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)

Elevated intracellular Ca(2+) triggers numerous signaling pathways including protein kinases such as the calmodulin-dependent kinases (CaMKs) and the extracellular signal-regulated kinases (ERKs). In the present study we examined Ca(2+)-dependent "cross-talk" between these two protein kinase families. Using a combination of pharmacological inhibitors and dominant-negative kinases (dnKinase), we identified a requirement for CaMKK acting through CaMKI in the stimulation of ERKs upon depolarization of the neuroblastoma cell line, NG108. Depolarization stimulated prolonged ERK and JNK activation that was blocked by the CaMKK inhibitor, STO-609; this inhibition of ERK activation by STO-609 was rescued by expression of a STO-609-insensitive mutant of CaMKK. However, activation of ERK by epidermal growth factor or carbachol were not suppressed by inhibition of CaMKK, indicating specificity for this "cross-talk." To identify the downstream target of CaMKK that mediated ERK activation upon depolarization, dnKinases were expressed. The dnCaMKI completely suppressed ERK2 activation whereas dnAKT/PKB or nuclear-targeted dnCaMKIV, other substrates for CaMKK, were not inhibitory. ERK activation upon depolarization or transfection with constitutively active (ca) CaMKI was blocked by dnRas. Additionally, depolarization of NG108 cells promoted neurite outgrowth, and this effect was blocked by inhibition of either CaMKK (STO-609) or ERK (UO126). Co-transfection with caCaMKK plus caCaMKI also stimulated neurite outgrowth that was blocked by inhibition of ERK (UO126). These data are the first to suggest that ERK activation and neurite outgrowth in response to depolarization are mediated by CaMKK activation of CaMKI.
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PMID:Calcium activation of ERK mediated by calmodulin kinase I. 1515 Feb 58

Although both the renin angiotensin system (RAS) and the paired homeobox 2 gene (Pax-2) seem critically important in renal organogenesis, whether and how they might interact has not been addressed. The present study asked whether a link between the RAS and Pax-2 exists in fetal renal cells, speculating that such an interaction, if present, might influence renal development. Embryonic kidney explants and embryonic renal cells (mouse late embryonic mesenchymal epithelial cells [MK4] and mouse early embryonic mesenchymal fibroblasts [MK3]) were used. Pax-2 protein and Pax-2 mRNA were detected by immunofluorescence, Western blot, reverse transcription-PCR, and real-time PCR. Angiotensin II (AngII) upregulated Pax-2 protein and Pax-2 mRNA expression via the AngII type 2 (AT(2)) receptor in MK4 but not in MK3 cells. The stimulatory effect of AngII on Pax-2 gene expression could be blocked by PD123319 (AT(2) inhibitor), AG 490 (a specific Janus kinase 2 inhibitor), and genistein (a tyrosine kinase inhibitor) but not by losartan (AT(1) inhibitor), SB203580 (specific p38 mitogen-activated protein kinase inhibitor), PD98059 (specific MEK inhibitor), SP600125 (JNK inhibitor), and diphenyleneiodonium chloride (an NADPH oxidase inhibitor). Moreover, embryonic kidney explants in culture confirmed that AngII upregulates Pax-2 gene expression via the AT(2) receptor. These studies demonstrate that the stimulatory effect of AngII on Pax-2 gene expression is mediated, at least in part, via the Janus kinase 2/signal transducers and activators of transcription signaling transduction pathway, suggesting that RAS and Pax-2 interactions may be important in renal development.
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PMID:Angiotensin II increases Pax-2 expression in fetal kidney cells via the AT2 receptor. 1515 56

Sucrose- and fructose-enriched diets produce hepatic insulin resistance in rats independently of obesity. In humans, fructose infusion results in impaired insulin regulation of glucose production. The aim of the present study was to identify intrahepatic mediators of sucrose- and fructose-induced hepatic insulin resistance. In study 1, male rats were fed a control diet (STD, 68% of energy from corn starch, 12% from corn oil) or a sucrose-enriched diet (HSD, 68% sucrose, 12% corn oil) for 1, 2, or 5 wk. HSD produced hepatic insulin resistance at all time points. Hepatic protein tyrosine phosphatase 1B protein levels and activity were increased at 5 wk only, whereas c-jun NH(2)-terminal kinase (JNK) activity was increased at all time points. Normalization of JNK activity in hepatocytes isolated from HSD rats improved insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins and insulin suppression of glucose release. In study 2, male rats were provided STD for 1 wk and then were either fasted or fasted and refed either STD or HSD for 3 or 6 h. Rats refed HSD were characterized by increased hepatic JNK activity and phosphorylation of IRS1 on Ser(307) after 6 h only. In study 3, hyperglycemic, hyperinsulinemic pancreatic clamps were performed for 3 or 6 h in the presence or absence of low or high intraportal fructose infusions. High intraportal fructose infusions, which increased portal vein fructose concentration to approximately 1 mM, increased hepatic JNK activity and phosphorylation of IRS1 on Ser(307) at 6 h only. These data suggest that sucrose- and fructose-induced hepatic insulin resistance are mediated, in part, via activation of JNK activity. Thus high rates of fructose metabolism in the liver appear to acutely activate stress pathways.
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PMID:Hepatospecific effects of fructose on c-jun NH2-terminal kinase: implications for hepatic insulin resistance. 1519 36

