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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Of the four major subtypes of lung cancer, three subtypes, namely squamous cell lung carcinomas, adenocarcinomas and large cell carcinomas are usually combined within the larger group of non-small cell lung carcinomas (NSCLC). However, the heterogeneity that exists within any given tumor has also been clearly demonstrated. In order to study whether or not the protein expression profile is different in the histological subtypes of NSCLC, the expression of several parameters including proto-oncogene and suppressor gene products, proliferative, apoptotic, angiogenic and resistance factors was evaluated immunohistochemically in 139 NSCLC (45 adenocarcinomas and 94 squamous cell lung carcinomas). In both histological subtypes the percentage of positively-stained parameters was determined. The expression of the proteins ERBB2, JUN, RAS and tissue factor was significantly higher in adenocarcinomas compared to squamous cell lung carcinomas. In contrast, all resistance proteins analyzed were more frequently expressed in squamous cell lung carcinomas in comparison to adenocarcinomas, though only GST-pi reached statistical significance. Apoptotic factors and angiogenic factors were higher in adenocarcinomas, but these differences did not reach statistical significance. In conclusion, the protein expression profiles of adenocarcinomas and squamous cell carcinomas differ from each other. Squamous cell lung carcinomas in comparison to adenocarcinomas are characterized by a down-regulation of some oncogenes and an up-regulation of several resistance factors. These findings could explain the different biological behaviour and treatment response of these tumours.
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PMID:Protein expression profiles of non-small cell lung carcinomas: correlation with histological subtype. 1217 21

Many drugs and xenobiotics induce signal transduction events leading to gene expression of either pharmacologically beneficial effects, or unwanted side effects such as cytotoxicity which can compromise drug therapy. Using dietary chemopreventive compounds (isothiocyanates and green tea polyphenols), which are effective against various chemically-induced carcinogenesis models in animals studies, we studied the signal transduction events and gene expression profiles. These compounds have typically generated cellular "oxidative stress" and modulated gene expression including phase II detoxifying enzymes GST and QR as well as cellular defensive enzymes, heme oxygenase 1 (HO-1) and GST via the antioxidant/electrophile response element (ARE/EpRE). Members of the bZIP transcription factor, Nrf2 which heterodimerizes with Maf G/K, were found to bind to ARE, and transcriptionally activate ARE. Additionally the mitogen-activated protein kinases (MAPK; ERK, JNK and p38) were differentially activated by these compounds, and involved in the transcriptional activation of ARE-mediated reporter gene. Transfection studies with various cDNA encoding for wild-type of MAPK and Nrf2 showed synergistic response during co-transfection and to these agents. However, by increasing the concentrations of these xenobiotics, caspase activities and apoptosis were observed which were preceded by mitochondria damage and cytochrome c mitochondria release. Further, increased concentrations led to rapid cell necrosis. [corrected] Thus, we have proposed a model, that at low concentrations, these compounds activate MAPK pathway leading to activation of Nrf2 and ARE with subsequent induction of phase II and other defensive genes which protect cells against toxic insults thereby enhancing cell survival, a beneficial homeostatic response. At higher concentrations, these agents activate the caspase pathways, leading to apoptosis, a potential cytotoxic effect if it occurred in normal cells. The studies of these signaling pathways may yield important insights into the pharmacodynamic and toxicodynamic effects of drugs and xenobiotics during pharmaceutical drug discovery and development.
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PMID:Antioxidants and oxidants regulated signal transduction pathways. 1221 68

In Triton-skinned phasic ileal smooth muscle, constitutively active recombinant p21-activated kinase (PAK3) has been shown to induce Ca(2+)-independent contraction, which is accompanied by phosphorylation of caldesmon and desmin (Van Eyk JE, Arrell DK, Foster DB, Strauss JD, Heinonen TY, Furmaniak-Kazmierczak E, Cote GP, and Mak AS. J Biol Chem 273: 23433-23439, 1998). In the present study, we investigated whether PAK has a broad impact on smooth muscle in general by testing the hypothesis that PAK induces Ca(2+)-independent contractions and/or Ca(2+) sensitization in tonic airway smooth muscle and that the process is mediated via phosphorylation of caldesmon. In the absence of Ca(2+) (pCa > 9), constitutively active glutathione-S-transferase-murine PAK3 (GST-mPAK3) caused force generation of Triton-skinned canine tracheal smooth muscle (TSM) fibers to approximately 40% of the maximal force generated by Ca(2+) at pCa 4.4. In addition, GST-mPAK3 enhanced Ca(2+) sensitivity of contraction by increasing force generation by 80% at intermediate Ca(2+) concentrations (pCa 6.2), whereas it had no effect at pCa 4.4. Catalytically inactive GST-mPAK3(K297R) had no effect on force production. Using antibody against one of the PAK-phosphorylated sites (Ser(657)) on caldesmon, we showed that a basal level of phosphorylation of caldesmon occurs at this site in skinned TSM and that PAK-induced contraction was accompanied by a significant increase in the level of phosphorylation. Western blot analyses show that PAK1 is the predominant PAK isoform expressed in murine, rat, canine, and porcine TSM. We conclude that PAK causes Ca(2+)-independent contractions and produces Ca(2+) sensitization of skinned phasic and tonic smooth muscle, which involves an incremental increase in caldesmon phosphorylation.
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PMID:Calcium-independent contraction and sensitization of airway smooth muscle by p21-activated protein kinase. 1251 68

