Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several cytoplasmic tyrosine kinases contain a conserved, non-catalytic stretch of approximately 100 amino acids called the src homology 2 (SH2) domain, and a region of approximately 50 amino acids called the SH3 domain. SH2/SH3 domains are also found in several other proteins, including phospholipase C-gamma (PLC gamma). Recent studies indicate that SH2 domains promote association between autophosphorylated growth factor receptors such as the epidermal growth factor (EGF) receptor and signal transducing molecules such as PLC gamma. Because SH2 domains bind specifically to protein sequences containing phosphotyrosine, we examined their capacity to prevent tyrosine dephosphorylation of the EGF and other receptors with tyrosine kinase activity. For this purpose, various SH2/SH3 constructs of PLC gamma were expressed in Escherichia coli as glutathione-S-transferase fusion proteins. Our results show that purified SH2 domains of PLC gamma are able to prevent tyrosine dephosphorylation of the EGF receptor and other receptors with tyrosine activity. The inhibition of tyrosine dephosphorylation paralleled the capacity of various SH2-containing constructs to bind to the EGF receptor, suggesting that the tyrosine phosphatase and the SH2 domain compete for the same tyrosine phosphorylation sites in the carboxy-terminal tail of the EGF receptor. Analysis of the phosphorylation sites protected from dephosphorylation by PLC gamma-SH2 revealed substantial inhibition of dephosphorylation of Tyr992 at 1 microM SH2. This indicates that Tyr992 and its flanking sequence is the high-affinity binding site for SH2 domains of PLC gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: identification of Tyr992 as the high-affinity binding site for SH2 domains of phospholipase C gamma. 153 35

We examined tyrosine kinase activity of epidermal growth factor (EGF) receptor in a total of 34 human gastric carcinomas as well as in non-neoplastic gastric mucosa from the same patients. EGF receptor kinase activity of the carcinoma tissues and the non-neoplastic mucosa were 1.28 +/- 1.00 (Mean +/- S.E.) and 0.16 +/- 0.04 respectively, if the EGF receptor kinase activity of human placenta is 10. Twenty-one (62%) carcinoma tissues showed higher EGF receptor kinase activity than corresponding non-neoplastic mucosa, while in 6 cases (18%) the kinase activity was higher in the non-neoplastic mucosa than in the tumor tissues. No obvious correlation was observed between the increased kinase activity in the tumors and histological type or tumor staging. One tumor showed extremely high receptor kinase activity with ERBB gene amplification. This tumor showed strong immunoreactivity to EGF itself.
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PMID:Tyrosine kinase activity of epidermal growth factor receptor in human gastric carcinomas. 159 97

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.
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PMID:Inhibition of EGF-induced cytoskeletal change in A431 cells by inhibitors of phosphatidylinositol turnover. 160 Aug 63

Human breast cancer cell proliferation is regulated by growth factors that bind to receptors with intrinsic tyrosine kinase (TK) activity, including the epidermal growth factor (EGF) receptor. To determine whether inhibition of receptor TK activity inhibits tumor growth, we studied the effects of a tyrosine kinase inhibitor, RG-13022, on cultured human breast cancer cells. RG-13022 represents a class of compounds which have been shown to inhibit preferentially the TK activity of the EGF receptor in a cell-free system and also to inhibit EGF-stimulated growth of cultured cells. RG-13022 significantly inhibited EGF-stimulated autophosphorylation of its receptor in two breast cancer cell lines that have abundant, although not amplified, EGF receptor content (MDA-231 and T47D). RG-13022 also inhibited EGF-stimulated DNA synthesis and proliferation of T47D and MCF-7 breast cancer cells in a reversible and dose-dependent manner. Inhibition was observed at 0.1 microM, and it was maximal at 10 microM. The effect was rapid (within 3 h), persisted for 18 h, and was partially reversed by 24 h at 1 microM. At 5 microM, inhibition persisted for more than 50 h. Inhibitory effects were also observed in a panel of estrogen receptor-positive and estrogen receptor-negative breast cancer cell lines. RG-13022 inhibited not only EGF-induced growth but also growth stimulated by insulin, insulin-like growth factor I, insulin-like growth factor II, or transforming growth factor alpha. RG-13022 also totally blocked estrogen-stimulated phosphorylation of the EGF receptor, as well as estrogen-induced cell proliferation, suggesting that functioning TK pathways are required for estrogen action. The TK inhibitor RG-13022 is a potent inhibitor of hormonally regulated growth of human breast cancer. Tyrosine kinase inhibitors have the potential of providing a new strategy for the "endocrine therapy" of breast cancer.
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PMID:Inhibition of breast cancer cell growth in vitro by a tyrosine kinase inhibitor. 161 36

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.
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PMID:Enhancement of epidermal growth factor (EGF) and insulin-stimulated tyrosine phosphorylation of endogenous substrates by sodium selenate. 164 2

Okadaic acid, a potent tumor promoter and inhibitor of phosphoserine/threonine protein phosphatases 1 and 2A, produces a large increase in epidermal growth factor (EGF) receptor phosphorylation in several cell types. The increases are limited to phosphoserine and phosphothreonine residues. 12-O-Tetradecanoylphorbol-13-acetate (TPA), a distinct tumor promoter and protein kinase C activator, also induces serine/threonine phosphorylation of the EGF receptor and is known to modulate receptor functions. Comparison of okadaic acid and TPA influences on the EGF receptor show significant differences. Okadaic acid did not promote phosphorylation of Thr-654, a major site of TPA-induced phosphorylation. However, other sites of phosphorylation were similar for the two tumor promoters. In vitro experiments with purified protein phosphatase 2A demonstrate the insensitivity of Thr-654 phosphorylation, which regulates EGF receptor function, to dephosphorylation by this okadaic acid-sensitive protein phosphatase. In contrast to TPA, okadaic acid did not attenuate the tyrosine kinase activity or ligand binding capacity of the EGF receptor. However, okadaic acid did produce a decrease in EGF-stimulated inositol phosphate formation in a manner distinct from that of TPA.
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PMID:Okadaic acid-induced hyperphosphorylation of the epidermal growth factor receptor. Comparison with receptor phosphorylation and functions affected by another tumor promoter, 12-O-tetradecanoylphorbol-13-acetate. 165 56

