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)

Recent clinical data indicates that the emergence of mutant drug-resistant kinase alleles may be particularly relevant for targeted kinase inhibitors. In order to explore how different classes of targeted therapies impact upon resistance mutations, we performed EGFR (epidermal-growth-factor receptor) resistance mutation screens with erlotinib, lapatinib and CI-1033. Distinct mutation spectra were generated with each inhibitor and were reflective of their respective mechanisms of action. Lapatinib yielded the widest variety of mutations, whereas mutational variability was lower in the erlotinib and CI-1033 screens. Lapatinib was uniquely sensitive to mutations of residues located deep within the selectivity pocket, whereas mutation of either Gly(796) or Cys(797) resulted in a dramatic loss of CI-1033 potency. The clinically observed T790M mutation was common to all inhibitors, but occurred with varying frequencies. Importantly, the presence of C797S with T790M in the same EGFR allele conferred complete resistance to erlotinib, lapatinib and CI-1033. The combination of erlotinib and CI-1033 effectively reduced the number of drug-resistant clones, suggesting a possible clinical strategy to overcome drug resistance. Interestingly, our results also indicate that co-expression of ErbB2 (v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2) has an impact upon the EGFR resistance mutations obtained, suggesting that ErbB2 may play an active role in the acquisition of drug-resistant mutations.
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PMID:Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations. 1858 8

Metabolic demand for sulfur-containing AA increases during inflammation in nonruminants. Therefore, Met supplementation may alleviate the negative effects of infection on N balance. Effects of gram-negative bacterial lipopolysaccharide (LPS) and supplemental dietary Met on N balance, serum hormones and haptoglobin, and plasma urea-N and AA were evaluated in 20 Angus-cross steers (BW = 262 +/- 6.3 kg). Treatments (2 x 2 factorial) were infusion of no LPS (-LPS) or a prolonged low dose of LPS (+LPS) and dietary supplementation of no (-MET) or 14 g/d (+MET) of rumen-protected Met (providing 7.9 g/d of dl-Met). Steers were adapted to a roughage-based diet (DMI = 1.4% of BW daily) and supplemental Met for 14 d, and were then infused (1 mL/min via intravenous catheter) with LPS on d 1 (2 microg/kg of BW) and 3 (1 microg/kg of BW) of a 5-d collection period. Blood was collected on d 1, before LPS infusion, and at 2, 4, 6, 8, 10, 12, and 24 h after LPS challenge. Diet samples, feed refusals, feces, and urine were collected daily for 5 d. Rectal temperature and serum concentrations of cortisol, prolactin, tumor necrosis factor-alpha, and haptoglobin increased, whereas thyroxine and triiodothyronine decreased for +LPS vs. -LPS steers (LPS x h; P < 0.01). Plasma urea-N was greater for +LPS than -LPS steers (LPS; P = 0.03), and serum IGF-1 was not affected (P > or = 0.26) by LPS or Met. Plasma concentrations of Thr, Lys, Leu, Ile, Phe, Trp, Asn, Glu, and Orn decreased, plasma Ala increased, and Gly and Ser initially increased, then declined in +LPS vs. -LPS steers (LPS x h; P < or = 0.04). Plasma Met was greater for +MET than -MET steers before LPS infusion, but declined in +MET steers after LPS infusion (LPS x Met x h; P < 0.01). By design, DMI was not different, but DM digested was less (P = 0.04) for +LPS than -LPS steers. Infusion of LPS did not affect (P > or = 0.24) N intake, fecal N excretion, or N digested, but resulted in greater (P < 0.01) urinary N excretion and less (P < 0.01) N retention. The absence of an LPS x Met interaction (P = 0.26) for N retention indicates that supplemental Met does not improve the N utilization of growing beef steers exposed to a gram-negative bacterial endotoxin. Decreases in plasma concentrations of several essential AA in +LPS steers suggest that metabolic demand for these AA likely increased in steers exposed to endotoxin.
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PMID:Effects of rumen-protected methionine supplementation and bacterial lipopolysaccharide infusion on nitrogen metabolism and hormonal responses of growing beef steers. 1884 91

