UNIPROT:P04626 - FACTA Search

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

In this study we evaluated phospholipase C-gamma 1 (PLC-gamma 1) expression, activity, and association with the epidermal growth factor (EGF) receptor in a series of human meningiomas as well as cultured meningioma cells. Phospholipase C-gamma 1 was detectable by immunoblot and immunohistochemistry in 13 of 13 meningioma specimens. Epidermal growth factor receptors were detected by immunoblot in six of nine meningiomas (67%) and by immunohistochemistry in 13 of 19 meningiomas (68%) but not in normal leptomeningeal cells. In two of three meningiomas EGF receptors and/or a 170-kd phosphotyrosine band precipitated with a PLC-gamma 1 antiserum. Both PLC-gamma 1 and EGF receptors also exhibited the same pattern of immunostaining on meningioma tissue sections. Phospholipase C-gamma 1 catalytic activity, measured in a PIP2 hydrolysis assay, was higher in nine EGF receptor-positive meningiomas than in six EGF receptor-negative meningiomas (P = .05; t test). Finally, treatment of cultured meningioma cells with transforming growth factor-alpha induced a 78% increase in PLC-gamma 1 catalytic activity. Thus, these data are consistent with the possibility that the EGF receptor tyrosine kinase regulates PLC-gamma 1 activity in native meningioma tissue.
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PMID:The epidermal growth factor receptor is associated with phospholipase C-gamma 1 in meningiomas. 811 14

The epidermal growth factor (EGF) receptor is expressed in a wide variety of cell types and is known to be present in the testis of many species including man. In the present study, specific 125I-labelled EGF binding was observed in isolated interstitial cell preparations from both the intact and Leydig cell-depleted rat testis. It was demonstrated that the population of cells to which 125I-labelled EGF binds has a different buoyant density from either of the two adult Leydig cell populations, and remains unchanged in the absence of Leydig cells following in-vivo treatment with ethane dimethane sulphonate (EDS). Cells of this density (1.064 g/ml) identified by electron microscopy were fusiform mesenchymal cells, identical to those suggested by others to be able to differentiate into Leydig cells in vitro, i.e. Leydig cell precursors. In a culture system using two interstitial cell preparations of different buoyant densities from immature rats, both EGF and transforming growth factor-alpha (TGF-alpha) caused increased [3H]thymidine incorporation in the less dense cell preparation. TGF-alpha was more potent than EGF. EGF increased testosterone production in both fractions in amounts which could be related to the amount of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD)-positive cells. This study demonstrated that rat Leydig cells (defined as those cells which bind 125I-labelled human chorionic gonadotrophin, have distinct buoyant densities, are 3 beta-HSD positive and are sensitive to EDS), do not bind 125I-labelled EGF. Rather, EGF binds to a mesenchymal cell without LH receptors which is resistant to EDS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Paracrine effects via the epidermal growth factor receptor in the rodent testis may be mediated by non-Leydig interstitial cells. 847 32

Improved methods for estimating the shape of the response curve for effects of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are needed in order to evaluate possible adverse health effects of TCDD. A mathematical model has been constructed to describe TCDD-mediated alterations in hepatic proteins in the rat. In this model it was assumed that TCDD mediates increases in the liver concentration of transforming growth factor-alpha (TGF-alpha) by a mechanism which requires the aryl hydrocarbon (Ah) receptor. TGF-alpha subsequently binds to the epidermal growth factor (EGF) receptor, a process which is known to cause internalization of this receptor in hepatocytes. This action is thought to be an early event in the generation of a mitogenic signal. Because TCDD decreases binding of EGF in the livers of intact female rats but not in ovariectomized rats, this effect was further assumed to be dependent on estrogen action. The model postulates Ah receptor-dependent effects on the concentration of cytochrome P450 1A2 (CYP1A2), which is involved in the metabolism of estradiol, and on the concentration of the estrogen receptor. The model also incorporates information on induction of cytochrome P450 1A1 (CYP1A1) by TCDD. The biochemical response curves for all these proteins were hyperbolic (Hill exponents in the equations for their expression were found to be 1), indicating a proportional relationship between target tissue dose and protein concentration at low administered doses of TCDD. The model successfully reproduced the observed tissue distribution of TCDD, the concentrations of CYP1A1 and CYP1A2, and the effects of TCDD on the Ah, estrogen, and EGF receptors over a wide dose range.
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PMID:A mechanistic model of effects of dioxin on gene expression in the rat liver. 851 76