HHV-8-GPCR is a chemokine-like receptor encoded by KSHV, the etiologic agent of KS. HHV-8-GPCR is constitutively active. Although it is homologous to mammalian CXCR2, it binds CXC and CC chemokines. Structure-function analysis showed that chemokines bind primarily to the amino terminus whereas signaling occurs in the absence of: the amino terminus, which is, therefore, not a tethered agonist. In in vitro systems, HHV-8-GPCR signals via multiple transduction pathways including, activation of phospholipase C and PKC, inhibition of adenylyl cyclase, activation of nuclear factor-kappaB; activation PI 3-kinase, p42/44 MAPK and Akt/PKB, and activation of JNK/SAPK, p38 MAPK and RAFTK. HHV-8-GPCR is important in the HHV-8 life cycle because HHV-8-GPCR-deficient viruses do not replicate in response to chemokines and exhibit, less efficient reactivation from latency. Although the role of HHV-8-GPCR in the pathogenesis of KS has not been defined, expression of HHV-8-GPCR resulted in the development of angioproliferative, KS-like tumors in transgenic mice. As endothelial cells may be targets of HHV-8 infection, HHV-8-GPCR has been studied in endothelial cells in vitro in which it affects cell adhesion and migration, increases cell survival, and stimulates secretion of proinflammatory cytokines and proangiogenic factors. Based on these findings and the observation that HHV-8-GPCR is expressed in only a few endothelial- like "spindle cells" within KS lesions, we propose that HHV-8-GPCR is involved in KS pathogenesis by stimulating secretion of proinflammatory/proangiogenic factors that act in a paracrine fashion to cause tumorigenesis.
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PMID:Insights into the viral G protein-coupled receptor encoded by human herpesvirus type 8 (HHV-8). 1520 3

Transforming growth factor-beta1 (TGF-beta1) is a potent inducer of apoptosis in normal hepatocytes, and acquiring resistance to TGF-beta1 may be a critical step in the development of hepatocellular carcinoma (HCC). In this study, we investigated the possible involvement of c-Src in the regulation of TGF-beta1-induced apoptosis. TGF-beta1 induced transient activation of c-Src and its subsequent caspase-mediated degradation concomitant with cell death in FaO hepatoma cells, which are sensitive to TGF-beta1. In response to TGF-beta1, activated c-Src was translocated into the cytoplasmic membrane, then relocated to the nuclei of apoptotic cells during its cleavage. In TGF-beta1-induced apoptotic cells, c-Src maintained its tight association with p85 FAK fragment cleaved by caspases, possibly contributing to focal adhesion disassembly. TGF-beta1-induced apoptosis was enhanced by either inhibition of c-Src activity using PP1 or PP2, or by overexpression of dominant-negative c-Src. In contrast, overexpression of constitutively active c-Src inhibited apoptosis suppressing TGF-beta1-induced activation of p38, JNK and caspases. In many HCC cell lines resistant to TGF-beta1, enhanced c-Src activity was detected. We hypothesize that activated c-Src in HCC may contribute to resistance against the apoptotic and/ or antiproliferative properties of TGF-beta1.
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PMID:Involvement of c-Src kinase in the regulation of TGF-beta1-induced apoptosis. 1520 64

