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

To gain insight into the mechanisms which control the mitogenic response to epidermal growth factor (EGF), we have partially purified and characterized several intracellular proteins which are phosphorylated on tyrosine residues following activation of the epidermal growth factor receptor (EGFR). Partial purification was achieved by immunoaffinity chromatography using immobilized anti-phosphotyrosine antibodies. Antisera generated against the partially purified proteins were used to identify at least five novel EGFR putative substrates, designated, on the basis of their apparent molecular weight, p97, p68, p61, p56, and p23. All of these proteins became specifically phosphorylated on tyrosine after EGF treatment of intact cells, as assessed by phosphoamino acid analysis, and none of them represented an EGFR degradation product. The phosphorylation of these proteins appeared to be relatively specific for the EGFR. In particular, an EGFR-related kinase, erbB-2 was much less efficient than EGFR at phosphorylating p97, p56, and p23 and incapable of phosphorylating p68. The identification of these novel EGFR putative substrates should lead to a better understanding of the mechanisms controlling the specificity of EGFR-mediated mitogenic signaling.
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PMID:Identification and biochemical characterization of novel putative substrates for the epidermal growth factor receptor kinase. 134 29

The expressions of epidermal growth factors (EGF), epidermal growth factor receptors (EGFR), and the c-erbB-2 oncoprotein were immunohistochemically examined in 25 cases of human pancreatic carcinoma and epineoplastic pancreatitis and in 10 non-cancerous/non-inflammatory pancreatic tissues. The positive rates of EGF, EGFR, and the c-erbB-2 oncoprotein in cancer tissues were 72%, 36%, and 28%, respectively. EGF was stained mainly in the cytoplasm and partly on the surfaces of the cancer cells. EGFR and the c-erbB-2 oncoprotein were stained mainly on the surfaces of the cancer cells and partly in the cytoplasm. The expressions of these 3 products correlated significantly with tumor invasion into the anterior and posterior areas surrounding the pancreas. In the EGF, EGFR, and c-erbB-2 positive cancer tissues, some stromal cells, that is fibroblasts and endothelial cells, were also positive. In the adjacent pancreatic tissues with inflammation, these products were noted in some ductal cells, acinar cells, fibroblasts and endothelial cells. No distinct staining was detected in non-cancerous/non-inflammatory tissues. The survival period for patients who tested positive for these three proteins was statistically shorter than for those who tested negative. These results suggest that the coexpression of EGF and EGFR and the expression of the c-erbB-2 oncoprotein are related to the existence of the invasion of human pancreatic cancer. Furthermore, an immunohistochemical examination of these three products is useful in forming a prognosis for pancreatic cancer patients.
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PMID:The immunohistochemical expressions of epidermal growth factors, epidermal growth factor receptors and c-erbB-2 oncoprotein in human pancreatic cancer. 134 73

The control of expression of the erbB-2 protein was examined in two mammary epithelial cells lines, HC11 and 31E. The erbB-2 protein content varied dramatically depending upon cell density and upon the presence of epidermal growth factor (EGF) in the culture medium. The changes in protein content were not due to variation in the erbB-2 mRNA level. Analysis of the metabolic turnover of the erbB-2 protein showed that its rate of degradation was two- to threefold higher in cells growing at low density than in cells confluent for 2 days. The addition of EGF to the culture medium caused an increase in the phosphoamino acid content and an increase in the turnover of the erbB-2 protein. Cell fractionation experiments were performed, and a shift in the cellular localization of the erbB-2 protein towards the lysosomal compartment in EGF-treated HC11 cells was found. This is reflected by an increase in the degradation rate of the erbB-2 protein. These findings suggest that in mammary epithelial cells the stability of the erbB-2 protein is an important regulatory control point in determining the level of the protein. The degradation rate is sensitive to cell confluency and is controlled by EGF receptor activity.
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PMID:Surface expression of erbB-2 protein is post-transcriptionally regulated in mammary epithelial cells by epidermal growth factor and by the culture density. 134 17