In a previous study (Shin, E. Y., Shin, K. S., Lee, C. S., Woo, K. N., Quan, S. H., Soung, N. K., Kim, Y. G., Cha, C. I., Kim, S. R., Park, D., Bokoch, G. M., and Kim, E. G. (2002) J. Biol. Chem. 277, 44417-44430) we reported that phosphorylation of p85 betaPIX, a guanine nucleotide exchange factor (GEF) for Rac1/Cdc42, is a signal for translocation of the PIX complex to neuronal growth cones and is associated with basic fibroblast growth factor (bFGF)-induced neurite outgrowth. However, the issue of whether p85 betaPIX phosphorylation affects GEF activity on Rac1/Cdc42 is yet to be explored. Here we show that Rac1 activation occurs in a p85 betaPIX phosphorylation-dependent manner. A GST-PBD binding assay reveals that Rac1 is activated in a dose- and time-dependent manner in PC12 cells in response to bFGF. Inhibition of ERK or PAK2, the kinases upstream of p85 betaPIX in the bFGF signaling, prevents Rac1 activation, suggesting that phosphorylation of p85 betaPIX functions upstream of Rac1 activation. To directly address this issue, transfection studies with wild-type and mutant p85 betaPIX (S525A/T526A, a non-phosphorylatable form) were performed. Expression of mutant PIX markedly inhibits both bFGF- and nerve growth factor (NGF)-induced activation of Rac1, indicating that phosphorylation of p85 betaPIX is responsible for activation of this G protein. Both wild-type and mutant p85 betaPIX displaying negative GEF activity (L238R/L239S) are similarly recruited to growth cones, suggesting that Rac1 activation is not essential for translocation of the PIX complex (PAK2-p85 betaPIX-Rac1). However, expression of mutant p85 betaPIX (L238R/L239S) results in retraction of the pre-existing neurites. Our results provide evidence that bFGF- and NGF-induced phosphorylation of p85 betaPIX mediates Rac1 activation, which in turn regulates cytoskeletal reorganization at growth cones, but not translocation of the PIX complex.
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PMID:Basic fibroblast growth factor stimulates activation of Rac1 through a p85 betaPIX phosphorylation-dependent pathway. 1455 70

Kinase Suppressor of Ras1 (KSR1) functions as a positive modulator of Ras-dependent signaling either upstream of or parallel to Raf-1, and pharmacologic inactivation of KSR1 may serve as a treatment for Rasdriven malignancies such as pancreatic cancer (Xing, H. R., Cordon-Cardo, C., Deng, X., Tong, W., Campodonico, L., Fuks, Z., and Kolesnick, R. (2003) Nat. Med. 9, 1266-1268). Although some studies demonstrated a requirement for KSR1 kinase activity for its action, others suggested KSR1 acts primarily as a scaffold facilitating assembly of the c-Raf-1/MEK module. We recently established a two-stage in vitro reconstitution assay to measure KSR1 kinase activity (Xing, H. R., Lozano, J., and Kolesnick, R. (2000) J. Biol. Chem. 275, 17276-17280). In this assay, KSR1, immunopurified to apparent homogeneity, never comes in contact with recombinant kinases other than c-Raf-1. In the first assay stage, activated KSR1 is incubated with recombinant c-Raf-1 and ATP. In the second stage, activated c-Raf-1 is separated from KSR1, and incubated with unactivated MEK1, unactivated MAPK, Elk-1, and ATP. Elk-1 phosphorylation serves as a specific readout for MAPK activation. However, because KSR1 constitutively associates with MEK1 and this interaction appears critical for KSR1 scaffolding function, it has been argued that the kinase activity detected is an artifact of KSR1-bound MEK1. To address these concerns, we depleted as much as 90% of KSR1-bound MEK1 by high salt washing without altering KSR1 kinase activity. Further, a complete inactivation of KSR1-bound MEK1 by pretreating with the MEK inhibitor PD 98059 prior to the first assay stage did not alter KSR1 kinase activity. In addition, the omission of exogenous recombinant GST-MEK1 from the reaction mixture during the second assay stage abolished Elk-1 phosphorylation confirming KSR1-bound MEK1 does not support MAPK activation in our in vitro assay. Moreover, a kinase-inactive mutant, FLAG-Ki-KSR1(D683A/D700A), which efficiently interacts with endogenous MEK1, lacks kinase activity. These results collectively support our contention that the kinase activity of KSR1 is an intrinsic property of this protein independent of KSR1-bound endogenous MEK.
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PMID:The kinase activity of kinase suppressor of Ras1 (KSR1) is independent of bound MEK. 2427 36

