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

Beginning at the fifth week of fetal life, successive generations of individual nephrons are induced by contact between metanephric mesenchyme and ureteric bud. Following phenotypic transformation, cells of each primitive renal vesicle undergo a phase of rapid cell division. In order to identify genes which might regulate nephron development in man, we screened adult and fetal kidney RNA for expression of a panel of growth-related genes. Among the genes which were expressed at higher levels in fetal kidney was the epidermal growth factor (EGF) receptor. There is controversy as to the most likely physiologic EGF receptor ligand in fetal kidney; we were able to identify a transcript for transforming growth factor-alpha (TGF-alpha) but not EGF on Northern blots of fetal kidney RNA. Since the abundance of TGF-alpha mRNA is low, we confirmed its presence by polymerase chain reaction amplification. Using specific radioimmunoassays, we also provide direct evidence for TGF-alpha but not EGF peptide in extracts of fetal kidney and mid-gestational amniotic fluid. We suggest that TGF-alpha/EGF receptor interactions may serve an important function in development of human fetal kidney.
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PMID:Expression of transforming growth factor-alpha and epidermal growth factor receptor in human fetal kidneys. 172 55

We have reported previously that human group C adenoviruses down-regulate the epidermal growth factor (EGF) receptor (EGF-R) (C. R. Carlin, A. E. Tollefson, H. A. Brady, B. L. Hoffman, and W. S. M. Wold, Cell 57:135-144, 1989). Expression of a 13.7-kDa protein encoded by a gene in the E3 transcription unit is necessary and sufficient for this effect (Carlin et al., Cell, 1989; B. L. Hoffman, A. Ullrich, W. S. M. Wold, and C. R. Carlin, Mol. Cell. Biol. 10:5521-5524, 1990). We show here that EGF-R down-regulation is accelerated in cells which overexpress the receptor when these cells are infected with virus mutants that overproduce the 13.7-kDa protein compared with wild-type virus. This is in contrast to EGF stimulation, for which others have shown that high concentrations of ligand are associated with low rates of receptor internalization in EGF-R-overexpressing cells (D. Kuppuswamy and L. J. Pike, J. Biol. Chem. 264:3357-3363, 1989; H. S. Wiley, J. Cell Biol. 107:801-810, 1988). We also show that the E3 protein is not present in media conditioned by infected cells and that it does not induce secretion of an EGF-like autocrine factor. Moreover, while mature membrane-bound EGF-R is down-regulated, the precursor of the membrane-bound form is not. Adenovirus infection also does not affect receptor-related molecules expressed in the secretory pathway. Interestingly, adenovirus-induced down-regulation is not regulated by concentrations of EGF associated with a slow rate of internalization in A431 cells. This suggests that 13.7-kDa protein expression triggers receptor entry by a novel ligand-independent pathway or, alternatively, that it compensates for a cellular factor that may be rate limiting during EGF-mediated endocytosis.
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PMID:Evidence for intracellular down-regulation of the epidermal growth factor (EGF) receptor during adenovirus infection by an EGF-independent mechanism. 172 83

In a preliminary study we demonstrated that the formation of the epidermal growth factor (EGF) receptor-ligand complex requires the participation of the highly conserved arginine 41 side chain of the growth factor peptide (Engler, D.A., Montelione, G.T., and Niyogi, S.K. (1990) FEBS Lett. 271, 47-50). In an attempt to gain further insight into the nature of this interaction(s), we used both site-directed mutagenesis and chemical modification reagents to produce human EGF (hEGF) analogues with altered chemical properties of the residue 41 side chain. Eight mutant analogues of hEGF were generated, substituting arginine 41 with lysine, glutamine, isoleucine, tyrosine, glycine, alanine, aspartate, or glutamate. Although each of the mutant analogues was able to displace wild-type hEGF fully in receptor competition binding assays, affinity of the receptor for the mutants was substantially reduced, varying from 0.4 to less than 0.01% of that observed for wild-type growth factor. At sufficiently high concentrations these mutants were able to stimulate DNA synthesis in mouse keratinocytes. Substitution of lysine for arginine 41 reduced the receptor affinity 250-fold from that observed for wild type, despite retention of the positive electrostatic charge. The lysine substitution leaves a reactive amine at position 41 and made it possible, using amine-specific chemical modification reagents, to produce selected arginine homologues that were tested for their effects on receptor binding, receptor tyrosine kinase activation, and stimulation of DNA synthesis in mouse keratinocytes. The reaction of lysine 41 with methyl acetimidate resulted in a lysineacetamidine product which only partially restored activity of the lysine hEGF mutant. However, reaction with O-methylisourea resulted in generation of an arginine 41 homologue (homoarginine) which restored full activity. The results indicate that the chemical properties inherent in the guanidinium group of the arginine 41 side chain of hEGF are responsible for optimal receptor-ligand association.
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PMID:Critical functional requirement for the guanidinium group of the arginine 41 side chain of human epidermal growth factor as revealed by mutagenic inactivation and chemical reactivation. 173 35

