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Query: UNIPROT:P06889 (Mol)
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Several physiological parameters were examined for inducing acinar cell proliferation and corresponding increased expression of beta 1-4 galactosyltransferase. In this study, dietary changes causing acinar cell proliferation included the following: the introduction of animals to a liquid diet (causing gland atrophy) followed by reintroduction of solid chow, gustatory stimulation provided by the introduction of 0.5% citric acid to animal drinking water, and removal of the submandibular gland with subsequent reliance on the parotid gland for salivary protein. Alterations in growth factor levels were produced by injecting animals with a chronic (3 day) regimen of either nerve growth factor or epidermal growth factor. Parotid gland proliferation could be blocked in all cases except EGF by the injection of propranolol, a beta-adrenoceptor antagonist, or the galactosyltransferase specific modifier protein, alpha-lactalbumin. EGF-induced proliferation could, however, be prevented by treating the animals with monoclonal antibody to EGF receptor or galactosyltransferase modifier protein alpha-lactalbumin. These results for normal acinar cell proliferation suggest a direct role for cell surface beta 1-4 galactosyltransferase in signalling and maintaining active cell growth.
Mol Cell Biochem 1990 Jun 01
PMID:Cell surface galactosyltransferase acts as a general modulator of rat acinar cell proliferation. 211 24

Epidermal growth factor (EGF) treatment of NIH 3T3 cells transfected with wild-type EGF receptor induced tyrosine phosphorylation of phospholipase C-gamma (PLC-gamma). The EGF receptor and PLC-gamma were found to be physically associated such that antibodies directed against PLC-gamma or the EGF receptor coimmunoprecipitated both proteins. The association between PLC-gamma and wild-type EGF receptor was dependent on the concentration of EGF, but EGF did not enhance the association between PLC-gamma and a kinase-negative mutant of the EGF receptor. Oligomerization of the EGF receptor was not sufficient to induce association of the EGF receptor with PLC-gamma, since the kinase-negative mutant receptor underwent normal dimerization in response to EGF yet did not associate with PLC-gamma. The form of PLC-gamma associated with the EGF receptor appeared to be primarily the non-tyrosine-phosphorylated form. It is concluded that the kinase activity of the EGF receptor is essential for association of PLC-gamma with the EGF receptor, possibly by stimulating receptor autophosphorylation.
Mol Cell Biol 1990 Feb
PMID:Tyrosine kinase activity is essential for the association of phospholipase C-gamma with the epidermal growth factor receptor. 215 14

Studies investigated the effects of benzo(a)pyrene (BP) treatment on epidermal growth factor (EGF) receptor binding and kinase activity in human placental cell cultures. Specific binding of 125I-EGF to cells from early gestation placentae was significantly decreased by 37 and 60% following exposure to 1 and 10 microM BP, respectively, for 24 hr. In contrast, cells cultured from term placentae showed no inhibitory effect of either concentration of BP. Specific binding of 125I-labeled insulin and insulin-like growth factors-I and -II to early gestation cells was decreased only 15-18% at 10 microM BP, which indicates that loss of membrane receptors appears to be selective for EGF. Scatchard analysis of early gestation cells revealed that BP was associated with a dose-dependent loss in the number of high affinity EGF binding sites. Evidence from cross-linking and autophosphorylation experiments confirmed that the Mr 170,000 binding protein was decreased in a dose-dependent manner following BP treatment. In comparison, term placental cells exhibit a 26% loss of EGF receptor autophosphorylation without alteration in binding following exposure to 10 microM BP. Thus, early gestation cells exhibit a BP-related down-regulation of EGF receptors, whereas term placental cells show receptor desensitization. No adverse effect of BP treatment was observed on the incorporation of [35S] methionine into proteins secreted by early gestation cells. Further experiments compared the effects of BP with the related poly-cyclic compounds beta-naphthoflavone, alpha-naphthoflavone, and 3-methylcholanthrene. In early gestation cells, EGF binding and receptor autophosphorylation were measurably decreased at 10 microM concentrations of these polycyclic compounds, but to a lesser extent than observed with BP. In term placental cells, however, EGF binding was unchanged or increased, whereas receptor autophosphorylation was decreased 10-26%. Thus, exposure of term placental cells to these polycyclic compounds leads to a dissociation between EGF binding and receptor protein kinase activity. Finally, aryl hydrocarbon hydroxylase activity was induced 20- to 200-fold in early placental cells exposed to BP, beta-naphthoflavone, and 3-methylcholanthrene. In summary, the direct effects of BP and related compounds observed on placental EGF receptors may indicate altered function of EGF in the regulation of cell growth and differentiation in the human placenta.
Mol Pharmacol 1990 Feb
PMID:Benzo(a)pyrene inhibits epidermal growth factor binding and receptor autophosphorylation in human placental cell cultures. 215 66