The soluble HLA-G1 (sHLA-G1) isoform was found to be secreted by trophoblast cells at the materno-fetal interface, which suggests that it may act as an immunomodulator during pregnancy. In this paper, we reported that GST-sHLA-G1a chain could bind to its receptor ILT-2 on NK92 cells and then the latter recruited Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1), which consequently dephosphorylated some important protein tyrosine kinases and blocked the activation of downstream molecules such as MEK and ERK so that the cytotoxicity of natural killer (NK) cells was inhibited. These results indicated that GST-sHLA-G1a chain might be exploited in new immunotherapy strategies aiming at inducing immunotolerance during allograft, xenograft and autoimmune situations. In addition, we found that modification of O-linked b-N-acetylglucosamine (O-GlcNAc) was involved in NK cells' activating and inhibitory signals. This may provide a novel molecular target for inducing immunotolerance but needs further study.
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PMID:Inhibition of the activating signals in NK92 cells by recombinant GST-sHLA-G1a chain. 1511 17

We examined the impact of purified bacterially synthesized GST-MDA-7 (IL-24) and ionizing radiation on the proliferation and survival of nonestablished human glioblastoma multiforme (GBM) cells. Glioma cell types expressing mutated PTEN and p53 molecules, activated ERBB1VIII, overexpressing wild type ERBB1 or without receptor overexpression were selected. In MTT assays, GST-MDA-7 caused a dose-dependent reduction in the proliferation of nonestablished glioma cells; however only at higher concentrations did GST-MDA-7 reduce cell viability. The anti-proliferative and cytotoxic effects of GST-MDA-7 were enhanced by radiation in a greater than additive fashion that correlated with JNK1/2/3 activation. The reduction in cell growth and enhancement in cell killing by the combination of GST-MDA-7 and radiation were blocked by an ROS scavenger, N-acetyl cysteine (NAC), a JNK1/2/3 inhibitor SP600125, a pan-caspase inhibitor (zVAD) and by an inhibitor of caspase 9 (LEHD), but not by an inhibitor of caspase 8 (IETD). Low concentrations of either GST-MDA-7 or radiation reduced clonogenic survival, however colony formation ability was significantly further decreased when the two treatments were combined, which was also blocked by inhibition of caspase 9 function. In general agreement with activation of the intrinsic caspase pathway, cell death correlated with reduced BCL-XL expression and with increased levels of the pro-apoptotic proteins BAD and BAX. Inhibition of caspase 9 after combination treatment blunted neither JNK1/2/3 activation nor the enhanced expression of BAD and BAX, but did block caspase 3 cleavage, reduced expression of BCL-XL and inhibition of ERK1/2 activity. In contrast, incubation with NAC blocked JNK1/2/3 activation and cell killing, but not the increases in BAD and BAX expression. These findings argue that after combination treatment JNK1/2/3 activation is a primary pro-apoptotic event and loss of BCL-XL expression and ERK1/2 activity are secondary caspase-dependent processes. This data also argues that GST- MDA-7 induces two parallel pro-apoptotic pathways via ROS-dependent and -independent mechanisms. Infection of primary human astrocytes with a recombinant adenovirus to express MDA-7, Ad.mda-7, but not infection with either Ad.cmv or Ad.mda-7SP- lacking MDA-7 secretion, resulted in the suppression of GBM cell colony formation in soft agar overlay assays, an effect that was enhanced in a greater than additive fashion by radiation. Collectively, our findings demonstrate that MDA-7 reduces proliferation and enhances the radiosensitivity of nonestablished human GBM cells in vitro, and when grown in 3 dimensions, and that sensitization occurs independently of basal EGFR/ERK1/2/AKT activity or the functions of PTEN and p53.
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PMID:MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells. 1532 89

