Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The epidermal growth factor (EGF) receptor (EGFR) can efficiently couple with mitogenic signaling pathways when it is transfected into interleukin-3 (IL-3)-dependent 32D hematopoietic cells. When expression vectors for erbB-2, which is structurally related to EGFR, or its truncated counterpart, delta NerbB-2, were introduced into 32D cells, neither was capable of inducing proliferation. This was despite overexpression and constitutive tyrosine kinase activity of their products at levels associated with potent transformation of fibroblast target cells. Thus, EGFR and erbB-2 couple with distinct mitogenic signaling pathways. The region responsible for the specificity of intracellular signal transduction was localized to a 270-amino acid stretch encompassing their respective tyrosine kinase domains. Thus, tissue- or cell-specific regulation of growth factor receptor signaling can occur at a point after the initial interaction of growth factor with receptor. Such specificity in signal transduction may account for the selection of certain oncogenes in some malignancies.
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PMID:EGF receptor and erbB-2 tyrosine kinase domains confer cell specificity for mitogenic signaling. 218 68

The erbB-2 gene product, gp185erbB-2, displays a potent transforming effect when overexpressed in NIH 3T3 cells. In addition, it possesses constitutively high levels of tyrosine kinase activity in the absence of exogenously added ligand. In this study, we demonstrate that its carboxy-terminal domain exerts an enhancing effect on erbB-2 kinase and transforming activities. A premature termination mutant of the erbB-2 protein, lacking the entire carboxy-terminal domain (erbB-2 delta 1050), showed a 40-fold reduction in transforming ability and a lowered in vivo kinase activity for intracellular substrates. When the carboxy-terminal domain of erbB-2 was substituted for its analogous region in the epidermal growth factor receptor (EGFR) (EGFR/erbB-2COOH chimera), it conferred erbB-2-like properties to the EGFR, including transforming ability in the absence of epidermal growth factor, elevated constitutive autokinase activity in vivo and in vitro, and constitutive ability to phosphorylate phospholipase C-gamma. Conversely, a chimeric erbB-2 molecule bearing an EGFR carboxy-terminal domain (erbB-2/EGFRCOOH chimera) showed reduced transforming and kinase activity with respect to the wild-type erbB-2 and was only slightly more efficient than the erbB-2 delta 1050 mutant. Thus, we conclude that the carboxy-terminal domains of erbB-2 and EGFR exert different regulatory effects on receptor kinase function and biological activity. The up regulation of gp185erbB-2 enzymatic activity exerted by its carboxy-terminal domain can explain, at least in part, its constitutive level of kinase activity.
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PMID:The carboxy-terminal domains of erbB-2 and epidermal growth factor receptor exert different regulatory effects on intrinsic receptor tyrosine kinase function and transforming activity. 218 97

As a first step toward developing a structural map of key sites on the epidermal growth factor (EGF) receptor, we have used resonance energy transfer to measure the distance of closest approach between the receptor-bound growth factor molecule and lipid molecules at the surface of the plasma membrane. EGF, specifically labeled at its amino terminus with fluorescein 5-isothiocyanate, was used as an energy donor in these experiments, while either octadecylrhodamine B or octadecylrhodamine 101, inserted into plasma membranes isolated from human epidermoid carcinoma (A431) cells, served as the energy acceptors. The energy transfer measurements indicate that the amino terminus of the bound growth factor is about 67 A away from the plasma membrane. On the basis of the dimensions of the EGF molecule, this suggests that EGF binds to a site on its receptor that is a considerable distance (52-82 A) from the surface of these cells. Identical results were obtained under conditions where the receptor functions as an active tyrosine kinase, suggesting that the relative juxtaposition of the EGF binding domain to the membrane surface does not change with receptor autophosphorylation or with the activation of the receptor tyrosine kinase activity.
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PMID:Location of the epidermal growth factor binding site on the EGF receptor. A resonance energy transfer study. 227 54

The epidermal growth factor (EGF) receptor, a tyrosine kinase which mediates the mitogenic and tumorigenic action of EGF on epithelial cells and fibroblasts, is a target for the regulatory action of other growth-modulating agents. We have identified at least three mechanisms by which heterologous agents such as tumor promoters regulate the EGF receptor: modulation of receptor binding or kinase activity through phosphorylation, down regulation of the receptor through internalization, and enhanced receptor synthesis through transcriptional activation. Both calcium- and sodium-dependent signaling pathways play a role in one or more of these processes.
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PMID:Regulation of the epidermal growth factor receptor by growth-modulating agents. 228 99

