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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bradykinin gave a biphasic increase in intracellular free Ca2+ concentration ([Ca2+]i) in serum-deprived Swiss 3T3 fibroblasts loaded with the photoprotein aequorin. Epidermal growth factor (EGF) alone did not increase [Ca2+]i, but when added after bradykinin there was an increase in [Ca2+]i. The EGF-dependent increase in [Ca2+]i was maximal at 3 min and disappeared with a half-life of 6 min after bradykinin. Removing Ca2+ from the external medium did not abolish either the bradykinin or the EGF-induced [Ca2+]i responses. Although prostaglandins E2 and F2 alpha also gave [Ca2+]i responses and permitted an EGF-dependent [Ca2+]i response, the effect of bradykinin did not appear to be mediated by prostaglandins since it was not blocked by indomethacin. Vasopressin and phorbol 12-myristate 13-acetate both gave a [Ca2+]i response but did not facilitate a [Ca2+]i response by EGF. Bradykinin or EGF alone did not increase DNA synthesis in growth-arrested Swiss 3T3 fibroblasts, but EGF added together with, or after, bradykinin increased DNA synthesis. The effect disappeared with a half-life of 180 min after the addition of bradykinin. It is concluded that stimulation of receptor protein tyrosine kinase is unlikely, by itself, to explain the increase in DNA synthesis produced by EGF. The observed increase in [Ca2+]i caused by EGF after bradykinin probably reflects the interaction of intracellular second messenger pathways leading to facilitation of DNA synthesis.
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PMID:An increase in intracellular free Ca2+ associated with serum-free growth stimulation of Swiss 3T3 fibroblasts by epidermal growth factor in the presence of bradykinin. 326 65

Epidermal growth factor (EGF) receptor (EGFR) can induce cell growth and transformation in a ligand-dependent manner. To examine whether the autophosphorylation of EGFR correlates with the capacity of the activated EGFR to induce cell growth and transformation, we truncated the human EGFR just after residue 1011, removing all three major autophosphorylation sites (DEL1011). Further, a point mutation was introduced at another autophosphorylation site, Tyr-992-->Phe (DEL1011+F992). The wild-type and mutant receptors were stably expressed in a NIH 3T3 variant cell line that expresses an extremely low level of endogenous EGFR and does not grow with EGF. As expected, DEL1011 and DEL1011+F992 were found to be severely impaired in EGF-induced autophosphorylation, due to the deletion of the appropriate target tyrosines. However, mutant receptors still could induce EGF-dependent DNA synthesis, morphological transformation, and anchorage-independent growth, although the extent of these was significantly reduced when compared with wild-type EGFR. EGF-induced tyrosine phosphorylation of Ras-GTPase activating protein-associated protein p62 and phospholipase C gamma 1 was dramatically reduced in the cells expressing DEL1011 and DEL1011+F992. On the other hand, tyrosine phosphorylation of Shc, complex formation of Shc-Grb2/Ash, and activation of microtubule-associated protein kinase were still fully induced upon EGF stimulation without binding of Shc or Grb2/Ash to the mutant receptor. Thus, tyrosine phosphorylation of Shc may play a crucial role for activating Ras and generating mitotic signals by the activated EGFR mutant.
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PMID:Epidermal growth factor-receptor mutant lacking the autophosphorylation sites induces phosphorylation of Shc protein and Shc-Grb2/ASH association and retains mitogenic activity. 750 13

Alteration of placental development directly interferes with fetal growth. Epidermal growth factor (EGF) plays a major role in placental implantation, growth and differentiation. EGF acts on its placental target cells, i.e. the trophoblasts, via a specific receptor (EGFR) which belongs to the tyrosine kinase receptor family. Abundant placental EGF receptors are located in the brush border at the fetomaternal interface. EGFR expression is modulated by trophoblast differentiation and by hormones or toxic substances such as smoke. Interestingly, in microvilli purified from placentae of infants with intrauterine growth retardation (IUGR) a decrease or absence of tyrosine kinase activity is observed. This suggests that an alteration of EGFR biological activity might interfere with the fetoplacental unit development.
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PMID:Epidermal growth factor receptor and human fetoplacental development. 773 66