Accumulating evidence suggests that protein tyrosine phosphorylation-based signaling pathways are under the regulation of reactive oxygen species. Although protein tyrosine phosphatases are directly regulated by reversible oxidation, it is not clear whether protein tyrosine kinases (PTKs) are also directly regulated by reduction/oxidation (redox). In this study we report a mechanism of direct oxidative inactivation specific for the PTKs in the Src and fibroblast growth factor receptor (FGFR) families, key enzymes in mammalian signal transduction. Src is fully active when reduced and retains 8-25% of the full activity toward various substrates when oxidized. This inactivation is caused by oxidation of a specific cysteine residue (Cys-277), which results in homodimerization of Src linked by a disulfide bridge. Cys-277 is located in the Gly loop in the catalytic domain. This cysteine residue is conserved only in 8 of the >90 PTKs in the human kinome, including 3 of the 10 Src family kinases and all 4 kinases of the FGFR family. FGFR1 is also reversibly regulated by redox because of this cysteine residue, whereas Csk, a PTK that lacks a cysteine residue at the corresponding position, is not similarly regulated. These results demonstrate a mechanism of direct redox regulation conserved in certain specific PTKs.
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PMID:Direct and specific inactivation of protein tyrosine kinases in the Src and FGFR families by reversible cysteine oxidation. 1927 57

Cell cycle regulation by differentiation signals is critical for eukaryote development. We investigated the roles of bone morphogenetic protein (BMP)-4, an important stimulator of osteoblast differentiation and bone formation, in regulating cell cycle distribution in four osteoblast-like cell lines and mouse primary osteoblasts, and the underlying mechanisms. In all cells used, BMP-4 induced G(0)/G(1) arrest. The molecular basis of the BMP-4 effect was analyzed, and the presentation on molecular mechanism is focused on human MG63 cells. BMP-4 induced p21(CIP1) and p27(KIP1) expressions and hence cell differentiation but had no effects on the expressions of cyclins A, B1, D1, and E, cyclin-dependent protein kinase-2, -4, and -6. Using specific small interfering RNA (siRNA), we found that BMP-4-induced G(0)/G(1) arrest, and p21(CIP1) and p27(KIP1) expressions were mediated by BMP receptor type IA (BMPRIA)-specific Sma- and Mad-related protein (Smad)1/5. BMP-4 induced transient phosphorylations of ERK; transfection of MG63 cells with ERK2, but not ERK1, -specific siRNA inhibited the BMP-4-induced responses in MG63 cells. Pretreatment of MG63 cells with Arg-Gly-Asp-Ser, which blocks the cell-extracellular matrix interaction, or transfection with beta(3) integrin-specific siRNA inhibited BMP-4-induced ERK and Smad1/5 phosphorylations. BMP-4 induced transient increases in associations of beta(3)-integrin with focal adhesion kinase and Shc, the dominant-negative mutants of which inhibited BMP-4-induced ERK and Smad1/5 phosphorylations. Our results indicate that BMP-4 induces G(0)/G(1) arrest and hence differentiation in osteoblast-like cells through increased expressions of p21(CIP1) and p27(KIP1), which are mediated by BMPRIA-specific Smad1/5. The extracellular matrix/beta(3) integrin/ focal adhesion kinase/Shc/ERK2 signaling pathway is involved in these BMP-4-induced responses in osteoblast-like cells.
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PMID:BMP-4 induction of arrest and differentiation of osteoblast-like cells via p21 CIP1 and p27 KIP1 regulation. 1981 88

