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)

Circadian rhythms in acid phosphatase (ACP), hexosaminidase (HEX) and beta-glucuronidase (RON) activity were studied in the pineal glands of adult male Syrian hamsters exposed to control (20 +/- 2 degrees C and 14:10 LD) conditions or to naturally decreasing autumn photoperiod and temperature conditions (outside) for 8 weeks. Testes and testosterone levels (p less than 0.001 in both instances) were severely depressed in animals exposed to natural environmental conditions illustrating that the treatment period was of sufficient length to produce pineal-mediated gonadal atrophy. Significant rhythms were found in all enzymes in the pineal glands of control and outside animals with the exception of HEX activity in the control animals. Significant acrophase differences in outside vs. control animals were noted in ACP (7.9 hr earlier, p less than 0.001) and RON (9.8 hr later, p less than 0.001). A significant drop in RON and HEX activity (p less than 0.01 in both instances) was noted in association with the acute lights exposure in the morning to which control animals were exposed. The around-the-clock mean value of each enzyme was significantly lower in outside vs. control hamsters. These results demonstrate that environmental changes which provoke the pineal-mediated depression in gonadal activity also alter the activity of and shift the circadian rhythmicity of lysosomal enzymes in the pineal itself.
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PMID:Pineal lysosomal enzyme circadian rhythms in male hamsters exposed to natural decreasing photoperiod and temperature conditions. 214 37

Human platelets contain platelet-derived growth factor (PDGF) in their alpha-granules which is released during platelet exocytosis. We show by immunoprecipitation and 125I-PDGF binding experiments that human platelets have functionally active PDGF alpha-receptors, but not beta-receptors. The PDGF alpha-receptor (PDGFR-alpha) was identified as a 170-kDa glycosylated protein-tyrosine kinase as found in other cell types. Stimulation of platelets with 0.1 unit/ml thrombin resulted in a significant increase (2-5-fold) of the tyrosine phosphorylation of the PDGFR-alpha, as determined by immunoprecipitation with phosphotyrosine antiserum as well as with PDGFR-alpha antiserum. The observed thrombin-induced autophosphorylation of the PDGFR-alpha was inhibited by the addition of a neutralizing monoclonal PDGF antibody. Thus, our results suggest that the platelet PDGFR-alpha is stimulated in an autocrine manner by PDGF secreted during platelet activation. Preincubation of platelets with PDGF inhibited thrombin-induced platelet aggregation and secretion of ATP + ADP and beta-hexosaminidase. Thrombin-induced platelet aggregation was also reversed when PDGF was added 30 s after thrombin stimulation. Inhibition of the autocrine PDGF pathway during platelet activation by the PDGF antibody led to a potentiation of thrombin-induced beta-hexosaminidase secretion. Thus, the PDGFR-alpha takes part in a negative feedback regulation during platelet activation. Our demonstration of PDGF alpha-receptors on human platelets and its inhibitory function during platelet activation identifies a new possible role of PDGF in the regulation of thrombosis.
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PMID:Negative feedback regulation of human platelets via autocrine activation of the platelet-derived growth factor alpha-receptor. 818 64

The activity of N-acetyl-beta-hexosaminidase was found to be significantly higher in the placentas collected after delivery from women in puerperium with symptoms of prolonged pregnancy or complicated by EPH gestosis, than in placentas from normal pregnancy. Isoelectrofocusing of placenta homogenates showed the presence of isoenzymes A, P and B of N-acetyl-beta-hexosaminidase. Different isoenzyme A patterns in homogenates were observed in placentas obtained from normal and prolonged pregnancies and in those complicated by EPH gestosis.
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PMID:Isoenzymes of N-acetyl-beta-hexosaminidase in complicated pregnancy. 1082 68

Aggregation of high-affinity IgE receptor FcepsilonRI induces sequential activation of nonreceptor-type protein-tyrosine kinases and subsequent tyrosine phosphorylation of cellular proteins, leading to degranulation in mast cells. A hematopoietic cell-specific adaptor protein, 3BP2, that was originally identified as an Abl SH3-binding protein was rapidly tyrosine phosphorylated by the aggregation of FcepsilonRI on rat basophilic leukemia RBL-2H3 cells. Tyrosine phosphorylation of 3BP2 did not depend on calcium influx from external sources. To examine the role of 3BP2 in mast cells, we overexpressed the SH2 domain of 3BP2 in the RBL-2H3 cells. Overexpression of 3BP2-SH2 domain resulted in a suppression of antigen-induced degranulation as assessed by beta-hexosaminidase release. Even though overall tyrosine phosphorylation of cellular protein was not altered, antigen-mediated tyrosine phosphorylation of phospholipase C-gamma (PLC-gamma) and calcium mobilization were significantly suppressed in the cells overexpressing the 3BP2-SH2 domain. Furthermore, antigen stimulation induced the association of 3BP2-SH2 domain with LAT and other signaling molecule complexes in the RBL-2H3 cells. FcepsilonRI-mediated phosphorylation of JNK and ERK was not affected by the overexpression of 3BP2-SH2 domain. These data indicate that 3BP2 functions to positively regulate the FcepsilonRI-mediated tyrosine phosphorylation of PLC-gamma and thereby the signals leading to degranulation.
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PMID:Regulation of FcepsilonRI-mediated degranulation by an adaptor protein 3BP2 in rat basophilic leukemia RBL-2H3 cells. 1220 Mar 78