We have used an antisense approach to investigate the role of overexpression of the normal human epidermal growth factor (EGF) receptor in the transformed phenotype of KB cells, which are a tumor derived human cell line. Initial experiments performed in vitro, showed that antisense RNA complementary to the entire coding region (AS-FL) or to parts of the EGF-R mRNA (AS-3', AS-5', and AS-K) effectively blocked translation of EGF-R mRNA. In addition, upon microinjection into KB cells, the in vitro synthesized antisense RNAs were able to inhibit transiently the synthesis of EGF-R. Inhibition was concentration-dependent, both in vitro and in cells, and the most effective constructs were those complementary to the entire coding region (AS-FL) or to the 3'-coding end of the mRNA (AS-3'). Transfection of the same EGF-R antisense RNA constructs into the human epidermoid carcinoma KB cell line gave rise to several clones stably expressing elevated levels of antisense RNA and resulting in low residual levels of EGF receptor. The most reduced clones exhibited a totally restored serum-dependent growth and were severely impaired in colony formation and growth in agar. In addition the severity of the phenotype was directly proportional to the residual amount of EGF-R expressed. We conclude that over-expression of normal EGF-R plays a direct primary role in the development of the transformed phenotype of this human cancer cell line.
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PMID:EGF-R antisense RNA blocks expression of the epidermal growth factor receptor and suppresses the transforming phenotype of a human carcinoma cell line. 173 67

The protein-tyrosine kinase activity of the epidermal growth factor (EGF) receptor is critical for EGF-stimulated cell growth, although little is known about the molecular details of its enzymatic activity. Previous studies have found that EGF receptor kinase activity can be stimulated by factors such as ammonium sulfate ((NH4)2SO4), but the manner in which (NH4)2SO4 induces this effect is unclear. Therefore, we have explored the processes by which (NH4)2SO4 potentiated tyrosine kinase activity to better understand not only the molecular events involved in (NH4)2SO4 activation, but also the kinetic properties and mechanism of the EGF receptor. In this study, the addition of an optimum concentration of (NH4)2SO4 (250 mM) resulted in a 5-fold stimulation of kinase activity toward the peptide substrate, angiotensin II. The sulfate group is primarily involved in this action, since other salts containing SO4(2-) increased kinase activity similarly, whereas salts containing Cl- and F- had less of an effect, and divalent salts such as HPO4(2-) and NaVO4(2-) were inhibitory at doses of 1 mM or more. In addition, EGF receptor kinase activation by (NH4)2SO4 did not strictly correlate with changes in the ionic strength or conductivity of the solution. However, several lines of evidence suggest that SO4(2-) directly alters the kinetic properties of the EGF receptor kinase: (1) the maximum velocity (Vmax) and Km (ATP) for EGF receptor phosphorylation of angiotensin II were substantially higher in the presence of (NH4)2SO4. (2) EGF receptor kinase activity in the absence of (NH4)2SO4 required either Mn2+ or Mg2+, yet in the presence of (NH4)2SO4, only Mn2+ supported the increase in kinase activity. (3) Ammonium sulfate addition altered the product inhibition pattern of ADP versus angiotensin II, suggesting that an enzyme-angiotensin II-ADP complex can form in the presence of (NH4)2SO4 but not in its absence. (4) The near-maximal rate of self-phosphorylation was not affected by (NH4)2SO4 but the apparent Km (ATP) was greatly increased. From these results, we propose a model for (NH4)2SO4 stimulation of EGF receptor kinase activity in which SO4(2-) interacts directly with the receptor or receptor-Mn(2+)-ATP complex and alters reactant binding and the catalytic efficiency of the tyrosine kinase.
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PMID:Potentiation of epidermal growth factor receptor protein-tyrosine kinase activity by sulfate. 173 63

Signals that can mediate ligand-induced receptor internalization and calcium regulation are present in a 48-amino acid "calcium-internalization" domain in the C' terminus of the epidermal growth factor (EGF) receptor. The basis of calcium and internalization regulation signalled by this 48-amino acid sequence was analyzed using deletion and substitution mutant receptors. Cells expressing truncated receptors containing either the NH2- or COOH-terminal portion of the 48-residue domain displayed high affinity EGF-dependent endocytosis and receptor down-regulation. These endocytosis-competent EGF receptor mutants that lacked any autophosphorylation site were unable to increase the concentration of intracellular calcium. To investigate the role of self-phosphorylation in EGF-induced calcium mobilization, phenylalanine was substituted for the single autophosphorylated tyrosine residue in this region of an internalization-competent truncated receptor. The receptor-mediated calcium response was abolished, while ligand-dependent receptor internalization was unimpaired. These results demonstrate that EGF-dependent receptor endocytosis and calcium mobilization are separate events. Tyrosine self-phosphorylation is required for increased [Ca2+]i, while structural features distinct from autophosphorylation are required for receptor internalization.
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PMID:Ligand-induced internalization and increased cell calcium are mediated via distinct structural elements in the carboxyl terminus of the epidermal growth factor receptor. 174 39