Bombay phenotype is one of the rare phenotypes in the ABO blood group system that fails to express ABH antigens on red blood cells. Nonsense or missense mutations in fucosyltransfrase1 (FUT1) and fucosyltransfrase2 (FUT2) genes are known to create this phenotype. This blood group is compatible with all other blood groups as a donor, as it does not express the H antigen on the red blood cells. In this study, we describe the establishment of human induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of a Bombay blood-type individual by the ectopic expression of established transcription factors Klf4, Oct4, Sox2, and c-Myc. Sequence analyses of fibroblasts and iPSCs revealed a nonsense mutation 826C to T (276 Gln to Ter) in the FUT1 gene and a missense mutation 739G to A (247 Gly to Ser) in the FUT2 gene in the Bombay phenotype under study. The established iPSCs resemble human embryonic stem cells in morphology, passaging, surface and pluripotency markers, normal karyotype, gene expression, DNA methylation of critical pluripotency genes, and in-vitro differentiation. The directed differentiation of the iPSCs into hematopoietic lineage cells displayed increased expression of the hematopoietic lineage markers such as CD34, CD133, RUNX1, KDR, alpha-globulin, and gamma-globulin. Such specific stem cells provide an unprecedented opportunity to produce a universal blood group donor, in-vitro, thus enabling cellular replacement therapies, once the safety issue is resolved.
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PMID:Generation of human induced pluripotent stem cells from a Bombay individual: moving towards "universal-donor" red blood cells. 1991 85

Costello syndrome (CS) is a developmental disorder characterized by postnatal reduced growth, facial dysmorphism, cardiac defects, mental retardation and skin and musculo-skeletal defects. CS is caused by HRAS germline mutations. In the majority of cases, mutations affect Gly(12) and Gly(13) and are associated with a relatively homogeneous phenotype. The same amino acid substitutions are well known as somatic mutations in human tumors and promote constitutive HRAS activation by impairing its GTPase activity. In a small number of cases with mild phenotype, a second class of substitutions involving codons 117 and 146 and affecting GTP/GDP binding has been described. Here, we report on the identification and functional characterization of two different three-nucleotide duplications resulting in a duplication of glutamate 37 (p.E37dup) associated with a homogeneous phenotype reminiscent of CS. Ectopic expression of HRAS(E37dup) in COS-7 cells resulted in enhanced growth factor-dependent stimulation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT signaling pathways. Recombinant HRAS(E37dup) was characterized by slightly increased GTP/GDP dissociation, lower intrinsic GTPase activity and complete resistance to neurofibromin 1 GTPase-activating protein (GAP) stimulation due to dramatically reduced binding. Co-precipitation of GTP-bound HRAS(E37dup) by various effector proteins, however, was inefficient because of drastically diminished binding affinities. Thus, although HRAS(E37dup) is predominantly present in the active, GTP-bound state, it promotes only a weak hyperactivation of downstream signaling pathways. These findings provide evidence that the mildly enhanced signal flux through the MAPK and PI3K-AKT cascades promoted by these disease-causing germline HRAS alleles results from a balancing effect between a profound GAP insensitivity and inefficient binding to effector proteins.
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PMID:Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation. 1999 90

Soluble APRIL (sAPRIL), the active form of a proliferation-inducing ligand (APRIL), is implicated in the proliferation of tumor cells. Suppressing APRIL function has been considered as a potential strategy for the therapy of APRIL-associated tumors. In the present study, we generated human sAPRIL and its two mutants, Gln187-D-sAPRIL (Gln187 deleted) and Gly187-sAPRIL (Gln187 replaced by Gly). In vitro experiments showed that the two mutants had similar specific binding capacity to lung carcinoma A549 cells compared to the wild-type sAPRIL, and both, especially Gly187-sAPRIL, exhibited significant antagonistic effect on sAPRIL-induced tumor cell proliferation in a dose-dependent manner, which might be predominantly mediated by blocking sAPRIL-induced MEK and ERK phosphorylation but not p38MAPK or JNK signaling. In vivo experiments with nude mice bearing A549 cell-derived xenograft tumor showed that only the Gly187-sAPRIL mutant could significantly suppress the tumor growth. These results suggest that Gln187 may be a crucial amino acid in APRIL-mediated tumor cell proliferation via the MEK-ERK signaling pathway and that the sAPRIL mutants may serve as novel potential antagonists of APRIL for the therapy of APRIL-associated cancers.
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PMID:Two Gln187 mutants of human soluble APRIL inhibit proliferation of lung carcinoma A549 cells. 1999 50