The role of growth factor signal transducers in the induction of the progesterone receptor by epidermal growth factor (EGF) and the potential sites of EGF antagonism by an antiestrogen were studied in fetal uterine cells in culture. The effects of EGF and estradiol were not additive, suggesting that EGF and estradiol are acting through common mechanisms where antiestrogens could possibly intervene. Fetal uterine cells in culture were found to contain specific, high affinity binding sites for [125I]EGF. Estradiol treatment of the cells led to a higher number of binding sites, but the site of action of 4-hydroxytamoxifen is not the EGF receptor because this antiestrogen had no effect on EGF binding. Activation of protein kinase C by a phorbol ester (12-O-tetradecanoylphorbol 13-acetate) increased progesterone receptor levels to a similar extent as EGF or estradiol. Increasing the intracellular cAMP concentrations by either adding dibutyryl cyclic AMP or activating adenylate cyclase with forskolin also raised progesterone receptor concentrations. Neither the phorbol ester nor dibutyryl cAMP had any effect on cell proliferation. 4-Hydroxytamoxifen completely abolished the effects of the phorbol ester and cAMP. In conclusion, the levels of an estrogen-induced steroid hormone receptor can be regulated by molecules involved in the signal transduction pathway of peptide factors. Moreover, in fetal uterine cells, a potent antiestrogen appears to act as a multiple antagonist but only on an estrogen-inducible response.
Mol Cell Endocrinol 1990 Mar 05
PMID:Stimulation of progesterone receptors by phorbol ester and cyclic AMP in fetal uterine cells in culture. 215 66

In response to epidermal growth factor (EGF) stimulation, the intrinsic protein tyrosine kinase of EGF receptor is activated, leading to tyrosine phosphorylation of several cellular substrate proteins, including the EGF receptor molecule itself. To test the mechanism of EGF receptor autophosphorylation in living cells, we established transfected cell lines coexpressing a kinase-negative point mutant of EGF receptor (K721A) with an active EGF receptor mutant lacking 63 amino acids from its carboxy terminus. The addition of EGF to these cells caused tyrosine phosphorylation of the kinase-negative mutant by the active receptor molecule, demonstrating EGF receptor cross-phosphorylation in living cells. After internalization the kinase-negative mutant and CD63 have separate trafficking pathways. This limits their association and the extent of cross-phosphorylation of K721A by CD63. The coexpression of the kinase-negative mutant together with active EGF receptors in the same cells suppressed the mitogenic response toward EGF as compared with that in cells that express active receptors alone. The presence of the kinase-negative mutant functions as a negative dominant mutation suppressing the response of active EGF receptors, probably by interfering with EGF-induced signal transduction. It appears, therefore, that crucial events of signal transduction occur before K721A and active EGF receptors are separated by their different endocytic itineraries.
Mol Cell Biol 1990 Aug
PMID:Evidence for epidermal growth factor (EGF)-induced intermolecular autophosphorylation of the EGF receptors in living cells. 216 34

The receptor for epidermal growth factor (EGF) and its analog transforming growth factor alpha (TGF alpha) is ubiquitous, implying quite general roles for EGF/TGF alpha in cell viability and tissue maintenance in adult tissues. There is also evidence that the EGF receptor is active in promoting wound healing and tissue regeneration in adult organs, such as skin, liver, and intestinal epithelium. It is likely that EGF receptors have more specific roles during the gestation period. For example, we have detected EGF receptors on the 3.5-day blastocyst (trophectoderm) surface and since TGF alpha-like mRNA sequences and peptides have been detected at this time (Rappolee et al., Science 241:1823, 1988), there is a strong implication for autocrine stimulation in pre- and peri-implantation stage embryos. Paracrine stimulation between the embryo and maternal tissues is also likely since both receptors and TGF alpha are present in decidual cells. Therefore EGF receptors may take part in growth regulation of the early embryo and in the process of implantation. Other examples where EGF receptors may play specific roles during embryonic development are discussed.
Mol Reprod Dev 1990 Sep
PMID:EGF receptor activities in mammalian development. 227 Nov 81

