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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogen interaction with specific receptors in many cell types leads to activation of the Na+/H+ antiport and a resultant cytoplasmic alkalinization. Since amiloride inhibits both Na+/H+ exchange and cell proliferation, it has been hypothesized that activation of the antiport is an obligatory requirement for mitogenesis. However, concentrations of amiloride which inhibit the antiport also inhibit other cellular processes, including protein synthesis and phosphorylation. We have used an epidermal growth factor (EGF) receptor gene-amplified human breast cancer cell line, the growth of which is inhibited by high levels of EGF in culture (MDA-468) and a variant, the growth of which is stimulated by EGF (MDA-468-S4), along with two potent amiloride analogues to examine whether activation of the Na+/H+ antiport and cytoplasmic alkalinization is necessary for both EGF-dependent effects to occur. At concentrations of the amiloride analogues which block Na+/H+ exchange in both cell types by 76-98%, the EGF-dependent alterations in [3H]thymidine incorporation or induction in c-myc or c-fos gene transcription were unaltered. These results were confirmed by a lack of effect of the amiloride analogues on both the growth-stimulatory and growth-inhibitory effects on EGF in an anchorage-independent growth assay. Similarly, in pH-altered media that prevented normal cytoplasmic alkalinization, the response of both MDA-468 and MDA-468-S4 to EGF activation was unaltered. In addition, activation of the Na+/H+ antiport alone was not sufficient to induce c-myc and c-fos transcription in either cell type. Taken together, these data suggest that neither the Na+/H+ antiport nor cytoplasmic alkalinization are necessary or sufficient for either EGF-dependent growth stimulation or growth inhibition in MDA-468 human breast cancer cells.
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PMID:Activation of the Na+/H+ antiport is not required for epidermal growth factor-dependent gene expression, growth inhibition or proliferation in human breast cancer cells. 253 20

Previous studies have shown that palytoxin, a non-(12-O-tetradecanoylphorbol-13-acetate)-type tumor promoter, is able to down-modulate the epidermal growth factor (EGF) receptor through a sodium-dependent pathway in Swiss 3T3 cells. A role for sodium is supported by the observation that the sodium proton exchanger monensin and the sodium-conducting ionophore gramicidin mimic palytoxin action by causing a decrease in both high and low affinity EGF binding. However, in addition to causing sodium influx, these agents can induce other cellular effects including changes in membrane polarization, intracellular pH, and macromolecular synthesis. To determine whether any of these factors might be responsible for palytoxin action in our system, we examined the role of each of them in palytoxin-induced inhibition of EGF binding. Although palytoxin depolarizes the membrane, the observation that potassium-induced depolarization of the membrane does not cause a decrease in EGF binding, in conjunction with the fact that monensin hyperpolarizes the membrane, indicates that depolarization of the membrane is not responsible for palytoxin-induced changes in the EGF receptor. An investigation of intra-cellular pH suggests that the palytoxin effects are not mediated by proton flux. In addition, nigericin-mediated changes in intracellular pH do not cause an inhibition of EGF binding. Finally, studies conducted in the presence of cycloheximide indicate that protein synthesis is not required for palytoxin action and that inhibition of EGF receptor biosynthesis does not account for palytoxin-induced loss of EGF-binding sites. These results suggest that sodium may act as a second messenger in the signal transduction mechanism by which palytoxin modulates the EGF receptor.
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PMID:Sodium as a mediator of non-phorbol tumor promoter action. Down-modulation of the epidermal growth factor receptor by palytoxin. 257 66

The epidermal growth factor (EGF) receptor tyrosine kinase activity is required for both the earliest EGF-stimulated post-binding events (enhancement of inositol phosphate formation and Ca2+ influx, activation of Na+/H+ exchange), and the ultimate EGF-induced mitogenic response. To assess the role of EGF receptor kinase in EGF-induced metabolic effects (2-deoxyglucose and 2-aminoisobutyric acid uptake), we used NIH3T3 cells (clone 2.2), which do not possess endogenous EGF receptors and which were transfected with cDNA constructs encoding either wild type or kinase-deficient human EGF receptor (HER). In addition, we tested the importance of three HER autophosphorylation sites (Tyr-1068, Tyr-1148, and Tyr-1173) in transduction of EGF-stimulated 2-deoxyglucose uptake. Taking our data together, we conclude the following: (i) HER tyrosine kinase activity is required to elicit EGF stimulation of both 2-deoxyglucose and 2-aminoisobutyric acid uptake; (ii) mutations on individual HER autophosphorylation sites, Tyr-1068, Tyr-1148, and Tyr-1173 do not impair EGF-stimulated 2-deoxyglucose uptake.
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PMID:Metabolic effects induced by epidermal growth factor (EGF) in cells expressing EGF receptor mutants. 278 9