Epidermal growth factor (EGF), its related peptide transforming growth factor (TGF-alpha) and their common receptor (EGFR) have been implicated in the control of cell proliferation and differentiation in the gastrointestinal epithelium and may play an important role in gastric carcinogenesis. We compared the immunohistochemical expression and topographic distribution of these peptides using Western blot analysis in gastric carcinoma precursor lesions and in non-cancer tissue. We observed: (i) increased and extended expression of TGF-alpha in normal mucosa and hyperplasia in carcinoma fields compared with non-cancer controls; (ii) increased expression of EGFR in intestinal metaplasia (IM) from carcinoma fields compared with controls; (iii) EGF expression was not detected in normal mucosa and only weakly in IM; (iv) coexpression of TGF-alpha/EGFR and EGF/EGFR was higher in intestinal metaplasia in carcinoma fields than in non-cancer controls. We conclude that altered expression of TGF-alpha/EGFR is associated with morphological changes during gastric carcinogenesis. In this regard increased expression of TGF-alpha is a very early event which is subsequently followed by up-regulation of EGFR and this has important biological and clinical implications.
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PMID:Expression of transforming growth factor alpha, epidermal growth factor receptor and epidermal growth factor in precursor lesions to gastric carcinoma. 781 44

Epidermal growth factor (EGF) is a mitogenic peptide that binds to surface membrane receptors (EGFR) of breast cancer cells. After binding, secondary transmitter molecules are activated by tyrosine phosphorylation of the intracellular receptor domaine. The activity of the EGF/EGFR system can be modulated by a variety of chemically unrelated compounds including cytostatic agents. The purpose of our present study was to determine the effects of mitotic inhibitors on EGF receptor binding on human breast cancer cells. We found that MDA-231 and MDA-468 cells bind substantially more [125I]EGF after preincubation with docetaxel, vinblastine and vincristine. This effect was concentration- and time-dependent, reaching a maximum at 3000 ng/ml and 48 h incubation for docetaxel, and 100 ng/ml and 48 h incubation for vinca alcaloids. Subsequent experiments showed an increase in the rate of EGF binding as well as maximal binding capacity. Scatchard analysis of binding experiments under equilibrium conditions indicated that this was due to an increase in the number of apparent EGF binding sites. Modulation of EGF receptor binding by docetaxel, vinblastine, and vincristine was not detectable when isolated membranes were used, indicating that intact cytoplasmatic mechanisms are required for the upregulation of EGF receptors.
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PMID:Effects of the microtubule-disturbing agents docetaxel (Taxotere), vinblastine and vincristine on epidermal growth factor-receptor binding of human breast cancer cell lines in vitro. 783 45

Epidermal growth factor (EGF) stimulates adenylyl cyclase in the heart via activation of the stimulatory GTP-binding protein Gs. Therefore, employing peptides corresponding to regions in the cytosolic domain of the EGF receptor, we have investigated the ability of sequences within the EGF receptor to activate Gs. A 13-aa peptide (EGFR-13) corresponding to the juxtamembrane region in the cytosolic domain of the EGF receptor stimulated GTP binding and GTPase activity of Gs. This peptide did not stimulate GTP binding to Gi but increased the GTPase activity of this protein. Additionally, phosphorylation of the protein kinase C site (threonine residue) within EGFR-13 decreased the ability of the peptide to stimulate Gs and increase GTPase activity of Gi. Further, in functional assays of Gs employing S49 cyc- cell membranes, EGFR-13 increased the ability of Gs to stimulate adenylyl cyclase; phospho-EGFR-13 and a 14-aa peptide corresponding to a sequence in the cytosolic domain of the EGF receptor did not alter the functional activity of Gs. Hence, the juxtamembrane region of the EGF receptor can activate Gs and, by stimulating GTPase activity of Gi, inactivates this latter G protein. Phosphorylation of the threonine residue within this region attenuates the activity of the peptide as a modulator of G-protein function.
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PMID:A region in the cytosolic domain of the epidermal growth factor receptor antithetically regulates the stimulatory and inhibitory guanine nucleotide-binding regulatory proteins of adenylyl cyclase. 789 52

Epidermal growth factor (EGF), a polypeptide with a potent mitogen activity, and its receptor [EGFR] have been previously identified in the kidney, but their expression in normal and diseased kidneys has not been fully elucidated. In order to evaluate EGFR in various histological types of renal injury, EGFR expression was studied by the immunohistochemical avidin-biotin complex (ABC) method with a monoclonal antibody EGFR1 on paraffin sections from 10 normal kidneys, 56 renal biopsies with various types of glomerulonephritis (GN), and 20 renal grafts with rejection. EGFR expression was observed in (a) 3 of 10 (30%) normal kidneys, (b) 17 of 39 (43.6%) renal biopsies with various types of GN mainly in membranous GN (57%) and in focal segmental glomerulosclerosis (FSG) (62.5%), (c) 6 of 17 (35.3%) biopsies with various types of systemic lupus erythematosus GN, and (d) 12 of 20 (60%) renal grafts with acute (42.9%) and chronic (69.2%) rejection. EGFR was mainly localized to the epithelial cells of the distal and collecting tubules and extraglomelar vessels, while it was observed less frequently in parietal epithelial cells and along glomerular basement membranes. Notably EGFR was detected in the epithelial cells adjacent to adhesions with Bowman's capsule and in the connective tissue of fibrocellular crescents. In conclusion, EGFR expression was observed more frequently in diseased than in normal kidneys. The increased incidence of EGFR expression in FSG, in chronic rejection, in small adhesions with Bowman's capsule and fibrocellular crescents suggest that EGF/EGFR may be correlated with a disturbed extracellular matrix production resulting in formation of early sclerotic lesions.
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PMID:Immunohistochemical study of epidermal growth factor receptor (EGFR) in various types of renal injury. 797 Jan 18

