Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q9UL75 (A431)
 5,640 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A431 cells have an abundance of Epidermal Growth Factor (EGF) receptors which possess intrinsic tyrosine kinase activity. Treatment of membranes isolated from A431 cells with EGF caused a 2-3 fold increase in phosphorylation of a synthetic peptide (Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly) which is a substrate for tyrosine kinase. Treatment of these membranes with 0.1 to 100 mM ethanol altered basal tyrosine kinase activity in a biphasic manner; increase at 10 mM and decrease at 100 mM ethanol. The treatment of the membranes with the same concentrations of ethanol also altered EGF's ability to stimulate tyrosine kinase activity: increase at 0.1 mM ethanol and decrease at 10 mM. Strikingly, EGF-stimulated tyrosine kinase was more sensitive to ethanol than the basal activity. Experiments with other alcohols showed a relationship between chain length and the inhibitory ability of the alcohol. These data demonstrate a biochemical effect of low concentrations of ethanol on tyrosine kinase. Interestingly, ethanol treatment of A431 cells inhibited EGF-stimulated phosphorylation of PLC-gamma 1 which is a substrate for EGF receptor tyrosine kinase. It is concluded that ethanol at low concentrations has significant modulatory effect on basal and EGF-stimulated tyrosine kinase, as well as PLC-gamma 1 phosphorylation.
 ...
PMID:Ethanol modulates epidermal growth factor-stimulated tyrosine kinase and phosphorylation of PLC-gamma 1. 132 Aug 73

Inostamycin, a novel microbial secondary metabolite, inhibited [3H]inositol and 32P1 incorporation into phosphatidylinositol (PtdIns) induced by epidermal growth factor (EGF) in cultured A431 cells, the IC50 being 0.5 micrograms/ml, without inhibiting macromolecular synthesis. The drug inhibited cellular inositol phosphate formation only when it was added at the same time as labeled inositol. It was found to inhibit in vitro CDP-DG:inositol transferase activity of the A431 cell membrane, the IC50 being about 0.02 micrograms/ml. It did not inhibit tyrosine kinase, PtdIns phospholipase C, or PtdIns kinase. Therefore, inhibition of PtdIns turnover by inostamycin must be due to the inhibition of CDP-DG:inositol transferase. Thus, inostamycin is a novel inhibitor of CDP-DG:inositol transferase.
 ...
PMID:Inhibition of CDP-DG: inositol transferase by inostamycin. 132 72

In order to determine the effect of calcium mobilization on mitogen-activated protein (MAP) kinase activation, we have treated human foreskin fibroblasts (HSWP cells) and human epidermal carcinoma (A431) cells with thapsigargin. Intracellular free calcium was monitored by single cell image analysis using fura-2 and correlated with MAP kinase stimulation as assessed by immunoprecipitation, kinase renaturation assays and immunoblotting. Thapsigargin stimulated the 44- and 42-kDa MAP kinase isozymes in both cell types with kinetics that were slightly delayed relative to enzyme stimulated by epidermal growth factor. Removal of external calcium did not significantly affect the activation of the MAP kinases by thapsigargin, indicating that intracellular calcium mobilization is sufficient to stimulate the enzymes. However, treatment of cells with EGTA under conditions which deplete both intra- and extracellular calcium inhibited stimulation by thapsigargin but not epidermal growth factor. Stimulation of the MAP kinases by the calcium ionophore ionomycin paralleled the activation observed with thapsigargin in both calcium-containing and calcium-free conditions. These results indicate that there are at least two independent pathways for stimulation of MAP kinase: one that is dependent on intracellular calcium mobilization, and one that is mediated by the tyrosine kinase epidermal growth factor receptor and is calcium-independent.
 ...
PMID:Activation of MAP kinases by calcium-dependent and calcium-independent pathways. Stimulation by thapsigargin and epidermal growth factor. 132 84

The morphology, karyotype, in vitro growth properties, and expression of tyrosine kinase receptors and proto-oncogenes are reported for a newly established large cell undifferentiated lung carcinoma cell line (RVH-6849). The results were analyzed concomitantly with those for two well-established cell lines from an adenocarcinoma of the lung (A549) and a squamous cell carcinoma (A431). All three cell lines demonstrated common ultrastructural features of epithelial cells, but only RVH-6849 had frequent aggregates of centrioles and annulate lamellae (AL) and was polyploid, having five to seven copies of chromosome 7 by karyotype analysis. All three cell lines expressed transforming growth factor alpha (TGF-alpha), epidermal growth factor receptor (EGFR), c-erb B-2, and c-met genes. RVH-6849 cells, however, expressed the most messenger RNA (mRNA) for TGF-alpha, c-erb B-2, and c-met. Only EGFR mRNA was expressed more in the other two cell lines, especially in A431 cells. AL represent an exaggerated form of the nuclear membrane-pore complex that is found in actively proliferating cells such as germ and some neoplastic cells. AL are suspected to be involved in the deposition or processing of mRNA: The enhanced coexpression of AL and mRNAs of three tyrosine kinase-containing receptors in RVH-6849 cells may represent such a relationship.
 ...
PMID:Annulate lamellae in a large cell lung carcinoma cell line with high expression of tyrosine kinase receptor and proto-oncogenes. 135

