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)

To study the roles of substance P and endogenous neutral endopeptidase in mediating cough, we measured cough responses in awake guinea pigs in response to exogenous substance P and capsaicin aerosols in the presence and absence of the neutral endopeptidase inhibitors leucine-thiorphan and phosphoramidon. Substance P stimulated cough in very low concentrations (10(-17)-10(-16) M). In a second study where the investigator did not know whether substance P or diluent alone was aerosolized, substance P (10(-16) M) caused cough. Leucine-thiorphan (10(-5) M) and phosphoramidon (10(-5) M) potentiated substance P-induced cough; NEP inhibitors also potentiated capsaicin-induced cough significantly. These findings suggest that substance P is a potent stimulator of cough responses, that capsaicin-induced cough is mediated by substance P or another similar neuropeptide, and that cough responses are modulated by endogenous neutral endopeptidase.
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PMID:Neutral endopeptidase inhibitors potentiate substance P- and capsaicin-induced cough in awake guinea pigs. 246 67

Pasteurella multocida produces a 146-kDa protein toxin (PMT), which activates multiple cellular signal-transduction pathways, resulting in the activation of PLCbeta, Rho, JNK, and ERK. In addition to an essential cysteine residue at position 1165, PMT contains several histidine residues in the catalytically important C-terminal part of the protein. To elucidate the role of the histidine residues, we treated PMT with the histidine-modifying substance diethyl pyrocarbonate (DEPC). DEPC inhibited PMT in a time- and concentration-dependent manner, suggesting that one or several histidine residues are essential for the biological activity of PMT. In experiments in which PMT was directly delivered into the cytosol of EBL cells by electroporation, we show that DEPC treatment inhibits the catalytically important histidine residues. Leucine substitutions of eight individual histidine residues in the C-terminal catalytic domain of PMT were constructed, and the effect on the biological activity of PMT was analyzed by determining PLCbeta, Rho, and ERK activation. Substitution of two histidine residues, H1205 and H1223, led to inactivation of the resulting PMT proteins, indicating that H1205 and H1223 play an important role in biological activity of the toxin. In addition, we show that the mutant toxins appear to be correctly folded, as judged by protease digestion. The precise function of H1205 and H1223 is not yet known. However, treatment of PMT with the cation chelating substance 1,10-phenantroline led to inactivation of the toxin, indicating that the essential histidine residues and cysteine 1165 might be involved in metal ion binding.
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PMID:His1205 and His1223 are essential for the activity of the mitogenic Pasteurella multocida toxin. 1271 39

The transmembrane protein Kekkon 1 (Kek1) has previously been shown to act in a negative feedback loop to downregulate the Drosophila Epidermal Growth Factor Receptor (DER) during oogenesis. We show that this protein plays a similar role in other DER-mediated developmental processes. Structure-function analysis reveals that the extracellular Leucine-Rich Repeat (LRR) domains of Kek1 are critical for its function through direct association with DER, whereas its cytoplasmic domain is required for apical subcellular localization. In addition, the use of chimeric proteins between Kek1 extracellular and transmembrane domains fused to DER intracellular domain indicates that Kek1 forms an heterodimer with DER in vivo. To characterize more precisely the mechanism underlying the Kek1/DER interaction, we used mammalian ErbB/EGFR cell-based assays. We show that Kek1 is capable of physically interacting with each of the known members of the mammalian ErbB receptor family and that the Kek1/EGFR interaction inhibits growth factor binding, receptor autophosphorylation and Erk1/2 activation in response to EGF. Finally, in vivo experiments show that Kek1 expression potently suppresses the growth of mouse mammary tumor cells derived from aberrant ErbB receptors activation, but does not interfere with the growth of tumor cells derived from activated Ras. Our results underscore the possibility that Kek1 may be used experimentally to inhibit ErbB receptors and point to the possibility that, as yet uncharacterized, mammalian transmembrane LRR proteins might act as modulators of growth factor signalling.
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PMID:Mechanism of inhibition of the Drosophila and mammalian EGF receptors by the transmembrane protein Kekkon 1. 1290 Apr 63