The activation of the epidermal growth factor (EGF) receptor tyrosine kinase activity is thought to represent a key initial step in EGF-mediated mitogenesis. The mechanisms underlying the regulation of the EGF receptor tyrosine kinase activity were examined through comparisons of the holoreceptor, purified from human placenta, and a soluble 42 kDa tyrosine kinase domain (TKD), generated by the limited trypsin proteolysis of the holoreceptor. The results of these studies highlight the importance of divalent metal ions (Me2+), i.e., Mn2+ and Mg2+, as activators of the tyrosine kinase activity. Manganese is an extremely effective activator of the holoreceptor tyrosine kinase, and under some conditions (low ionic strength) it completely alleviates the need for EGF to stimulate activity. In contrast, Mg2+ only weakly stimulates the holoreceptor tyrosine kinase activity in the absence of EGF, but promotes essentially full activity in the presence of the growth factor. Like the holoreceptor, the soluble TKD is highly active in the presence of Mn2+. However, the isolated TKD is completely inactive in the presence of Mg2+, and, in fact, Mg2+ inhibits the Mn2(+)-stimulated tyrosine kinase activity. The differences in the effects of Mn2+ and Mg2+ on the isolated TKD were further demonstrated by monitoring the effects of Me2+ on the modification of a reactive cysteine residue(s) on the TKD. While Mn2+ potentiates the inhibition by cysteine-directed reagents of the tyrosine kinase activity, Mg2+ has no effect on either the rate or the extent of the inhibition. Both the regulation by Mn2+ of the kinase activity of the TKD and the potentiation by Mn2+ of the cysteine reactivity of the TKD occur over a millimolar concentration range, which implicates a direct binding interaction by the metal ion. Overall, these results demonstrate that there are two key activator sites on the EGF receptor, i.e., the EGF binding site on the extracellular domain and a Me2+ binding site on the cytoplasmic TKD. Me2+ interactions with the cytoplasmic kinase domain apparently result in conformational changes which regulate the levels of tyrosine kinase activity, influence the degree to which this activity is responsive to EGF, and probably account for the effects of Me2+ on the aggregation state of the receptor (Carraway, K.L., III, Koland, J.G. and Cerione, R.A. (1989) J. Biol. Chem. 264, 8699-8707). In general, Mg2(+)-induced conformation changes prime the receptor for activation by EGF, while Mn2+ can fully activate the receptor tyrosine kinase and thereby short-circuit growth factor control.
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PMID:Activation of the EGF receptor tyrosine kinase by divalent metal ions: comparison of holoreceptor and isolated kinase domain properties. 235 10

Antisera were prepared against three synthetic peptides with amino acid sequences identical to those surrounding the three major autophosphorylation sites of the epidermal growth factor (EGF) receptor. The affinity-purified antibodies reacted strongly in an enzyme-linked immunosorbent assay against the immunizing peptide but showed little cross-reaction with the other two phosphorylation site peptides. EGF receptors labelled by autophosphorylation could be specifically precipitated by each of the phosphorylation site antibodies. The antibodies recognised EGF receptors labelled at each of the autophosphorylation sites, indicating that they could bind to the immunizing sequences irrespective of their states of phosphorylation. The antibodies were able to inhibit EGF receptor autophosphorylation without affecting EGF-stimulated tyrosine kinase activity towards exogenous peptide substrates, suggesting that the kinase and autophosphorylation sites were in distinct domains. Immunofluorescent staining of A431 cells showed that the autophosphorylation site sequences resided inside the cell. The autophosphorylation sites were shown to be within a domain of 20 000 mol. wt. which could be cleaved from the receptor through limited proteolysis by the calcium-dependent protease, calpain. The position of cleavage of the EGF receptor by the protease was mapped to lie between residues 996 and 1059. These results are discussed in the context of a model for the structure and function of the human EGF receptor.
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PMID:Antibodies to the autophosphorylation sites of the epidermal growth factor receptor protein-tyrosine kinase as probes of structure and function. 241 53