Spleen tyrosine kinase (Syk), a nonreceptor protein kinase initially found to be expressed only in hemopoietic cells, has now been shown to be expressed in nonhemopoietic cells and to mediate signaling of various cytokines. Whether Syk plays any role in TNF signaling was investigated. Treatment of Jurkat T cells with TNF activated Syk kinase but not ZAP70, another member of Syk kinase family, and the optimum activation occurred at 10 s and with 1 nM TNF. TNF also activated Syk in myeloid and epithelial cells. TNF-induced Syk activation was abolished by piceatannol (Syk-selective inhibitor), which led to the suppression of TNF-induced activation of c- JNK, p38 MAPK, and p44/p42 MAPK. Jurkat cells that did not express Syk (JCaM1, JCaM1/lck) showed lack of TNF-induced Syk, JNK, p38 MAPK, and p44/p42 MAPK activation, as well as TNF-induced IkappaBalpha phosphorylation, IkappaBalpha degradation, and NF-kappaB activation. TNF-induced NF-kappaB activation was enhanced by overexpression of Syk by Syk-cDNA and suppressed when Syk expression was down-regulated by expression of Syk-small interfering RNA (siRNA-Syk). The apoptotic effects of TNF were reduced by up-regulation of NF-kappaB by Syk-cDNA, and enhanced by down-regulation of NF-kappaB by siRNA-Syk. Immunoprecipitation of cells with Syk Abs showed TNF-dependent association of Syk with both TNFR1 and TNFR2; this association was enhanced by up-regulation of Syk expression with Syk-cDNA and suppressed by down-regulation of Syk using siRNA-Syk. Overall, our results demonstrate that Syk activation plays an essential role in TNF-induced activation of JNK, p38 MAPK, p44/p42 MAPK, NF-kappaB, and apoptosis.
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PMID:TNF activates Syk protein tyrosine kinase leading to TNF-induced MAPK activation, NF-kappaB activation, and apoptosis. 1524 Jun 95

alpha-, beta-, and gamma-Herpesviruses encode putative viral protein kinases. The herpes simplex virus UL13, varicella-zoster virus ORF47, and Epstein-Barr virus BGLF4 genes all show protein kinase domains in their protein sequences. Mutational analysis of these herpesviruses demonstrated that the viral kinase is important for optimal virus growth. Previous studies have shown that ORF36 of Kaposi's sarcoma herpesvirus (KSHV) has protein kinase activity and is autophosphorylated on serine. The gene for ORF36 is expressed during lytic growth of the virus and has been classified as a late gene. Inspection of the ORF36 sequence indicated potential motifs that could be involved in activation of cellular transcription factors. To analyze the function of ORF36, the cDNA for this viral gene was tagged with the FLAG epitope and inserted into an expression vector for mammalian cells. Transfection experiments in 293T and SLK cells demonstrated that expression of ORF36 resulted in phosphorylation of the c-Jun N-terminal kinase. Autophosphorylation of ORF36 is important for JNK activation because a mutation in the predicted catalytic domain of ORF36 blocked its ability to phosphorylate JNK. Western blot analysis, using phosphospecific antibodies, revealed that mitogen-activated kinases MKK4 and MKK7 were phosphorylated by ORF36 but not by the kinase-negative mutant. Binding experiments in transfected cells also demonstrated that both the wild type and kinase-negative mutant of ORF36 form a complex with JNK, MKK4, and MKK7. In addition, using a tetracycline-inducible Rta BCBL-1 cell line (TREx BCBL1-Rta), JNK was phosphorylated during lytic replication, and inhibition of JNK activation blocked late viral gene expression but not early viral gene expression. In summary, these studies demonstrate that KSHV ORF36 activates the JNK pathway; thus this cell signaling pathway may function in the KSHV life cycle by regulating viral and/or cellular transcription.
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PMID:ORF36 protein kinase of Kaposi's sarcoma herpesvirus activates the c-Jun N-terminal kinase signaling pathway. 1524 71

In March 2003, a novel coronavirus was isolated from patients exhibiting atypical pneumonia, and was subsequently proven to be the causative agent of the disease now referred to as SARS (severe acute respiratory syndrome). The complete genome of the SARS-CoV (SARS coronavirus) has since been sequenced. The SARS-CoV nucleocapsid (SARS-CoV N) protein shares little homology with other members of the coronavirus family. In the present paper, we show that SARS-CoV N is capable of inducing apoptosis of COS-1 monkey kidney cells in the absence of growth factors by down-regulating ERK (extracellular-signal-regulated kinase), up-regulating JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and affecting their downstream effectors. SARS-CoV N expression also down-regulated phospho-Akt and Bcl-2 levels, and activated caspases 3 and 7. However, apoptosis was independent of the p53 and Fas signalling pathways. Furthermore, activation of the p38 MAPK pathway was found to induce actin reorganization in cells devoid of growth factors. At the cytoskeletal level, SARS-CoV N down-regulated FAK (focal adhesion kinase) activity and also down-regulated fibronectin expression. This is the first report showing the ability of the N protein of SARS-CoV to induce apoptosis and actin reorganization in mammalian cells under stressed conditions.
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PMID:The SARS coronavirus nucleocapsid protein induces actin reorganization and apoptosis in COS-1 cells in the absence of growth factors. 1529 14