The cell recognition of bioactive ligands immobilized on polymeric surfaces is strongly dependent on ligand presentation at the cell/material interface. While small peptide sequences such as Arg-Gly-Asp (RGD) are being widely used to obtain biomimetic interfaces, surface characteristics after immobilization as well as presentation of such ligands to cell receptors deserve more detailed investigation. Here, we immobilized an RGD-based sequence on poly(epsilon-caprolactone) (PCL), a largely widespread polymeric material used in biomedical applications, after polymer aminolysis. The surface characteristics along with the efficacy of the functionalization was monitored by surface analysis (FTIR-ATR, contact angle measurements, surface free energy determination) and spectrophotometric assays specially adapted for the analytical quantification of functional groups and/or peptides at the interface. Particular attention was paid to the evaluation of a number, morphology, and penetration depth of immobilized functional groups and/or peptides engrafted on polymeric substrates. In particular, a typical morphology in peptide distribution was evidenced on the surface raised from polymer crystallites, while a significant penetration depth of the engrafted molecules was revealed. NIH3T3 fibroblast adhesion studies verified the correct presentation of the ligand with enhanced cell attachment after peptide conjugation. Such work proposes a morphological and analytical approach in surface characterization to study the surface treatment and the distribution of ligands immobilized on polymeric substrates.
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PMID:Surface investigation on biomimetic materials to control cell adhesion: the case of RGD conjugation on PCL. 2034 26

Proteinase-activated receptor-2 (PAR-2) expression levels are altered in several CNS disorders with these changes being proposed to either exacerbate or diminish the disease state depending on the cell type in which this occurs. Here we present data investigating the consequence of PAR-2 activation on kainate (KA)-induced neurotoxicity in organotypic hippocampal slices cultures (OHSC). Exposure of OHSC to the PAR-2 activators trypsin or Ser-Leu-Ile-Gly-Arg-Leu (SLIGRL) induced no neurotoxicity when applied alone but was neuroprotective against KA-induced neurotoxicity. SLIGRL-mediated neuroprotection involved astrocytic activation as the neuroprotective effect was abolished following OHSC pre-treatment with fluoroacetate. Moreover, co-application of either reparixin or LY341495, antagonists of the CXCR2 chemokine receptor and metabotropic glutamate receptors respectively, inhibited the SLIGRL-mediated neuroprotection. SLIGRL application inhibited both p38 MAPK and ERK activity in OHSC, but not the JNK 1/2 signalling pathway. Accordingly, the co-application of the p38 MAPK and ERK inhibitors SB203580 and UO126 reduced KA-induced cell death, mimicking PAR-2-mediated neuroprotection. These data indicate that PAR-2 activation is neuroprotective and involves astrocytic activation, gliotransmitter release, and the subsequent inhibition of MAPK signalling cascades, providing further evidence for PAR-2 as an interesting therapeutic target in certain CNS disorders.
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PMID:Astrocytic activation and an inhibition of MAP kinases are required for proteinase-activated receptor-2-mediated protection from neurotoxicity. 2040 64

Prolonged (12h) exposure of SH-SY5Y neuroblastoma cells to the mu-opioid receptor (MOPr) agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) causes homologous desensitization as well as heterologous desensitization of the extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation induced by insulin-like growth factor (IGF)-I. Brief (15 min) but not prolonged exposure to DAMGO transregulates the insulin-like growth factor-I (IGF-I) receptor, as evidenced by its phosphorylation in the absence of IGF-I. Silencing of beta-arrestin 2 uncouples the crosstalk between the two receptors, thus maintaining IGF-I-mediated receptor phosphorylation and ERK 1/2 activation even after prolonged DAMGO exposure. Furthermore, MOPr-induced activation of IGF-I receptor requires the tyrosine kinase c-Src.
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PMID:beta-Arrestin 2-mediated heterologous desensitization of IGF-IR by prolonged exposure of SH-SY5Y neuroblastoma cells to a mu opioid agonist. 2064 33


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