In human epidermoid carcinoma KB cells, a glycoprotein of Mr = 190,000 (gp190) has been shown to be phosphorylated on tyrosine residues upon EGF stimulation (Kadowaki et al., 1987, J. Biol. Chem. in press). Using a specific antibody to the c-terminal portion of the human c-erbB-2 gene product, we have found that gp190 is the human c-erbB-2 gene product which is structurally closely related to the epidermal growth factor (EGF) receptor. Since monoclonal antibody specific for the EGF receptor abolished both EGF binding to its receptor and tyrosine phosphorylation of the c-erbB-2 gene product, we have concluded that activation of EGF receptor tyrosine kinase activity upon EGF binding leads to the phosphorylation of the c-erbB-2 gene product on its tyrosine residues.
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PMID:A Mr = 190,000 glycoprotein phosphorylated on tyrosine residues in epidermal growth factor stimulated KB cells is the product of the c-erbB-2 gene. 243 18

We previously showed that the epidermal growth factor (EGF) receptor in human A431 epidermoid carcinoma cells undergoes a slow post-translational modification whereby it acquires (t1/2 = 30-40 min) EGF binding capacity (Slieker, L.J., et. al. (1986) J. Biol. Chem., 261, 15233-15241). This activation occurs in the endoplasmic reticulum and requires core N-linked glycosylation. By employing both anti-EGF receptor and anti-phosphotyrosine antibodies to immunoprecipitate receptor pulse-labeled with [35S]methionine, we demonstrate here that the EGF receptor also acquires tyrosine kinase autophosphorylation activity post-translationally (t1/2 = 10-15 min). The acquisition of tyrosine kinase activity is independent of the acquisition of EGF binding capacity, since it precedes the latter process and does not require N-linked glycosylation.
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PMID:Biosynthesis of the epidermal growth factor receptor: post-translational glycosylation-independent acquisition of tyrosine kinase autophosphorylation activity. 245 10

The human epidermoid carcinoma cell line A431, containing an amplification in the epidermal growth factor (EGF) receptor gene, was examined for its sensitivity to the growth inhibitory effects of synthetic double-stranded RNAs (dsRNAs). Poly(I).poly(C), poly(A).poly(U) and rln.r(C13,U)n at 5 to 100 micrograms/ml produced 20 to 60% growth inhibition, whereas poly(ICLC) produced 40 to 80% growth inhibition at 0.05 to 25 micrograms/ml.Poly(I).poly(C) did not cause the secretion of interferon (IFN) into the medium, and addition of polyclonal antibodies to IFN-alpha and IFN-beta did not block the growth inhibition produced by poly(I).poly(C). Clone 29, which proliferates in response to EGF, and clone 29R, which is sensitive to the growth inhibitory effects of EGF, showed sensitivities to the antiproliferative effects of poly(I).poly(C) similar to those of the parent cell line. Incubation of cell membrane extracts with poly(I).poly(C) or treatment of cells with the dsRNA did not affect EGF receptor tyrosine kinase activity. On the other hand, poly(I).poly(C) produced a dose-dependent induction of (2',5')oligo(A) synthetase activity and degradation of 45S preribosomal RNA and 28S and 18S rRNA. These results indicate that the growth inhibitory properties of poly(I).poly(C) in A431 cells are independent of the action of IFN but are associated with degradation of rRNA, an effect that may be related to the (2',5')oligo(A)-RNase L pathway.
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PMID:The epidermal growth factor- and interferon-independent effects of double-stranded RNA in A431 cells. 245 91

The neu (c-erbB-2) gene encodes a transmembrane protein with tyrosine kinase activity that appears to be a growth factor receptor. Antibody was generated by immunization of rabbits with a synthetic polypeptide that was based on an internal sequence at the carboxy terminus of the molecule. This antibody was used to survey the expression of neu in human skin by immunohistochemistry. Significant protein was found in the squamous cell layer of the surface epidermis, in squamous cell carcinomas, in the external root sheath of hair follicles, and in eccrine gland secretory cells; it was poorly expressed in the basal cell layer and in a basal cell carcinomas. Increased neu expression appears to be associated with the differentiation of keratinocytes.
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PMID:Distribution of neu (c-erbB-2) protein in human skin. 247 Aug 27


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