The epidermal growth factor (EGF) receptor-associated protein tyrosine kinase activity has been suggested to play important roles in the EGF-enhanced, clathrin-coated pit-mediated receptor internalization (W. S. Chen, C. S. Lazar, M. Peonie, R. Y. Tsien, G. N. Gill, and M. G. Rosenfeld, 1987, Nature 328, 820-823) but the kinase substrate important for this process has not been identified. This study demonstrates that the EGF receptor, partially purified from A431 epidermoid carcinoma cells, catalyzes the phosphorylation of one of the two clathrin light chains, clathrin light chain a (LCa). The phosphorylation activity is stimulated by EGF and immunoprecipitated by an EGF receptor monoclonal antibody. The phosphorylation occurs exclusively on tyrosine residues. Amino acid composition of the major tryptic phosphopeptide of the EGF receptor-phosphorylated LCa corresponds closely to that of residues 1 to 97 of LCa. A stoichiometry of 0.2 mol phosphate/mol LCa was attained after 60 min at 30 degrees C and a Km value of 1.7 microM was determined for the reaction. LCa of either neuronal or non-neuronal origin could serve as a substrate. In addition to the EGF receptor tyrosine kinase, a particulate src-related protein tyrosine kinase purified from bovine spleen (C. M. E. Litwin, H.-C. Cheng, and J. H. Wang, 1991, J. Biol. Chem. 226, 2557-2566) was shown in this study to also phosphorylate the light chains. However, in contrast to the EGF receptor phosphorylation, both clathrin light chains a and b were phosphorylated by the spleen kinase, suggesting that the two tyrosine kinases have differential site specificities. Given the specificity of LCa phosphorylation by the EGF receptor, we propose that LCa phosphorylation on a tyrosine residue(s) may be important in EGF-induced receptor internalization.
 ...
PMID:Differential in vitro phosphorylation of clathrin light chains by the epidermal growth factor receptor-associated protein tyrosine kinase and a pp60c-src-related spleen tyrosine kinase. 137 Jun 1

Previous studies of tumor necrosis factor (TNF) action on tumor cells revealed a possible role for tyrosine phosphorylation of epidermal growth factor (EGF) receptor in the growth-regulatory activities of this cytokine (N. J. Donato, G. E. Gallick, P. A. Steck, and M. G. Rosenblum, J. Biol. Chem., 264: 20474-20481, 1989). EGF receptor immunoprecipitated from [32P] phosphate-equilibrated A431 cells demonstrated that TNF treatment resulted in both a time- and concentration-dependent stimulation of EGF receptor phosphorylation, which was maximal (approximately 3-fold) after 10-20 min of TNF exposure (10 nM). Incubation of A431 cells with an equivalent concentration of EGF resulted in similar stimulation of EGF receptor phosphorylation, albeit at different phosphotyrosine levels. Antiphosphotyrosine immunoblot analysis confirmed these results but suggested that the extent and kinetics of TNF-induced tyrosine phosphorylation were distinct from those obtained in EGF-treated cells. Resolution of tryptic phosphopeptides from EGF receptor demonstrated that TNF-induced phosphorylation of EGF receptor was similar, but not identical, to profiles obtained from EGF-treated cells and distinct when compared to the actions of phorbol ester. Unlike EGF, TNF was unable to directly stimulate EGF receptor tyrosine kinase activity in membranes prepared from A431 cells. In addition, TNF treatment had no significant effect on either the high- or low-affinity ligand-binding sites on EGF receptor and did not alter the kinetics or extent of ligand-induced internalization of EGF receptors. However, EGF receptor biosynthesis was consistently increased upon prolonged treatment with TNF (4-12 h). Our results suggest that TNF regulates both phosphorylation and biosynthesis of EGF receptor in a manner distinct from that of both EGF and phorbol ester, and studies of the differential phosphorylation of EGF receptor may aid in understanding the molecular mode of TNF action.
 ...
PMID:Tumor necrosis factor regulates tyrosine phosphorylation on epidermal growth factor receptors in A431 carcinoma cells: evidence for a distinct mechanism. 137 52