Serially transplantable rat mammary tumor (RMT) cells are not dependent on exogenous epidermal growth factor (EGF) and insulin-like growth factor-I for continuous growth in serum-free medium. Previously, we found that conditioned medium obtained from these cells contained EGF-like mitogenic activity and stimulated tyrosine phosphorylation of a 185-kDa protein in EGF-dependent mammary epithelial cells. This protein is distinct from the EGF receptor and resembles a 185-kDa tyrosine-phosphorylated protein present in RMT cells themselves. The results of the studies reported here indicate that the tyrosine-phosphorylated p185 detected in growth factor-independent RMT cells and in human mammary epithelial cells exposed to RMT-conditioned medium was activated erbB-2 protein. Partial purification of the activating factor present in RMT-conditioned medium yielded a heparin-binding growth factor with biochemical properties similar to those of neu differentiation factor/heregulin (NDF/HRG). RNA-polymerase chain reaction analysis demonstrated that RMT cells expressed mRNA for NDF/HRG, and western-blot analysis confirmed the presence of the 45-kDa secreted form of NDF/HRG in conditioned medium from the growth factor-independent RMT cells. The biological activity of partially purified rat NDF/HRG was examined and found to be the same as that of the pure growth factor. In addition, we found that RMT-conditioned medium, fractionated on an anion-exchange column and by reverse-phase high-pressure liquid chromatography, contained a potent EGF-like growth factor that was distinct from NDF/HRG. This factor competes with 125I-EGF for binding to EGF receptors and has an apparent molecular mass of 6600 Da. This factor copurifies by high-pressure liquid chromatography with pure transforming growth factor-alpha (TGF-alpha), and the cells are positive for TGF-alpha mRNA. Thus, growth factor-independent RMT cells also synthesize and secrete TGF-alpha. These results indicate that growth factor-independent cells secrete two growth factors with overlapping biological activities and suggest that autocrine loops mediated by these factors are important in the growth factor-independent proliferation of the RMT cells.
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PMID:Growth factor-independent proliferation of rat mammary carcinoma cells by autocrine secretion of neu-differentiation factor/heregulin and transforming growth factor-alpha. 859 80

Human parotid tumors were evaluated for the activation of the phosphotyrosine signaling pathway by Western blot, enzyme activity assay, and reverse transcriptase-polymerase chain reaction. Warthin's tumor and mucoepidermoid carcinomas had the greatest level of tyrosine phosphorylated proteins identified in plasma membrane fractions. These tumors, along with pleomorphic adenocarcinoma, showed high levels of membrane expression of the tyrosine kinase receptor, c-erbB-2, and phosphatidylinositol-3-kinase. Expression of the epidermal growth factor receptor was confined to normal tissue. The level of mRNA for c-erb was elevated only in mucoepidermoid carcinomas. Messenger RNA levels for ras were unchanged from control levels in all tumors, while the level of src mRNA was higher in the tumor samples than the normal parotid tissue. The activities of several signal transduction kinases, including protein kinase A and C were elevated in tumor tissue (7.7- to 18.9- and 0.4- to 3.7-fold higher, respectively), relative to surrounding normal tissue. While the level of glandular amylase was reduced (22%-0% of normal levels) in the tumor tissue, epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) content was dramatically higher in the neoplastic tissue (10- to 170-fold and 4.6- to 6.0-fold, respectively). These results suggest that with the presence of elevated levels of EGF, TGFalpha, and the oncoprotein receptor c-erbB-2 in the membrane of parotid tumors, cell proliferation and activation of the phosphotyrosine signal transduction pathway may involve autocrine stimulation through the expression of high levels of growth factor and receptor in the same tissue.
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PMID:Alterations in the level of phosphotyrosine signal transduction constituents in human parotid tumors. 863 6