The N-formyl peptide receptor (FPR) is a G protein-coupled chemoattractant receptor that mediates diverse leukocyte functions when stimulated by bacteria-derived N-formyl peptides such as fMet-Leu-Phe (fMLF). Impaired neutrophil responsiveness to fMLF parallels increased susceptibility to periodontal microorganisms among patients with localized juvenile periodontitis (LJP). To determine whether the recently identified FPR mutations in LJP patients are responsible for selective loss of receptor-mediated functions, we prepared and analyzed RBL-2H3 cells expressing FPR bearing Phe110 to Ser (FPR-F110S) or Cys-126 to Trp (FPR-C126W) replacement as well as a FPR double mutant (FPR-FSCW). All mutant receptors were expressed normally on the cell surface, but were unable to mediate release of beta-hexosaminidase upon fMLF stimulation. FPR-C126W effectively mediated fMLF uptake, an indication of receptor-mediated endocytosis, whereas FPR-F110S and FSCW exhibited markedly reduced ability to uptake fMLF. Both FPR-F110S and FPR-C126W were defective in chemotaxis and displayed reduced Ca2+ mobilization, but mutation at both positions partially restored the ability to respond to fMLF in chemotaxis assay and was nearly normal in Ca2+ mobilization assay. All mutants exhibited diminished accumulation of inositol phosphates. FPR-F110S displayed a delayed and significantly reduced ERK phosphorylation whereas FPR-FSCW nearly lost the ability to phosphorylate ERK. Taken together, these results indicate compromised signaling capabilities due to the FPR mutations, but the loss of function is selective and could be partially rescued by mutations at both positions.
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PMID:Normal cell surface expression and selective loss of functions resulting from Phe110 to Ser and Cys126 to Trp substitutions in the formyl peptide receptor. 1519 97

Effects of hyaluronic acid (HA) on allergic inflammation were investigated. HA exerted negative effects on beta-hexoaminidase secretion and histamine release in antigen-stimulated rat basophilic leukemia (RBL2H3) cells. HA inhibited interaction between IgE and FcepsilonRI and between FcepsilonRI and PKCdelta. HA inhibited CD44 interaction with PKCalpha, indicating that HA targets CD44. PKCalpha and -delta were responsible for increased Rac1 activity and expression of p47(phox), p67(phox). HA inhibited phosphorylation of PKCalpha and -delta. Rac1 was responsible for increased ROS, and NADPH oxidase was the main source for ROS. The inhibition of PKC prevented antigen from increasing phosphorylation of ERK and p38 MAPK. ERK, p38 MAPK, and ROS, were responsible for secretion of beta-hexosaminidase, histamine release, and induction of chemokines. HA suppressed induction of chemokines, such as MIP-2 and Sprr-2a. CD44 mediated effect of antigen on phosphorylation of ERK, p38MAPK, ROS production, secretion of beta-hexosaminidase, and histamine release. GPCR did not mediate allergic function of antigen or affect anti-allergic function of HA. In vivo anti-allergic effect of HA was investigated using Nc/Nga mice model of DNFB-induced atopic dermatitis. HA reduced skin lesions in Nc/Nga mice treated with DNFB, decreased expression levels of MIP-2, Sprr-2a, and serum IgE level. In conclusion, hyaluronic acid exerts negative effect on allergic inflammation by targeting CD44 and inhibiting FcepsilonRI signaling.
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PMID:Hyaluronic acid targets CD44 and inhibits FcepsilonRI signaling involving PKCdelta, Rac1, ROS, and MAPK to exert anti-allergic effect. 1828 79

Gain-of-function mutations in the proto-oncogene c-kit have been considered the molecular mechanism of neoplastic proliferation of mast cells. However, the importance of c-kit gene mutations is not well evaluated in canine mast cell tumors (MCTs). In the present study, we established and characterized a mast cell line, HRMC, derived from a dog with MCT. We also examined c-kit mutations in HRMC cells and assessed an inhibitory effect of a tyrosine kinase inhibitor, STI571, on HRMC cells. HRMC cells had cytoplasmic metachromatic granules, chymase and tryptase, and expressed both KIT and FcepsilonRI on the cell surface. HRMC cells contained histamine and released beta-hexosaminidase through FcepsilonRI cross-linking and calcium ionophore stimulation. Nucleotide sequence analysis demonstrated no mutations in an open reading frame of c-kit cDNA and genomic DNA of the juxtamembrane domain of c-kit in HRMC cells. STI571 did not show any inhibitory effects on the proliferation of HRMC cells. These findings clearly demonstrated the existence of c-kit mutations-independent neoplastic canine mast cell proliferation. The growth factor-independent mast cell line established in this study might be valuable to explore novel mechanisms of c-kit mutations-independent neoplastic proliferation of mast cells in dogs.
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PMID:Identification of c-kit mutations-independent neoplastic cell proliferation of canine mast cells. 1868 74