An evolutionary recombination hotspot around the GSDML-GSDM locus at human chromosome 17q21 is closely linked to an oncogenomic recombination hotspot around the PPP1R1B-STARD3-TCAP-PNMT-PERLD1 (MGC9753)-ERBB2-C17orf37 (MGC14832)-GRB7 locus at human chromosome 17q12. Here, we identified DFNA5L (GSDMDC1) gene related to GSDM and GSDML genes by using bioinformatics. Human DFNA5L gene at chromosome 8q24.3 was linked to ZC3HDC3, PP3856, EEF1D, and TIGD5 genes. NM_024736.4 (AK127941.1), AK022212.1, BC008904.2, and BC069000.1 cDNAs were derived from human DFNA5L gene. BC008904.2 was the representative human DFNA5L cDNA, while NM_024736.4 was an aberrant human DFNA5L cDNA with frame shifts due to the retention of introns 1, 3, 4, 5 and 8. Human DFNA5L mRNA was expressed in placenta, pancreatic cancer, prostate cancer, melanoma, salivary gland tumor, Jarkat T cells, and Ramos B cells. Complete coding sequence of rat Dfna5l cDNA was determined by assembling 11 exons of rat Dfna5l gene within AC120830.4 genome sequence, and that of mouse Dfna5l cDNA was derived from 1810036L03 (NM_026960.1). Exon-intron boundaries were conserved among human DFNA5L and rodent Dfna5l genes. Human DFNA5L (484 aa) showed 59.5% total-amino-acid identity with rat Dfna5l (488 aa), and 58.7% total-amino-acid identity with mouse Dfna5l (487 aa). DFNA5L orthologs were DNFA5 (GSDM) domain containing DFNA5 DC or GSDMDC proteins with Coiled-coil and Leucine zipper domains. Human DFNA5L, GSDM, GSDML, MLZE, DFNA5 and their mammalian orthologs were found to constitute the DFNA5 DC (GSDMDC) family. Because DFNA5 and MLZE are cancer-associated genes, DFNA5L, GSDM, and GSDML are predicted cancer associated genes.
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PMID:Identification and characterization of human DFNA5L, mouse Dfna5l, and rat Dfna5l genes in silico. 1528 81

DACT1 (DAPPER1), Frizzled receptors, MUSK receptor, VANGL1, VANGL2, PRICKLE1, PRICKLE2, DAAM1, Casein kinases, MARK3 (PAR1), PP2C, AXIN1, AXIN2, NKD1, NKD2, FRAT1, FRAT2 and CXXC4 are WNT signaling molecules associating with Dishevelled family proteins. Human DACT1 is the ortholog of Xenopus Dapper and Frodo, and human DACT2 (DAPPER2) is the paralog of human DACT1. Here, we identified and characterized rat Dact1 (Dapper1) and Dact2 (Dapper2) genes by using bioinformatics. Rat Dact1 gene, consisting of four exons, was located within AC136677.3 genome sequence. Rat Dact2 gene, consisting of four exons, was located within AC139434.3 genome sequence. Dact1 was mapped to rat chromosome 6q24, and Dact2 gene to rat chromosome 1q12. Rat Dact1 (778 aa) showed 93.7, 82.9, 60.3, 58.7 and 48.6% total-amino-acid identity with mouse Dact1, human DACT1, Xenopus Dapper, Xenopus Frodo and zebrafish dact1, respectively. Rat Dact2 (768 aa) showed 86.6, 59.6 and 38.3% total-amino-acid identity with mouse Dact2, human DACT2 and zebrafish dact2, respectively. Dact1 orthologs were more evolutionarily conserved than Dact2 orthologs. Seven DAPH domains (DAPH1-DAPH7), originally identified as the regions conserved between human DACT1 and DACT2, were conserved among mammalian Dact1 orthologs and Dact2 orthologs. DAPH2 domain, corresponding to the Leucine zipper motif, was located within the coiled-coil region. DAPH3 domain was the Serine rich region. DAPH7 domain was the C-terminal PDZ binding region. This is the first report on the rat Dact1 and Dact2 genes.
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PMID:Identification and characterization of rat Dact1 and Dact2 genes in silico. 1587 Sep 12