Previous investigators have noted that certain ovarian cancer cell lines secrete and respond to transforming growth factor-alpha (TGF-alpha), suggesting that endogenous activation of the epidermal growth factor (EGF) receptor through autocrine or paracrine mechanisms might contribute to the proliferative response. In order to determine whether autocrine stimulation was partly responsible for the proliferative response in ovarian cancer, we investigated whether the EGF receptor expressed by ovarian cancer cell lines was constitutively activated as assessed by the presence of tyrosine phosphorylation. A specific anti-phosphotyrosine antibody was used in conjunction with an immunoblotting technique in order to detect EGF receptor phosphorylation in ovarian cancer cell lines in the absence and presence of exogenous EGF. The effects of neutralising anti-EGF receptor antibody on the proliferation of ovarian cancer cell lines was also examined. We found no evidence for constitutive tyrosine phosphorylation of the p170 EGF receptor in eight epithelial ovarian cancer cell lines tested, although each line demonstrated inducible phosphorylation in response to exogenous EGF. The absence of constitutive EGF receptor activation was also noted when cells were grown under high density conditions, thus excluding a role for membrane-bound EGF or TGF-alpha in this process. Media conditioned by five ovarian cancer cell lines, as well as malignant ascites obtained from 12 different ovarian cancer patients, were not capable of stimulating EGF receptor phosphorylation. Finally, the proliferation of ovarian cancer cell lines was not significantly inhibited in the presence of neutralising anti-EGF receptor antibody. These data suggest that EGF receptor activation through autocrine pathways is not a major mechanism for the growth of many ovarian cancer cell lines. Other pathways of signal transduction which bypass the requirement for EGF receptor activation may be important in the proliferation for ovarian cancer cells. Such EGF receptor-independent pathways may limit the effectiveness of strategies designed to inhibit ovarian cancer cell growth through disruption of EGF receptor function.
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PMID:Absence of constitutive EGF receptor activation in ovarian cancer cell lines. 869 62

The epidermal growth factor (EGF) receptor is overexpressed in human pancreatic cancers and cultured cell lines. TP40 is a chimeric protein composed of transforming growth factor-alpha (TGF-alpha) linked to a modified Pseudomonas exotoxin A (PE40) that exerts growth inhibitory effects on cells bearing a high number of EGF receptors. Therefore, we compared the effect of TP40 on the growth of Chinese hamster ovary (CHO), cells expressing varying levels of the EGF receptor and on the growth of two human pancreatic cancer cell lines. The growth of CHO cells devoid of endogenous EGF receptors was minimally altered by high concentrations of TP40, even following a 72-h incubation period. In contrast, in CHO cells expressing approximately 95,000 and 438,000 EGF receptors per cell, one-half maximal growth inhibition occurred at 5 and 3 ng/ml TP40, respectively. Following a 72-h incubation in T3M4 and COLO 357 human pancreatic cancer cells, one-half maximal growth inhibition occurred at 0.2 and 0.4 ng/ml TP40, respectively. This effect was significantly greater than that of native Pseudomonas exotoxin A. These findings indicate that human pancreatic cancer cells are markedly sensitive to the growth inhibitory effects of TP40 and raise the possibility that TP40 may have a therapeutic role in this disorder.
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PMID:Cytotoxic effects of TGF-alpha-Pseudomonas exotoxin A fusion protein in human pancreatic carcinoma cells. 878 29

The study of human transforming growth factor-alpha (TGF-alpha) in complex with the epidermal growth factor (EGF) receptor extracellular domain has been undertaken in order to generate information on the interactions of these molecules. Analysis of 1H NMR transferred nuclear Overhauser enhancement data for titration of the ligand with the receptor has yielded specific data on the residues of the growth factor involved in contact with the larger protein. Significant increases and decreases in nuclear Overhauser enhancement cross-peak intensity occur upon complexation, and interpretation of these changes indicates that residues of the A- and C-loops of TGF-alpha form the major binding interface, while the B-loop provides a structural scaffold for this site. These results corroborate the conclusions from NMR relaxation studies (Hoyt, D. W., Harkins, R. N., Debanne, M. T., O'Connor-McCourt, M., and Sykes, B. D. (1994) Biochemistry 33, 15283-15292), which suggest that the C-terminal residues of the polypeptide are immobilized upon receptor binding, while the N terminus of the molecule retains considerable flexibility, and are consistent with structure-function studies of the TGF-alpha/EGF system indicating a multidomain binding model. These results give a visualization, for the first time, of native TGF-alpha in complex with the EGF receptor and generate a picture of the ligand-binding site based upon the intact molecule. This will undoubtedly be of utility in the structure-based design of TGF-alpha/EGF agonists and/or antagonists.
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PMID:NMR study of the transforming growth factor-alpha (TGF-alpha)-epidermal growth factor receptor complex. Visualization of human TGF-alpha binding determinants through nuclear Overhauser enhancement analysis. 894 77