Allergy is an immune dysfunction caused by degranulation from mast cells in the early phase and cytokine secretion in the late phase of the cell. The purpose of this study was to investigate the effects of adlay (Job's tears, Coix lachryma-jobi L. var. ma-yuen Stapf) testa against beta-hexosaminidase release as a marker of degranulation in rat basophilic leukemia (RBL)-2H3 cells. The ethyl acetate fraction from ethanolic extracts of adlay testa (ATE-EtOAc) exhibited potent inhibitory activity that suppressed degranulation from RBL-2H3 cells stimulated by 1 microM A23187. The 20%-80% EtOAc/Hex subfractions of ATE-EtOAc significantly inhibited histamine release with a IC(50) of 75-100 microg/mL. In addition, the ATE-EtOAc subfractions suppressed interleukin (IL)-4, IL-6, and tumor necrosis factor-alpha secretion in RBL-2H3 cells, indicating that adlay testa were able to inhibit cytokine secretion. In order to explore the inhibitory mechanism of adlay testa in mast cell degranulation, we examined the activation of intracellular signaling molecules. Adlay testa inhibited the phosphorylation ERK expression. Furthermore, the two major active compounds, 4-hydroxyacetophenone and p-coumaric acid, were isolated from the ATE-EtOAc subfractions. These results suggest that ATE had an inhibitory effect on allergic response via the ERK signaling transduction in RBL-2H3 cells.
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PMID:Mast cell-dependent allergic responses are inhibited by ethanolic extract of adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) testa. 2010 6

Rab7b is a recently identified member of the Rab GTPase protein family and has high similarity to Rab7. It has been reported that Rab7b is lysosome associated, that it is involved in monocytic differentiation and that it promotes lysosomal degradation of TLR4 and TLR9. Here we investigated further the localization and function of this GTPase. We found that wild-type Rab7b is lysosome associated whereas an activated, GTP-bound form of Rab7b localizes to the Golgi apparatus. In contrast to Rab7, Rab7b is not involved in EGF and EGFR degradation. Depletion of Rab7b or expression of Rab7b T22N, a Rab7b dominant-negative mutant, impairs cathepsin-D maturation and causes increased secretion of hexosaminidase. Moreover, expression of Rab7b T22N or depletion of Rab7b alters TGN46 distribution, cation-independent mannose-6-phosphate receptor (CI-MPR) trafficking, and causes an increase in the levels of the late endosomal markers CI-MPR and cathepsin D. Vesicular stomatitis virus G protein (VSV-G) trafficking, by contrast, is normal in Rab7b-depleted or Rab7b-T22N-expressing cells. In addition, depletion of Rab7b prevents cholera toxin B-subunit from reaching the Golgi. Altogether, these data indicate that Rab7b is required for normal lysosome function, and, in particular, that it is an essential factor for retrograde transport from endosomes to the trans-Golgi network (TGN).
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PMID:Rab7b controls trafficking from endosomes to the TGN. 2037 62

Smokers are less likely to develop some inflammatory and allergic diseases. In Brown-Norway rats, nicotine inhibits several parameters of allergic asthma, including the production of Th2 cytokines and the cysteinyl leukotriene LTC(4). Cysteinyl leukotrienes are primarily produced by mast cells, and these cells play a central role in allergic asthma. Mast cells express a high-affinity receptor for IgE (FcepsilonRI). Following its cross-linking, cells degranulate and release preformed inflammatory mediators (early phase) and synthesize and secrete cytokines/chemokines and leukotrienes (late phase). The mechanism by which nicotine modulates mast cell activation is unclear. Using alpha-bungarotoxin binding and quantitative PCR and PCR product sequencing, we showed that the rat mast/basophil cell line RBL-2H3 expresses nicotinic acetylcholine receptors (nAChRs) alpha7, alpha9, and alpha10; exposure to exceedingly low concentrations of nicotine (nanomolar), but not the biologically inactive metabolite cotinine, for > or = 8 h suppressed the late phase (leukotriene/cytokine production) but not degranulation (histamine and hexosaminidase release). These effects were unrelated to those of nicotine on intracellular free calcium concentration but were causally associated with the inhibition of cytosolic phospholipase A(2) activity and the PI3K/ERK/NF-kappaB pathway, including phosphorylation of Akt and ERK and nuclear translocation of NF-kappaB. The suppressive effect of nicotine on the late-phase response was blocked by the alpha7/alpha9-nAChR antagonists methyllycaconitine and alpha-bungarotoxin, as well as by small interfering RNA knockdown of alpha7-, alpha9-, or alpha10-nAChRs, suggesting a functional interaction between alpha7-, alpha9-, and alpha10-nAChRs that might explain the response of RBL cells to nanomolar concentrations of nicotine. This "hybrid" receptor might serve as a target for novel antiallergic/antiasthmatic therapies.
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PMID:Nicotine inhibits Fc epsilon RI-induced cysteinyl leukotrienes and cytokine production without affecting mast cell degranulation through alpha 7/alpha 9/alpha 10-nicotinic receptors. 2050 47


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