In mammalian systems, detoxification enzymes of the GST (glutathione S-transferase) family regulate JNK (c-Jun N-terminal kinase) signal transduction by interaction with JNK itself or other proteins upstream in the JNK pathway. In the present study, we have studied GSTs and their interaction with components of the JNK pathway from Diptera. We have evaluated the effects of four Delta class Anopheles dirus GSTs, GSTD1-1, GSTD2-2, GSTD3-3 and GSTD4-4, on the activity of full-length recombinant Drosophila HEP (mitogen-activated protein kinase kinase 7; where HEP stands for hemipterous) and the Drosophila JNK, as well as the reciprocal effect of these kinases on GST activity. Interestingly, even though these four GSTs are alternatively spliced products of the same gene and share >60% identity, they exerted different effects on JNK activity. GSTD1-1 inhibited JNK activity, whereas the other three GST isoforms activated JNK. GSTD2-2, GSTD3-3 and GSTD4-4 were inhibited 50-80% by HEP or JNK but GSTD1-1 was not inhibited by JNK. However, there were some similarities in the actions of HEP and JNK on these GSTs. For example, binding constants for HEP or JNK inhibiting a GST were similar (20-70 nM). Furthermore, after incubation of the GSTs with JNK, both JNK and the GSTs changed catalytic properties. The substrate specificities of both GSTs and JNK were also altered after their co-incubation. In addition, glutathione modulated the effects of JNK on GST activity. These results emphasize that different GST spliceforms possess different properties, both in their catalytic function and in their regulation of signalling through the JNK pathway.
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PMID:Reciprocal regulation of glutathione S-transferase spliceforms and the Drosophila c-Jun N-terminal kinase pathway components. 1525 Aug 26

Cbl proteins are ubiquitin protein ligases, which ubiquitinate activated tyrosine kinases and target them for degradation. Both c-Cbl and Cbl-b have an ubiquitin associated (UBA) domain at their C-terminal end. We observed that high molecular weight ubiquitinated proteins constitutively coimmunoprecipitated with transfected and endogenous Cbl-b, but not c-Cbl. The binding site for these ubiquitinated proteins was mapped to the UBA domain of Cbl-b (UBAb). GST-fusion proteins containing the UBAb interacted with ubiquitinated proteins and polyubiquitin chains in vitro, whereas those containing the UBA domain of c-Cbl (UBAc) did not. The UBAb had a much greater affinity for polyubiquitin chains than for monoubiquitin. Analysis of the UBAb and UBAc demonstrate that the affinity for ubiquitin is determined by multiple amino-acid differences between the two domains. Overexpression of the UBAb, but not overexpression of the UBAc, inhibited a variety of ubiquitin-mediated processes such as degradation of ubiquitinated proteins (i.e. EGFR, Mdm-2, and Siah-1). This in vivo result is consistent with the differences in ubiquitin binding observed in vitro between the UBAb and UBAc. This difference in ubiquitin-binding may reflect distinct regulatory functions of c-Cbl and Cbl-b.
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PMID:Cbl-b interacts with ubiquitinated proteins; differential functions of the UBA domains of c-Cbl and Cbl-b. 1527 20

Infection with lesion-derived Leishmania mexicana amastigotes inhibited LPS-induced IL-12 production by mouse bone marrow-derived macrophages. This effect was associated with expression of cysteine peptidase B (CPB) because amastigotes of CPB deletion mutants had limited ability to inhibit IL-12 production, whereas preincubation of cells with a CPB inhibitor, cathepsin inhibitor IV, was able to suppress the effect of wild-type amastigotes. Infection with wild-type amastigotes resulted in a time-dependent proteolytic degradation of IkappaBalpha and IkappaBbeta and the related protein NF-kappaB. This effect did not occur with amastigotes of CPB deletion mutants or wild-type promastigotes, which do not express detectable CPB. NF-kappaB DNA binding was also inhibited by amastigote infection, although nuclear translocation of cleaved fragments of p65 NF-kappaB was still observed. Cysteine peptidase inhibitors prevented IkappaBalpha, IkappaBbeta, and NF-kappaB degradation induced by amastigotes, and recombinant CPB2.8, an amastigote-specific isoenzyme of CPB, was shown to degrade GST-IkappaBalpha in vitro. LPS-mediated IkappaBalpha and IkappaBbeta degradation was not affected by these inhibitors, confirming that the site of degradation of IkappaBalpha, IkappaBbeta, and NF-kappaB by the amastigotes was not receptor-driven, proteosomal-mediated cleavage. Infection of bone marrow macrophages with amastigotes resulted in cleavage of JNK and ERK, but not p38 MAPK, whereas preincubation with a cysteine peptidase inhibitor prevented degradation of these proteins, but did not result in enhanced protein kinase activation. Collectively, our results suggest that the amastigote-specific cysteine peptidases of L. mexicana are central to the ability of the parasite to modulate signaling via NF-kappaB and consequently inhibit IL-12 production.
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PMID:Inhibition of lipopolysaccharide-induced macrophage IL-12 production by Leishmania mexicana amastigotes: the role of cysteine peptidases and the NF-kappaB signaling pathway. 1532 92


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