Recent studies have shown that selective cyclooxygenase-2 (COX-2) inhibitors induce growth inhibition and cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism by which COX-2 inhibitors regulate the cell cycle and whether or not growth signal pathways are involved in the growth inhibition remain unclear. In this study, we investigated the mechanisms of growth inhibition and cell cycle arrest by etodolac, a selective COX-2 inhibitor, in HCC cell lines, HepG2 and PLC/PRF/5, by studying cell cycle regulatory proteins, and the MAP kinase and PDK1-PKB/AKT signaling pathways. Etodolac inhibited growth and PCNA expression and induced cell cycle arrest in both HCC cell lines. Etodolac induced p21WAF1/Cip1 and p27Kip1 expression and inhibited CDK2, CDK4, CDC2, cyclin A and cyclin B1 expression, but did not affect cyclin D1 or cyclin E. HGF and 10% FBS induced ERK phosphorylation, but phosphorylation of p38, JNK and AKT was down-regulated by etodolac. PD98059, a selective inhibitor of ERK phosphorylation, induced growth inhibition, the expression of p27Kip1 and cell cycle arrest. In conclusion, p21WAF1/Cip1, p27Kip1, CDK2, CDK4, CDC2, cyclin A, cyclin B1 and the MAP kinase signaling pathway are involved in growth inhibition and cell cycle arrest by a selective COX-2 inhibitor in HCC cell lines.
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PMID:Involvement of cell cycle regulatory proteins and MAP kinase signaling pathway in growth inhibition and cell cycle arrest by a selective cyclooxygenase 2 inhibitor, etodolac, in human hepatocellular carcinoma cell lines. 1529 30

Rat neonatal ventricular myocytes exposed to simulated ischaemia and reperfusion (SI/R) were used as an in vitro model to delineate the role(s) of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH(2)-terminal protein kinase (JNK), as well as PKB in apoptosis. Exposure of the myocytes to SI (simulated ischaemia - energy depletion induced by KCN and 2-deoxy- D-glucose) reduced cell viability, as measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, and stimulated apoptosis as evidenced by caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage. However, morphological evidence of increased apoptosis, detected by staining with Hoechst 33342, was only seen in response to reperfusion. This suggests that although ischaemic conditions are sufficient to induce cellular markers of apoptosis (PARP cleavage and caspase-3 activation), reperfusion is required to complete the apoptotic pathway in these cells. Furthermore, SI resulted in a rapid, strong, biphasic activation of p38 concomitant with a weak and transient activation of the two ERK isoenzymes, p42/p44-MAPK. Reperfusion for 5 minutes resulted in a strong phosphorylation of p42/p44-MAPK, while no additional p38 activation was seen at this stage. On the other hand, p46/p54-MAPK (JNK) was phosphorylated in response to 5 minutes of reperfusion only and not during SI alone. A peak of PKB/Akt (Ser(473)) activity was seen within 5 minutes of exposure to SI, whereas PKB/Akt (Thr(308)) phosphorylation remained at the baseline level. Both PKB/Akt phosphorylation sites (Ser(473) and Thr(308)) were phosphorylated after 5 minutes of reperfusion. Inhibition of PI-3-kinase activity, using wortmannin, decreased phosphorylation on both sites during SI. However, only SI/R-induced PKB/Akt phosphorylation on Thr(308) was reduced by wortmannin. Myocytes pre-treated with SB203580, a p38-inhibitor, displayed a significant increase in cell viability [63.67 +/- 1.85 to 84.33 +/- 4.8% (p < 0.05)] and attenuation of the apoptotic index during SI/R [22.6 +/- 2.94% to 9 +/- 0.43% (p < 0.001)], while SP600125, a specific JNK inhibitor, caused a significant increase in caspase-3 activation [1.66 +/- 0.03 fold to 2.56 +/- 0.27 fold (p < 0.001)] and apoptotic index [22.6 +/- 2.94% to 32.75 +/- 6.13% (p < 0.05)]. However, PD98059, an ERK inhibitor, failed to affect apoptosis during SI/R. Inhibition of PI-3-kinase prevented the increase in mitochondrial viability usually observed during reperfusion. Interestingly, wortmannin caused a significant increase in PARP cleavage during reperfusion, but had no effect on caspase-3 activation or the apoptotic index. Our results suggest that p38 has a pro-apoptotic role while JNK phosphorylation is protective in our cell model and that these kinases act via caspase-3 to prevent or promote cell survival in response to SI/R-induced injury.
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PMID:p38 and JNK have distinct regulatory functions on the development of apoptosis during simulated ischaemia and reperfusion in neonatal cardiomyocytes. 1530 13


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