Several newly synthesized 4-hydroxycinnamamide derivatives such as 3-(3',5'-di-isopropyl-4'-hydroxybenzylidene)-2-oxindol (ST 280), 3-(3',5'-di-methylthiomethyl-4'-hydroxybenzylidene)-2-oxindole (ST 458), alpha-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamamide (ST 638) and 3-(3'-ethoxy-4'-hydroxy-5'-phenylthiomethylbenzylidene)-2-pyrol idinone (ST 642) were found to inhibit tyrosine-specific protein kinase activity of the epidermal growth factor (EGF) receptor with IC50 values of 0.44 microM, 0.44 microM, 0.37 microM and 0.85 microM, respectively. None of them showed inhibitory effect on the enzyme activities of serine- and/or threonine-specific protein kinases such as cAMP-dependent protein kinase, Ca2+/phospholipid-dependent protein kinase C, casein kinase I and casein kinase II. In addition, none of them had effect on Na+/K+-ATPase or 5'-nucleotidase. The results suggest that the compound ST 280, ST 458, ST 638 and ST 642 are potent and specific inhibitors of tyrosine-specific protein kinase.
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PMID:Specific inhibitors of tyrosine-specific protein kinase, synthetic 4-hydroxycinnamamide derivatives. 282 Mar 97

We describe the properties of two monoclonal antibodies produced to a synthetic peptide consisting of residues 985 to 996 from the cytoplasmic domain of the epidermal growth factor (EGF) receptor. We have examined a group of ten human tumors including cervical, ovarian, and vulval carcinomas for expression of EGF receptors by immunohistological staining using one of these antibodies and another monoclonal antibody to the extracellular domain of the molecule. The tumors were examined using a sensitive amplified enzyme system and a less sensitive indirect staining method. There was generally a good correlation in staining intensity with the two monoclonal antibody reagents. Both antibodies showed strong staining of squamous cell carcinomas and usually weak or heterogeneous patterns with the adenocarcinomas. Samples of each tumor were solubilized in detergent and analyzed for the presence of functional EGF receptors by immunoprecipitation and autophosphorylation. Three of the squamous cell tumors gave labeled bands, Mr 170,000, on sodium dodecyl sulfate:polyacrylamide gels. DNA was extracted from seven of the tumors and digested with two restriction endonucleases, and the fragments were analyzed on Southern blots using probes representing the extracellular and cytoplasmic domains of the molecule. The tumor DNA showed no apparent rearrangements or amplifications when compared to the EGF receptor gene in human placental DNA. These results suggest that there is a high level of EGF receptors on some squamous cell tumors.
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PMID:Expression of epidermal growth factor receptors on human cervical, ovarian, and vulval carcinomas. 299 7

Southern blot-hybridization analysis of DNAs from human tumors demonstrated amplification of the epidermal growth factor (EGF) receptor gene in 10 of 12 squamous cell carcinoma cell lines tested and in none of 18 tumor cell lines of nonsquamous cell carcinomas. The degree of amplification in the squamous cells varied from 2- to 50-fold relative to the epidermal keratinocyte. Hybridization analysis of the RNA showed that the amplification of the EGF receptor gene is accompanied with an increase of the 5.6 kilobases of EGF receptor mRNA. Scatchard plot analysis and sodium dodecyl sulfate-polyacrylamide gel analysis of the EGF receptor revealed that the synthesis of the EGF receptor is also greater in the cells with amplified EGF receptor gene. In contrast, Southern blot analysis of DNAs of primary tumors showed that incidence of amplification of the EGF receptor gene in squamous cells (1 of 6) was almost as frequent as in nonsquamous cells (1 of 4). These results show that amplification of the EGF receptor gene is commonly found in various tumors. In addition, our data suggest that primary squamous cell carcinomas with amplified EGF receptor gene may readily adapt to growth in tissue culture.
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PMID:High incidence of amplification of the epidermal growth factor receptor gene in human squamous carcinoma cell lines. 299 10