In this investigation, 83 human mammary carcinomas were examined for the expression of oestrogen receptor (ER), epidermal growth factor receptor (EGF-R), epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), c-erbB-2, histological grade, mitotic index and nodal status, all of which are reportedly prognostically significant factors (Bloom and Richardson 1957; Baak et al. 1985; Wright et al. 1989). ER expression was biochemically recognized in 43.4% of mammary carcinomas, and EGF-R, EGF, TGF-alpha and c-erbB-2 were histochemically recognized in 25.3, 14.5, 27.7 and 18.0% of mammary carcinomas examined respectively, using conventional sections of buffered formalin-fixed, paraffin-embedded tissue and monoclonal or polyclonal antibodies. There were significant relationships between negative ER and positive EGF-R or TGF-alpha; positive EGF-R and TGF-alpha; positive EGF-R and c-erbB-2; and positive c-erbB-2 and TGF-alpha. The single changes which were the negative ER and the positive c-erbB-2 correlated with histological grade and mitotic index. Co-expression of EGF-R and TGF-alpha correlated with positive nodal status. Therefore, the present investigation indicates that the negative ER, single expression of c-erbB-2 and co-expression of EGF-R and TGF-alpha are important markers which contribute indirectly to prognosis, which reconfirms previous findings on the former two while adding the new finding that immunohistochemical demonstration of expression of EGF-R and TGF-alpha may provide useful information for selecting the appropriate treatment.
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PMID:Immunohistochemical studies on oncogene products (EGF-R, c-erbB-2) and growth factors (EGF, TGF-alpha) in human breast cancer: their relationship to oestrogen receptor status, histological grade, mitotic index and nodal status. 134 90

The erbB oncogene encodes an altered form of the epidermal growth factor (EGF) receptor that lacks the extracellular ligand binding domain. This oncogene is exclusively leukemogenic. However, an increase in oncogenic potential and a broadening of the tissue specificity of tumor formation occurs after retroviral transduction of erbB. The increased oncogenic potential correlates with structural alterations within the erbB gene. One common event is the deletion of a serine phosphorylation site located within the COOH-terminal domain. This site of phosphorylation has been demonstrated to be required for EGF-induced desensitization of signaling by the EGF receptor (Countaway, J. L., Nairn, A. C., and Davis, R.J. (1992) J. Biol. Chem. 267, 1129-1140). Here we show that the mutation of erbB at this negative regulatory serine phosphorylation site causes fibroblast transformation in vitro and is associated with an increased oncogenic potential in vivo.
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PMID:Increased oncogenic potential of ErbB is associated with the loss of a COOH-terminal domain serine phosphorylation site. 134 14

The proto-oncogene designated erbB2 or HER2 encodes a 185-kilodalton transmembrane tyrosine kinase (p185erbB2), whose overexpression has been correlated with a poor prognosis in several human malignancies. A 45-kilodalton protein heregulin-alpha (HRG-alpha) that specifically induced phosphorylation of p185erbB2 was purified from the conditioned medium of a human breast tumor cell line. Several complementary DNA clones encoding related HRGs were identified, all of which are similar to proteins in the epidermal growth factor family. Scatchard analysis of the binding of recombinant HRG to a breast tumor cell line expressing p185erbB2 showed a single high affinity binding site [dissociation constant (Kd) = 105 +/- 15 picomolar]. Heregulin transcripts were identified in several normal tissues and cancer cell lines. The HRGs may represent the natural ligands for p185erbB2.
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PMID:Identification of heregulin, a specific activator of p185erbB2. 135 Mar 81

In this work, we have used Xenopus oocyte maturation as a read-out for examining the ability of the neu tyrosine kinase (p185neu) to participate with the epidermal growth factor (EGF) receptor in a common signal transduction pathway. We find that unlike the case for the EGF receptor, which elicits EGF-dependent maturation of these oocytes as reflected by their germinal vesicle breakdown (GVBD), neither the normal neu tyrosine kinase (p185val664) nor the oncogenic form of neu (p185glu664) are able to effectively trigger this maturation event. However, expression of p185glu664 causes a specific and significant promotion of the progesterone-induced GVBD, reducing the half-time for this maturation even from approximately 9 h to approximately 5 h. Stimulation of the progesterone-induced GVBD did not occur following the expression of a kinase-deficient p185neu protein (in which a lysine residue at position 758 was changed to alanine). Essentially identical results were obtained when the mRNAs coding for fusion proteins comprised of the extracellular domain of the receptor for immunoglobulin E (IgE), and the membrane-spanning and tyrosine kinase domains of normal or oncogenic p185neu (designated IgER/p185val664 and IgER/p185glu664, respectively), were injected into oocytes. Antigen-induced crosslinking of IgER/p185val164 proteins expressed in oocytes caused a reduction in the half-time for the progesterone-stimulated GVBD from approximately 9 h to approximately 7 h. Thus, the aggregation of the membrane-spanning and/or tyrosine kinase domains of p185val664 partially mimics the effects of the oncogenic forms of p185neu. Overall, the results of these studies suggest that the activation of the p185neu tyrosine kinase by a point mutation within its membrane-spanning helix, or an aggregation event, can result in the facilitation of oocyte maturation events that are elicited by other factors (e.g. progesterone). However, the activated p185neu tyrosine kinases are not able to mimic the EGF-stimulated EGF receptor tyrosine kinase in triggering oocyte maturation, which suggests that the EGF receptor and the p185neu tyrosine kinase do not input into identical signal transduction pathways in these cells.
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PMID:The effects of the normal and oncogenic forms of the neu tyrosine kinase, and the corresponding forms of an immunoglobulin E receptor/neu tyrosine kinase fusion protein, on Xenopus oocyte maturation. 135 69