Cultured human pancreatic cancer cells produce a number of growth factors, including transforming growth factor-alpha (TGF-alpha). These cells also overexpress the epidermal growth factor (EGF) receptor and exhibit a parallel increase in EGF receptor mRNA levels. TGF-alpha, which binds to the EGF receptor, is more potent than EGF in enhancing the anchorage-independent growth of several pancreatic cancer cell lines, including T3M4 cells. In contrast, EGF is more efficient than TGF-alpha with respect to EGF receptor downregulation and tyrosine phosphorylation in T3M4 cells. Further, T3M4 cells recycle EGF, but markedly degrade TGF-alpha. It is suggested that the production of multiple growth factors, the overexpression of the EGF receptor, the recycling of EGF, and the attenuated ability of TGF-alpha to downregulate the EGF receptor combine to enhance the growth advantage of human pancreatic cancer cells.
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PMID:Growth factors and pancreatic cancer. 174 52

Retinoic acid and dexamethasone have antagonistic effects on epidermal growth factor (EGF) receptor expression in fetal rat lung (FRL) cells: Receptor synthesis is enhanced by retinoic acid and reduced by dexamethasone. In the presence of actinomycin D, neither agent has the capacity to modify receptor synthesis or 125I-EGF binding capacity. Northern blot analysis demonstrates a tenfold increase in EGF mRNA following retinoic acid treatment and a 60% decrease in receptor message levels after dexamethasone treatment. To dissect the mechanisms of these effects, the expression of mRNA was separated from effects requiring protein synthesis by the use of cycloheximide and actinomycin D. Ligand binding, EGF receptor protein synthesis, and mRNA levels were measured in cultures of FRL cells that were incubated with retinoic acid or dexamethasone in the presence of cycloheximide, then washed and reincubated with fresh media containing actinomycin D, but not retinoic acid, dexamethasone, or cycloheximide. The results demonstrate that dexamethasone reduces the expression of EGF receptor mRNA in the absence of protein synthesis. In contrast, the mechanism by which retinoic acid increases the expression of EGF receptor mRNA requires protein synthesis. These data indicate that, in FRL cells, dexamethasone negatively regulates EGF receptor mRNA in a direct manner, while retinoic acid controls transcription of an intermediate protein, possibly a transcription factor, that subsequently increases transcription of receptor message.
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PMID:Dexamethasone and retinoic acid regulate the expression of epidermal growth factor receptor mRNA by distinct mechanisms. 174 17

The ability of transforming growth factor-alpha (TGF-alpha) to interact with the gastric mucosal epidermal growth factor (EGF) receptor was investigated using a mucosal membrane preparation. TGF-alpha inhibited specific binding of [125I]EGF to its receptor, but the IC50 for TGF-alpha was at least 100 fold greater than that observed for unlabeled EGF. Cross-linking studies revealed no attachment of [125I]TGF-alpha to EGF-receptor size components, and the unlabeled TGF-alpha was only weakly effective in inhibiting cross-linking of [125I]EGF to the 170 kDa receptor. However, when the cytosolic fraction was reconstituted with the membrane preparation, an enhancement in binding of [125I]TGF-alpha to the EGF receptor occurred in a manner dependent on the concentration of cytosolic protein. Hence the binding characteristics of TGF-alpha to the EGF receptor in gastric mucosa are different from those for EGF.
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PMID:Transforming growth factor-alpha binds to the epidermal growth factor receptor in gastric mucosa. 180 86

The present study was undertaken to elucidate the ultrastructural differences between tumor cell clones with high growth or highly metastatic potential and those with low growth or weakly metastatic potential. Transmission, scanning and immuno-electron microscopy revealed a remarkable variance of surface microvilli between these two types of tumor cell clones. Greater numbers of microvilli appeared on the tumor cells which possess high growth or highly metastatic potential than on those of tumor cells with low growth or weakly metastatic potential. In contrast, gap junctions and desmosomes were more occasionally seen on the weakly metastatic tumor cells than the highly metastatic tumor cells. Immuno-electron microscopy revealed that epidermal growth factor (EGF) receptor and c-neu oncogene product, which is closely related to the EGF-receptor, were positively stained on the microvilli of tumor cells with high growth potential, whereas the tumor cells with low growth potential showed almost no staining. Western blot analysis also revealed that in the tumor cells with high growth potential, positive expression of c-neu at 185 kDa was stronger than in the tumor cells with low growth potential. The findings suggest that increased numbers of microvilli are closely related to the growth and metastatic potential of tumor cells.
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PMID:Relationship between development of microvilli on tumor cells and growth or metastatic potential of tumor cells. 182 34


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