The essential amino acid leucine has been described to specifically activate signaling pathways leading to the activation of the translational machinery and the increase of total protein synthesis. Regulation of type I collagen production by hepatic stellate cells (HSC) is a multistep process involving transcriptional and post-transcriptional mechanisms. In the present work we studied the effect of leucine on translation regulation of collagen alpha1(I) production in HSC and the signaling pathways involved. Treatment of HSC with 5 mM leucine did not alter half-life or steady state levels of procollagen alpha1(I) mRNA, but caused an increase in procollagen alpha1(I) protein that correlated with changes of components involved in translational regulation, like enhanced 4E-BP1, Mnk-1, and eIF4E phosphorylation. Leucine also induced mTOR, ERK, and Akt phosphorylation in HSC, without affecting p38 and JNK activation. Pre-treatment of HSC with PD098059, wortmannin, or rapamycin prevented the profibrogenic action of leucine due to the inhibition of different molecular mechanisms. These results suggest leucine is a profibrogenic agent for HSC, activating signaling pathways that lead to an enhancement of collagen alpha1(I) production through translational regulation.
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PMID:Leucine stimulates procollagen alpha1(I) translation on hepatic stellate cells through ERK and PI3K/Akt/mTOR activation. 1689 53

Leucine-rich repeats (LRRs) are 20-29-aa motifs that mediate protein-protein interactions and are present in a variety of membrane and cytoplasmic proteins. Many LRR proteins with neuronal functions have been reported. Here, we summarize an emerging group of synaptic LRR proteins, which includes densin-180, Erbin, NGL, SALM, and LGI1. These proteins have been implicated in the formation, differentiation, maintenance, and plasticity of neuronal synapses.
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PMID:Leucine-rich repeat proteins of synapses. 1747 52

Leucine-rich repeat C4 (LRRC4) has been shown to inhibit glioma cell proliferation, however, little is known about the mechanism(s) underlying the action of LRRC4. Here, we show that two glioblstoma U251 cell clones stably expressing LRRC4 were established. LRRC4 expression significantly inhibited the expression of some cytokines and their receptors determined by microarray and Western blot assays, and dramatically reduced cytokine-induced AP-1, NF-kB, and CyclinD1 activation in glioma cells. Furthermore, LRRC4 expression in glioma cells significantly downregulated spontaneous and cytokine-induced expression of K-RAS and phosphorylation of c-Raf, ERK, AKT, NF-kBp65, p70S6K, and PKC, suggesting that LRRC4 inhibited receptor tyrosine kinase (RTK) signaling pathways. Moreover, treatment with bFGF, IGF1, or IGF2 stimulated LRRC4(-/-), but not the LRRC4(+), glioma cell proliferation, indicating that LRRC4 mitigated cytokine-stimulated proliferation in glioma cells. In addition, treatment of LRRC4(-/-) glioma cells with EGF, IGF2, or PDGF promoted long distance mobilization, but induced little migration in LRRC4(+) glioma cells, suggesting that LRRC4 retarded cytokine-promoted glioma cell migration in vitro. Finally, human vessel endothelial cells (ECV304) treated with VEGF grew, aligned and formed hollow tube-like structures in vitro. In contrast, LRRC4(+) ECV304 treated with VEGF failed to form vessel-tube structures. Collectively, LRRC4 expression inhibited the expression of some growth factors, cytokines and their receptors, and the capacity of glioma cells responding to cytokine stimulation, leading to inhibition of glioma cell proliferation. Conceivably, induction of LRRC4 expression may provide new intervention for human glioma in the clinic.
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PMID:LRRC4 inhibits glioblastoma cell proliferation, migration, and angiogenesis by downregulating pleiotropic cytokine expression and responses. 1754 39