The mutant c-erbB-2 protein with Glu instead of Val-659 exhibited transforming activity in NIH 3T3 cells. This protein showed enhanced tyrosine kinase activity in vitro and enhanced autophosphorylation at Tyr-1248 located proximal to the carboxyl terminus. Enhanced tyrosine phosphorylation of several cellular proteins was detected in cells expressing the Glu-659 c-erbB-2 protein. Introduction of an additional mutation at the ATP-binding site (Lys-753 to Met) of this protein resulted in abolition of its transforming ability. These data indicate that the transforming potential of c-erbB-2 is closely correlated with elevated tyrosine kinase activity of the gene product. To investigate the role of autophosphorylation in cell transformation, we introduced an additional mutation at the autophosphorylation site of the Glu-659 c-erbB-2 protein (Tyr-1248 to Phe). This mutant protein exhibited lower tyrosine kinase activity and lower transforming activity. On the other hand, when the carboxyl-terminal 230 amino acid residues were deleted from the c-erbB-2 protein, the tyrosine kinase activity and cell-transforming activity of the protein were enhanced. Thus, the carboxyl-terminal domain, which contains the major autophosphorylation site, Tyr-1248, may regulate cellular transformation negatively and autophosphorylation may eliminate this negative regulation.
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PMID:The transforming potential of the c-erbB-2 protein is regulated by its autophosphorylation at the carboxyl-terminal domain. 167 Dec 96

90 primary breast carcinomas and 18 metastases were immunostained for c-erbB-2 protein and neuron specific enolase. 30 tumours were c-erbB-2 negative and NSE positive, 23 tumours were NSE negative and c-erbB-2 positive. 1 tumour expressed focal immunoreactivity for both markers. 54 of the 108 tumours (50%) did not express either marker. Hormone immunoreactivity was present in single cells and in small groups of cells in 18 of the 31 NSE positive tumours. Bombesin, neurotensin and prealbumin were present in 4 cases each, followed by beta-endorphin and VIP in 3 cases each, leu-enkephalin in 2 cases and gastrin, serotonin, substance P, glucagon and somatostatin in 1 case each. None of 10 NSE negative breast carcinomas were comprised of cells expressing immunoreactivity for hormones. By immunoelectron microscopic examination the c-erbB-2 protein was shown to be present on the cell membrane, on smooth areas, microvilli and in coated pits. Immunoreactivity was also expressed in vesicles in cytoplasm and along rough endoplasmic reticulum. The study shows that c-erbB-2 protein expression and neuroendocrine activity are present in different tumour cell populations. This supports the hypothesis that the presence of c-erbB-2 protein, indicating an elevated cellular tyrosine kinase activity with stimulation of growth, intracellular Ca++, and phosphatidylinositol derivates, means that the same cell does not need regulation of the same factors by stimulation of peptide hormone receptors. Thus the production of autocrine and paracrine factors is switched off.
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PMID:C-erbB-2 protein and neuroendocrine expression in breast carcinomas. 167 29

The epidermal growth factor receptor (EGFR) and gp185erbB-2 are closely related tyrosine kinases. Despite extensive sequence and structural homology, these two receptors display quantitative and qualitative differences in their ability to couple with mitogenic signalling pathways. By using chimeric molecules between EGFR and erbB-2, we found that the determinants responsible for the specificity of mitogenic signal transduction are located in the amino-terminal half of the tyrosine kinase domain of either receptor. In the EGFR, mutational analysis within this subdomain revealed that deletion of residues 660 to 667 impaired receptor mitogenic activity without affecting its tyrosine kinase properties. This sequence is therefore likely to contribute to the specificity of substrate recognition by the EGFR kinase.
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PMID:The juxtamembrane regions of the epidermal growth factor receptor and gp185erbB-2 determine the specificity of signal transduction. 167 18

The c-erbB-2 oncogene, is a member of tyrosine kinase oncogene family and expected to play a role in the regulation of cell growth. In the present study, prognostic significance of the expression of c-erbB-2 oncoprotein was investigated by immunocytochemical assay with 130 primary breast cancer patients. The positive expression of c-erbB-2 oncoprotein was found in 53 out of 130 patients (40.8%). There was no significant correlation between expression of c-erbB-2 oncoprotein and conventional prognostic factors, estrogen receptor (ER), axillary lymph node metastasis and epidermal growth factor receptor (EGFR). Relapse free survival rate of the patients with positive c-erbB-2 expression was significantly worse than those with negative at 49 month after operation. Similar result was found in overall survival rate but the difference was not significant. Furthermore, when patients were stratified by regional nodal status, in the patients with lymph node metastasis, the prognosis of the patients with positive c-erbB-2 expression was significantly worse than those with negative, while no significant difference was found in the patients without lymph node metastasis. These results suggest that c-erbB-2 oncoprotein may act as a prognostic factor independently, predicting the prognosis of breast cancer patients.
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PMID:[Prognostic significance of expression of c-ERBB-2 oncoprotein in breast cancer patients]. 167 44


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