Expression of epidermal growth factor (EGF) receptor is often increased in various human carcinomas. Therefore, inhibition of the EGF/EGF receptor-induced signaling pathway may help to suppress these carcinomas. In the presence of Ca2+, EGF induces elongation of A431 cells in approximately 30 min. The cell elongation was shown to be accompanied by a reorganization of actin filaments. These phenotypical changes were specifically inhibited by a tyrosine kinase inhibitor, erbstatin, and inhibitors of phosphatidylinositol (PI) turnover such as psi-tectorigenin and inostamycin. The amount of filamentous actin was increased by EGF, which was also inhibited by these compounds. Long-term treatment of A431 cells with EGF induced the disappearance of cytoskeleton and aggregation of the cells, which was again inhibited by the PI turnover inhibitors. Thus tyrosine kinase and phosphatidylinositol turnover inhibitors were shown to inhibit the signaling pathways of EGF-induced cytoskeletal organization of A431 cells.
 ...
PMID:Inhibition of EGF-induced cytoskeletal change in A431 cells by inhibitors of phosphatidylinositol turnover. 160 Aug 63

Sodium selenate stimulated tyrosine phosphorylation of the epidermal growth factor (EGF) receptor in A431 cells and enhanced the tyrosine phosphorylation of endogenous proteins in response to EGF in A431 cells and insulin in NIH 3T3 HIR3.5 cells. These effects occurred without changes in ligand binding, were not abolished by mercaptoethanol in the case of the EGF receptor, and appeared distinct from the effects of vanadate. These results support a role for selenium or selenoproteins in regulating EGF and insulin receptor tyrosine kinase activity and suggest a mechanism whereby selenium-containing compounds contribute to cell growth.
 ...
PMID:Enhancement of epidermal growth factor (EGF) and insulin-stimulated tyrosine phosphorylation of endogenous substrates by sodium selenate. 164 2

Previously it was reported (Bremer, E.G., Schlessinger, J., and Hakomori, S.-I. (1986) J. Biol. Chem. 261, 2434-2440) that ganglioside GM3 inhibited epidermal growth factor (EGF)-stimulated phosphorylation of the EGF receptor in Triton X-100-treated preparations of human epidermoid carcinoma (A431) cell membranes. In addition, these authors reported that GM3 inhibited the growth of A431 cells. In contrast, a modified ganglioside, de-N-acetyl GM3, enhanced the EGF-dependent tyrosine kinase activity of the EGF receptor. In this work and in subsequent studies (Hanai, N., Dohi, T., Nores, G. A., and Hakomori, S.-I. (1988) J. Biol. Chem. 263, 6296-6301), the tyrosine kinase activity of the receptor from A431 cell membranes was assayed in the presence of Triton X-100. In this report, we confirm that GM3 inhibited and de-N-acetyl GM3 stimulated EGF receptor autophosphorylation in the presence of Triton X-100. However, in the absence of detergents, ganglioside GM3 inhibited EGF-stimulated receptor autophosphorylation, whereas de-N-acetyl GM3 had no effect on EGF-stimulated receptor autophosphorylation. The effects of these gangliosides on receptor autophosphorylation were measured in both A431 cell plasma membranes and in 3T3 cell membranes permeabilized to [32P]ATP by a freeze-thaw procedure, in intact A431 cells permeabilized with alamethicin, and in intact A431 cells grown in the presence of [32P]orthophosphate. Thus, the inhibitory effect of GM3 on receptor autophosphorylation was demonstrated in the presence and in the absence of detergent; the stimulatory effect of de-N-acetyl GM3 was observed only in the presence of detergent. We also demonstrate that ganglioside GM3 inhibited EGF-stimulated growth of transfected murine fibroblasts (3T3) that express the gene for human EGF receptor (Velu, T. J., Beguinot, L., Vass, W. C., Zhang, K., Pastan, I., and Lowy, D. R. (1989) J. Cell. Biochem. 39, 153-166). De-N-acetyl ganglioside GM3 had no effect on the growth of these cells. Growth of control fibroblasts, which lack endogenous EGF receptors (Pruss, R. M., and Herschman, H. R. (1977) Proc. Natl. Acad. Sci. U.S.A. 74, 3918-3921), was not affected by the presence of either ganglioside. Similarly, ganglioside GM3, but not de-N-acetyl ganglioside GM3, inhibited the EGF-dependent incorporation of [3H]thymidine into DNA by transfected fibroblasts. Incorporation of labeled thymidine into DNA of control fibroblasts was not affected by the presence of either ganglioside. These studies indicate that ganglioside GM3, but not its deacetylated analogue, can affect EGF receptor kinase activity in intact membranes.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Effects of gangliosides GM3 and De-N-acetyl GM3 on epidermal growth factor receptor kinase activity and cell growth. 164 42

The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less than or equal to 1 microM. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.
 ...
PMID:Sulfonylbenzoyl-nitrostyrenes: potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase. 165 14


1 2 3 4 5 6 7 8 9 10 Next >>