Epidermal growth factor (EGF) and its receptor (EGFR) were measured in 60 breast cancers (BC), 6 benign mammary tumors (BM), 8 samples of normal breast (NB), 6 endometrial carcinomas (EC) and 30 lung cancers (LC). EGF was measured in plasma, saliva and urine from 20 patients with BC, before and after tumor excision, and in 8 patients with metastatic disease. The median EGF in BM and BC was significantly higher (P < 0.05) than in NB. No significant correlation between EGF and EGFR was found in BC. Neither tumor excision nor the spreading of the disease significantly modified the EGF concentrations in biological fluids. In LC there was an inverse relationship between EGF and EGFR (rs = -0.36; P = 0.09), which disappeared in normal lung. It is concluded that EGF may play a role in malignant transformation; however, the weak correlation between EGF and EGFR lessens the importance of EGF in either autocrine or paracrine stimulation of tumor growth.
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PMID:Epidermal growth factor in human breast cancer, endometrial carcinoma and lung cancer. Its relationship to epidermal growth factor receptor, estradiol receptor and tumor TNM. 851 68

Epidermal growth factor is a potential mitogen for many different human tumours. Its effect is mediated via a bispecific receptor (EGFR), the expression of which correlates well with invasive disease. We investigated the modulation of EGFR by cytokines produced following bacillus Calmette Guerin (BCG)-immunotherapy. Our data demonstrate the IFN gamma, TNF alpha and IL-1 alpha can decrease the expression of EGFR on some bladder tumour cell lines. IFN gamma reduced EGFR expression on two of eight cell lines (RT4, SD). However, IL-1 and TNF did not share this activity. When cells were treated with a combination of all three cytokines, EGFR was decreased on three cell lines (RT4, RT112, SD) and furthermore, the change in the receptor expression was even more marked. Treatment with phorbol ester (thereby activating protein kinase C) resulted in rapid disappearance of the receptor from the cell surface. Interestingly, the decrease of EGFR expression did not require protein synthesis. Although the cytokines studied could down modulate EGFR, this only occurred on three out of eight cell lines; therefore, it is unlikely that the suppression of proliferative activity caused by cytokine-induced decrease of EGFR expression is central to the antitumour action of BCG therapy, but in a proportion of tumours this mechanism may be involved.
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PMID:Cytokine modulation of epidermal growth factor receptor expression on bladder cancer cells is not a major contributor to the antitumour activity of cytokines. 856 66

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) regulate branching morphogenesis of fetal mouse submandibular gland (SMG) rudiments in vitro. The EGF system (EGF, TGF-alpha, and their shared receptor, EGFR) also regulates expression of integrins and their ligands in the extracellular matrix. We show here that inhibition of EGFR tyrosine-kinase activity by a tyrphostin retards in vitro development of SMGs. Using total RNA isolated from pooled SMGs taken from intact mouse fetuses, mRNA transcripts for EGF, TGF-alpha, and EGFR were detected by reverse transcription-polymerase chain reaction (RT-PCR), and age-dependent variations in the levels of these mRNA were quantitatively determined by nuclease protection assays. These findings suggest that the EGF system is operative in the in vivo development of this gland. alpha6-Integrin subunit was localized by immunofluorescence at the basal surface of epithelial cells. Branching morphogenesis of cultured SMG rudiments was inhibited by anti-alpha6 antibodies. Synthesis of alpha6-subunit in cultured SMGs, detected by metabolic labeling and immunoprecipitation, was increased by EGF and drastically reduced by tyrphostin. RT-PCR revealed that mRNAs for alpha6- and beta1- and beta4-integrin subunits are expressed at all ages between embryonic day 13 and postnatal day 7. These findings suggest that 1) the EGF system is a physiologic regulator of development of fetal mouse SMG, and 2) one mechanism by which it acts may be by regulating expression of integrins, which in turn control interaction of epithelial cells with the extracellular matrix.
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PMID:Epidermal growth factor system is a physiological regulator of development of the mouse fetal submandibular gland and regulates expression of the alpha6-integrin subunit. 902 52


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