Autophosphorylation of gp185erbB-2 in vivo is confined to its carboxy terminus and is required for optimal erbB-2 transforming activity under conditions of receptor overexpression. It remains unresolved, however, to what extent autophosphorylation regulates erbB-2 mitogenic signaling in normal cells, nor is the biochemical basis for such a regulatory function known. To address these issues, we utilized a chimeric molecule encompassing the extracellular domain of the epidermal growth factor (EGF) receptor (EGFR) fused to the transmembrane and intracellular domains of the erbB-2 product. In this EGFR/erbB-2 chimera, erbB-2 kinase activity is regulated by EGF binding. An EGFR/erbB-2 mutant bearing multiple Tyr----Phe substitutions at erbB-2 autophosphorylation sites (EGFR/erbB-2 5P) displayed markedly reduced phosphotyrosine content following EGF stimulation in comparison with the non-mutated chimera. When expressed in NR6 cells, the EGFR/erbB-2 5P mutant was unable to deliver a sizeable mitogenic signal when activated by EGF at physiological levels. In intact cells, the 5P mutant was still able to stimulate phosphorylation of the gamma isozyme of phospholipase C (PLC-gamma), a prototype erbB-2 substrate, although with a delayed time course, indicating that the 5P mutation decreased the affinity of the erbB-2 kinase for this substrate. This conclusion was further supported by the inability of the 5P mutant to associate with PLC-gamma in co-immunoprecipitation experiments. We infer that a major role of autophosphorylation is to increase the affinity of the erbB-2 kinase for its cellular substrates, so that, under physiological conditions, autophosphorylation is absolutely required for erbB-2 mitogenic signaling.
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PMID:erbB-2 autophosphorylation is required for mitogenic action and high-affinity substrate coupling. 135 97

MCF-10A cells are a spontaneously immortalized untransformed human mammary epithelial cell line. We have previously shown that overexpression of a human point-mutated c-Ha-ras proto-oncogene, the rat c-neu (c-erbB-2) proto-oncogene, or the human transforming growth factor-alpha (TGF-alpha) gene in MCF-10A cells leads to in vitro transformation of such cells. To ascertain whether the introduction of two of these genes into MCF-10A human mammary epithelial cells induces a completely tumorigenic phenotype, we infected MCF-10A Ha-ras and MCF-10A TGF-alpha cells with a recombinant retroviral vector containing the human c-erbB-2 proto-oncogene and the hygromycin-resistance gene. Ten MCF-10A TGF-alpha/c-erbB-2 (MCF-10A TE) and 10 MCF-10A Ha-ras/c-erbB-2 (MCF-10A HE) hygromycin-resistant clones were randomly selected and expanded into cell lines. MCF-10A TE and MCF-10A HE clones expressed a 10-fold to 40-fold increase in p185 erbB-2 protein levels compared with parental uninfected cells. These cells exhibited a fourfold increase in their growth rate in serum-free medium and showed a strongly reduced mitogenic response to exogenous epidermal growth factor or TGF-alpha compared with MCF-10A cells. Moreover, both MCF-10A TE and MCF-10A HE clones exhibited a fivefold to 20-fold higher cloning efficiency in soft agar than MCF-10A Ha-ras, MCF-10A c-erbB-2, or MCF-10A TGF-alpha clones. However, neither MCF-10A TE nor MCF-10A HE cells were able to grow as tumors in vivo when they were injected into nude mice. These results suggest that c-Ha-ras, c-erbB-2, and TGF-alpha genes have an additive effect on the in vitro transformation of an immortalized human mammary epithelial cell line, but that additional genetic changes such as activation of other proto-oncogenes or inactivation of a tumor suppressor gene may be necessary to elicit a fully tumorigenic phenotype.
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PMID:Additive effects of c-erbB-2, c-Ha-ras, and transforming growth factor-alpha genes on in vitro transformation of human mammary epithelial cells. 135 42

This review considers the biology of the type 1 growth factor receptor family which is increasingly recognised as important in the control of normal cell proliferation and in the pathogenesis of human cancer. The family currently comprises three closely related members: the epidermal growth factor (EGF) receptor, c-erbB-2 and c-erbB-3, all of which show abnormalities of expression in various human tumours. The family of factors related to EGF has also expanded recently and now includes transforming growth factor alpha, heparin-binding EGF, amphiregulin, cripto and heregulin, as well as several other potential ligands for the c-erbB2-2 receptor. The involvement of these receptors and growth factors in human cancer has implications for the design of novel forms of therapy for cancer, and we review recent advances and future avenues for investigation.
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PMID:The type 1 (EGFR-related) family of growth factor receptors and their ligands. 135 72


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