Treatment of cells with tumor-promoting phorbol diesters, which causes activation of protein kinase C, leads to phosphorylation of the epidermal growth factor (EGF) receptor at threonine-654. Addition of phorbol diesters to intact cells causes inhibition of the EGF-induced tyrosine-protein kinase activity of the EGF receptor and it has been suggested that this effect of phorbol diesters is mediated by the phosphorylation of the receptor by protein kinase C. We measured the activity of protein kinase C in A431 cells by determining the incorporation of [32P]phosphate into peptides containing threonine-654 obtained by trypsin digestion of EGF receptors. After 3 h of exposure to serum-free medium, A431 cells had no detectable protein kinase C activity. Addition of EGF to these cells resulted in [32P] incorporation into threonine-654 as well as into tyrosine residues. This indicates that EGF promotes the activation of protein kinase C in A431 cells. The phosphorylation of threonine-654 induced by EGF was maximal after only 5 min of EGF addition and the [32P] incorporation into threonine-654 reached 50% of the [32P] in a tyrosine-containing peptide. This indicates that a significant percentage of the total EGF receptors are phosphorylated by protein kinase C. A variety of external stimuli activate Na+/H+ exchange, including EGF, phorbol diesters, and hypertonicity. To ascertain whether activation of protein kinase C is an intracellular common effector of all of these systems, we measured the activity of protein kinase C after exposure of A431 cells to hyperosmotic conditions and observed no effect on phosphorylation of threonine-654, therefore, activation of Na+/H+ exchange by hypertonic medium is independent of protein kinase C activity. Since stimulation of protein kinase C by phorbol diesters results in a decrease in EGF receptor activity, the stimulation of protein kinase C activity by addition of EGF to A431 cells contributes to a feedback mechanism which results in the attenuation of EGF receptor function.
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PMID:Epidermal growth factor (EGF) promotes phosphorylation at threonine-654 of the EGF receptor: possible role of protein kinase C in homologous regulation of the EGF receptor. 302 81

The epidermal growth factor (EGF) receptor is present in the mouse placenta in both a low- and a high-affinity form having approximate values for Ka of 10(7) M-1 and 10(9) M-1, respectively. No significant difference (P greater than or equal to 0.05) in the number of receptors existed between placental membrane preparations from days 10 and 17, both for the low- and the high-affinity receptor. The number of both high- and low-affinity receptors was significantly lower (P less than 0.05) for day 14 placental membranes than for either day 10 or day 17 placental membranes. Cross-linking of 125I-EGF to placental membranes resulted in the specific labelling of two major receptor forms with approximate molecular weights of 170,000 and 154,000, as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis.
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PMID:Characterization of the mouse placental epidermal growth factor receptor: changes in receptor number with day of gestation. 349 85

We have characterized the epidermal growth factor (EGF) receptor in human meningioma (biopsy) microsomes, cellularly derived microsomes, and intact meningioma cells in culture. Scatchard analysis of competition studies reveals both high and low affinity EGF binding sites in the meningiomas tested [dissociation constant (Kd) = 0.9 nM, maximum number of binding sites (Bmax) = 280 fmol/mg protein; Kd = 5.0 nM, Bmax = 660 fmol/mg protein, respectively]. The binding of 125I-EGF is specific since it is abolished by excess unlabeled EGF but not by excess unlabeled platelet-derived growth factor or insulin. Meningioma cultures preincubated with platelet-derived growth factor (10 ng/ml) at 37 degrees C shifted the 125I-EGF competition curve to the right but did not affect receptor number (100,000 sites/cell) when compared to cultures preincubated at 4 degrees C. Cross-linking studies performed with ethyleneglycol bis(succinimidyl succinate) followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography reveal a major band of specifically bound EGF (Mr approximately 150,000), although the normal (Mr approximately 170,000) and another putative proteolytic form (Mr approximately 125,000) can also be seen. These results indicate that human meningiomas contain a mixed population of EGF binding sites and exhibit properties of previously described EGF receptors.
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PMID:Characterization of the epidermal growth factor receptor in human meningioma. 349 42

A method is presented for the preparation of a "native" epidermal growth factor (EGF) receptor-kinase complex of molecular weight 170,000 from A-431 cells. Although this receptor complex is capable of binding EGF, noncovalently, in quantities similar to the previously isolated 150,000 complex (Cohen, S., Carpenter, G., and King, L., Jr. (1980) J. Biol. Chem. 255, 4834-4842), the 170,000 preparation has 5 to 10 times the intrinsic kinase activity (autophosphorylation). However, the 170,000 kinase activity toward other proteins is lower than that of the 150,000 preparation. Both the 170,000 and 150,000 kinase activities are enhanced by EGF. The 170,000 and 150,000 proteins are also capable of forming covalent linkages to 125I-EGF, and each is precipitated by antisera directed against the 170,000 protein. We suggest the 150,000 protein is a proteolytic degradation product of the 170,000 protein. The EGF-enhanced kinase activity of the 170,000 preparation remains associated with the 125I-EGF-binding activity following EGF affinity chromatography, electrophoresis in nondenaturing gels, or immunoprecipitation with antisera directed against the sodium dodecyl sulfate (SDS) gel-purified 170,000 protein. These results indicate that the receptor, kinase, and substrate domains are linked, possibly covalently.
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PMID:A native 170,000 epidermal growth factor receptor-kinase complex from shed plasma membrane vesicles. 627 90


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