p70 Ribosomal protein S6 kinase is a critical down-stream effector of a mitogen-stimulated signaling pathway that is selectively inhibited by the immunosuppressant rapamycin. The purpose of this study was to quantify S6 kinase expression in psoriatic involved, uninvolved, and normal epidermis and to characterize regulation of S6 kinase activity in cultured normal human keratinocytes. S6 kinase activity was increased 4-fold in psoriatic lesions (1.63 +/- 0.25 pmol per min per mg, n = 6), compared to nonlesional (0.44 +/- 0.12 pmol per min per mg, n = 6, p < 0.01), and normal (0.35 +/- 0.14 pmol per min per mg, n = 7, p < 0.01) epidermis. In contrast, S6 kinase mRNA and protein levels were not significantly different among psoriatic lesional, nonlesional, and normal epidermis. In keratinocytes, S6 kinase activity was stimulated 3-fold by mitogenic epidermal growth factor (EGF) receptor ligands, EGF and transforming growth factor-alpha (TGF-alpha), but not by cytokines interleukin-1alpha, tumor necrosis factor-alpha, interferon-gamma, or transforming growth factor-beta1. TGF-alpha stimulation of S6 kinase activity was inhibited in a concentration-dependent manner by rapamycin (IC50 < 0.2 nM) and the specific EGF receptor antagonist PD153035 (IC50 = 20 nM). Rapamycin also inhibited EGF-stimulated proliferation of keratinocytes (IC50 = 0.2 ng per ml) with a potency similar to that reported for inhibition of T-cell proliferation. We conclude: (i) the mitogenic signaling pathway(s) regulating S6 kinase is activated in psoriatic lesions, thus accounting for increased S6 kinase activity in the absence of increased S6 kinase gene or protein expression; (ii) S6 kinase activation in lesional keratinocytes likely occurs in response to EGF receptor stimulation by TGF-alpha and/or amphiregulin, which are known to be elevated in psoriatic lesions; and (iii) keratinocyte as well as T-cell mitogenic signaling pathways are susceptible to inhibition by rapamycin, suggesting that rapamycin may be of therapeutic benefit in the treatment of psoriasis.
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PMID:Activation of ribosomal protein S6 kinase in psoriatic lesions and cultured human keratinocytes by epidermal growth factor receptor ligands. 898 Feb 96

The growth and differentiation of olfactory sensory neurons are regulated tightly. We had shown previously, by immunohistochemistry, that transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) receptor are present in the olfactory epithelium of untreated adult rats and that TGF-alpha is a potent mitogen of olfactory epithelium in vitro. Expression of EGF receptor and TGF-alpha was detected primarily in horizontal basal cells and supporting cells but rarely in globose basal cells, which suggested that EGF receptor is not a likely candidate for the mitotic regulator of sensory neurons. In order to expand the search for candidate regulators, we have now examined other members of the EGF family of receptors and ligands. By utilizing reverse transcriptase-polymerase chain reaction (RT-PCR) methodology, we have detected the messenger RNA encoding the protein of the neu gene (p185neu) and Neu differentiation factor (NDF) isoforms in the olfactory mucosa. Immunohistochemical localization of p185neu and NDF indicates expression of these proteins in the olfactory epithelium of adult rats in regions where globose basal cells and immature sensory neurons are found, as well as in the ensheathing cells of the olfactory nerve. The presence of neu and NDF transcripts in the olfactory tissue and the localization of their encoded polypeptides to proliferative regions of the epithelium suggest involvement of these gene products in the regulated proliferation/differntiation of the sensory neurons.
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PMID:Expression of neu and Neu differentiation factor in the olfactory mucosa of rat. 901 Jul 26

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