Gliomas take a number of different genetic routes in the progression to glioblastoma multiforme, a highly invasive variant that is mostly unresponsive to current therapies. The alpha-chemokine stromal cell-derived factor (SDF)-1 alpha binds to the seven transmembrane G-protein-coupled CXCR-4 receptor and acts to modulate cell migration and proliferation by activating multiple signal transduction pathways. Leucine-rich repeats containing 4 (LRRC4), a putative glioma suppressive gene, inhibits glioblastoma cells tumorigenesis in vivo and cell proliferation and invasion in vitro. We also previously demonstrated that LRRC4 controlled glioblastoma cells proliferation by ERK/AKT/NF-kappa B signaling pathway. In the present study, we demonstrate that CXC chemokine receptor 4 (CXCR4) is expressed in human glioblastoma U251 cell line, and that SDF-1 alpha increases the proliferation, chemotaxis, and invasion in CXCR4+ glioblastoma U251 cells through the activation of ERK1/2 and Akt. The reintroduction of LRRC4 in U251 cells inhibits the expression of CXCR4 and SDF-1 alpha/CXCR4 axis-mediated downstream intracellular pathways such as ERK1/2 and Akt leading to proliferate, chemotactic and invasive effects. Furthermore, we provide evidence for proMMP-2 activation involvement in the SDF-1 alpha/CXCR4 axis-mediated signaling pathway. LRRC4 significantly inhibits proMMP-2 activation by SDF-1 alpha/CXCR4 axis-mediated ERK1/2 and Akt signaling pathway. Collectively, these results suggest a possible important "cross-talk" between LRRC4 and SDF-1 alpha/CXCR4 axis-mediated intracellular pathways that can link signals of cell proliferation, chemotaxis and invasion in glioblastoma, and may represent a new target for development of new therapeutic strategies in glioma.
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PMID:LRRC4 inhibits human glioblastoma cells proliferation, invasion, and proMMP-2 activation by reducing SDF-1 alpha/CXCR4-mediated ERK1/2 and Akt signaling pathways. 1754 98

The amino acid leucine causes an increase of collagen alpha1(I) synthesis in hepatic stellate cells through the activation of translational regulatory mechanisms and PI3K/Akt/mTOR and ERK signaling pathways. The aim of the present study was to evaluate the role played by reactive oxygen species on these effects. Intracellular reactive oxygen species levels were increased in hepatic stellate cells incubated with leucine 5 mM at early time points, and this effect was abolished by pretreatment with the antioxidant glutathione. Preincubation with glutathione also prevented 4E-BP1, eIF4E and Mnk-1 phosphorylation induced by leucine, as well as enhancement of procollagen alpha1(I) protein levels. Inhibitors for MEK-1 (PD98059), PI3K (wortmannin) or mTOR (rapamycin) did not affect leucine-induced reactive oxygen species production. However, preincubation with glutathione prevented ERK, Akt and mTOR phosphorylation caused by treatment with leucine. The mitochondrial electron chain inhibitor rotenone and the NADPH oxidase inhibitor apocynin prevented reactive oxygen species production caused by leucine. Leucine also induced an increased phosphorylation of IR/IGF-R that was abolished by pretreatment with either rotenone or apocynin. Therefore, leucine exerts on hepatic stellate cells a prooxidant action through NADPH oxidase and mitochondrial Reactive oxygen species production and these effects mediate the activation of IR/IGF-IR and signaling pathways, finally leading to changes in translational regulation of collagen synthesis.
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PMID:Reactive oxygen species (ROS) mediate the effects of leucine on translation regulation and type I collagen production in hepatic stellate cells. 1770 24


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