In summary, although TGF-alpha was initially found in tumors, a number of later studies, some of them from the author's laboratory, have shown that TGF-alpha should no longer be considered a tumor associated growth factor. Rather, TGF-alpha is a normal physiological ligand for the EGF receptor. Table 2 lists some of the normal cellular sources of TGF-alpha. Our list is incomplete, but we know that TGF-alpha is made in keratinocytes and a number of epithelial cells, including gut and breast epithelial cells. It seems very likely that TGF-alpha is a major growth factor secreted by cells of epithelial origin. Zena Werb's and Russell Ross's groups have shown that activated macrophages make TGF-alpha. We have shown that brain makes TGF-alpha and Jeff Kudlow has found TGF-alpha made in the pituitary. Data from several sources, including David Lee, the author's laboratory, and Zena Werb's laboratory has shown that TGF-alpha is made during embryonic development. Therefore, it is now important to look at TGF-alpha in its normal physiological context. Finally, it should be stressed that, as was mentioned above, TGF-alpha is not necessarily a secreted growth factor 50 amino acids long. There is quite a bit of processing of the larger precursor that may or may not take place. This processing, which determines the ultimate size and location of the molecule, is also likely to influence its physiological action.
Mol Reprod Dev 1990 Sep
PMID:Transforming growth factor-alpha. 227 Nov 84

From the results of these studies of the activities of the various EGF receptor mutants we were able to disassociate the ability of EGF to increase intracellular calcium from its ability to induce genes and to cause morphological transformation and growth. These results lead us to the following concept. The kinase domain has a C-terminal border at about residue 957. The remainder of the C-terminus is regulatory. The 164 amino acids from residue 1022 to 1186 constitute an inhibitory region for the kinase. It contributes to ligand-induced internalization because this is reduced in a mutant receptor truncated to residue 1052. Proximally within the C-terminus kinase inhibitory domain is a domain that is required for endocytosis and for raising intracellular calcium that we call the calcium internalization (CAIN) domain. In summary, we have found that the kinase activity of the EGF receptor is required for its function even when all of the self-phosphorylation sites have been removed. The EGF receptor has several distinct cytoplasmic domains that are important for its activity to regulate gene expression, DNA synthesis, and the intracellular calcium level. Biological signaling occurs from the cell surface via essential protein tyrosine kinase activity with ligand-induced internalization serving to abbrogate the biological signal.
Mol Reprod Dev 1990 Sep
PMID:Regulation of EGF receptor expression and function. 227 Nov 86

While steroid hormones act as endocrine effectors of growth and development of normal breast and of carcinogenesis and progression of malignant breast, recent evidence suggests that local hormonal effectors also exist. These are the growth regulatory growth factors. This article summarizes current status of our understanding of structure and function of growth factors secreted by the normal and malignant mammary epithelium. While growth inhibitory factors and their receptors generally suppress development of the transformed phenotype and promote differentiation, growth stimulatory factors and their receptors may be necessary for both normal proliferation and early stages of malignant progression of breast cancer. Overexpression of two receptors, c-erbB-2 and EGF receptor, have also been associated with poor prognosis in the clinical disease.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Stimulatory and inhibitory growth factors and breast cancer. 228 93

The EGF receptor is a potential target for antitumor therapy, because it is expressed at high levels on many human tumor cells and appears to be involved in autocrine stimulation of cell growth in a number of experimental studies. Anti-EGF receptor MAbs, which block ligand binding, can prevent the growth in culture of cells that are stimulated by EGF or TGF-alpha. Growth of human tumor xenografts bearing high levels of EGF receptors is also inhibited. A Phase I trial in patients with squamous cell carcinoma of the lung has demonstrated the capacity of a single dose of 120 mg anti-EGF receptor MAb to localize in such tumors and to achieve saturating concentrations in the blood for more than 3 days, without causing toxicity.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Anti-epidermal growth factor receptor monoclonal antibodies as potential anti-cancer agents. 228 2


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