PMID:SOCS3 as a tumor suppressor in breast cancer cells, and its regulation by PRL. 1911

Because viruses are obligate parasites, numerous partnerships between measles virus and cellular molecules can be expected. At the entry level, measles virus uses at least two cellular receptors, CD150 and a yet to be identified epithelial receptor to which the virus H protein binds. This dual receptor strategy illuminates the natural infection and inter-human propagation of this lymphotropic virus. The attenuated vaccine strains use CD46 as an additional receptor, which results in a tropism alteration. Surprisingly, the intracellular viral and cellular protein partnership leading to optimal virus life cycle remains mostly a black box, while the interactions between viral proteins that sustain the RNA-dependant RNA polymerase activity (i.e., transcription and replication), the particle assembly and the polarised virus budding are documented. Hsp72 is the only cellular protein that is known to regulate the virus transcription and replication through its interaction with the viral N protein. The viral P protein is phosphorylated by the casein kinase II with undetermined functional consequences. The cellular partnership that controls the intracellular trafficking of viral components, the assembly and/or the budding of measles virus, remains unknown. The virus to cell innate immunity war is better documented. The 5' triphosphate-ended virus leader transcript is recognised by RIG-I, a cellular helicase, and induces the interferon response. Measles virus V protein binds to the MDAS helicase and prevents the MDA5-mediated activation of interferon. By interacting with STAT1 and Jak1, the viral P and V proteins prevent the type I interferon receptor (IFNAR) signalling. The virus N protein interacts with eIF3-p40 to inhibit the translation of cellular mRNA. The H protein binds to TLR2, which then transduces an activation signal and CD150 expression in monocytes. The P protein activates the expression of the ubiquitin modifier A20, thus blocking the TLR4-mediated signalling. Few other partnerships between measles virus components and cellular proteins have been postulated or demonstrated, and they need further investigations to understand their physiopathological outcome.
...
PMID:Measles virus interaction with host cells and impact on innate immunity. 1919 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---