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)

The discovery of EGFR gene amplification in glioblastoma multiforme has prompted interest in experimental therapies to target the receptor on brain tumor cells. To develop an animal model for in vivo study of such strategies, we transfected C6 glioma cells with a plasmid containing the neomycin resistance gene and the human EGFR gene under the control of the glucocorticoid-inducible MMTV promoter. Following selection with G418, individual clones that expressed EGFR at high levels were selected. Kinetics of EGF binding fit a dual site model indicating the presence of both high (KA = 2.5 x 10(9) M-1) and low (KA = 3.3 x 10(7) M-1) affinity receptors. To assess growth in vivo, graded numbers of either wild-type or transfected cells were implanted into the brains of CD Fischer 344 rats. No differences in survival were observed between groups of animals injected with either wild-type or transfected cells at inocula of 10(3) or 10(4) respectively. In addition, one-third of animals (7/21) challenged with 10(5) or 10(6) transfected cells survived > 50 days compared to 0% of animals (0/12) challenged with 10(5) or 10(6) wild-type cells. Such an effect suggests greater immunogenicity of transfected cells, but only at the larger inocula. Since C6 glioma cells will grow in both outbred and inbred strains, our model should have a number of applications including the in vivo study of EGFR targeting for glioma therapy.
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PMID:The effect of epidermal growth factor receptor (EGFR) expression on in vivo growth of rat C6 glioma cells. 747

The receptor erbB2/neu is a member of the epidermal growth factor receptor (EGFR or erbB) family that also includes erbB3 and erbB4. Amplification of the erbB2/neu gene is found in many cancer types and its overexpression is correlated with a poor prognosis for breast and ovarian cancer patients. Investigation of the biology of erbB2 led to the identification of a family of ligands termed neuregulins which included the neu-differentiation factors, the heregulins, a ligand with acetylcholine-receptor-inducing activity and glial growth factor. Several lines of evidence suggest that heterodimerization of erbB2 with other erbB receptors is required for neuregulin signalling. Here we investigate the developmental role of erbB2 in mammalian development in mice carrying an erbB2 null allele. We find that mutant embryos die before E11, probably as a result of dysfunctions associated with a lack of cardiac trabeculae. Development of cranial neural-crest-derived sensory ganglia was markedly affected. DiI retrograde tracing revealed that the development of motor nerves was also compromised. Our results demonstrate the importance of erbB2 in neural and cardiac development.
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PMID:Requirement for neuregulin receptor erbB2 in neural and cardiac development. 747 64

Ligand dependent activation of receptor tyrosine kinases is mediated by an allosteric dimerization process that is responsible for the stimulation of protein tyrosine kinase activity and receptor autophosphorylation. In order to gain further insight into the processes which control this process, we have generated EGF receptor mutants that contain inserts of 20-40 amino acids in their juxtamembrane regions, on each side of the receptor's single transmembrane domain. An EGF receptor mutant with an insertion on the cytoplasmic side of the transmembrane domain exhibited typical EGF binding characteristics, ligand-dependent tyrosine autophosphorylation, as well as ligand-induced DNA synthesis. However, an EGF receptor mutant with an insertion on both sides of the transmembrane domain was found to be constitutively activated. This mutant also exhibited dramatically reduced EGF binding, but dimerized and had enhanced tyrosine kinase activity even in the absence of ligand. Moreover, NIH3T3 cells expressing this mutant receptor formed colonies in soft agar in the absence of EGF. This represents a novel example of a constitutively activated receptor, and provides further support for receptor dimerization as a mechanism for activation of EGFR and other receptor tyrosine kinases.
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PMID:Activation of the EGF receptor by insertional mutations in its juxtamembrane regions. 747 77

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

Human tumors can constitutively express cytokines and growth factors, but the extent of this expression has not been investigated. Using 44 different probes to cytokines, growth factors, and their receptors, we tested 21 melanoma and 5 melanocyte cultures for RNA transcript expression by reverse transcriptase-polymerase chain reaction. With 30 amplification cycles, expression of the cytokines interleukin (IL)-1 beta, IL-6, leukemia inhibitory factor (LIF), IL-7, gro alpha, IL-8 and the p35 chain of IL-12 was detected in more than 60% of melanomas. Concomitant receptors for IL-6 and IL-7 were also detected. IL-1 alpha, IL-5, Rantes, IL-10, interferon (IFN)-beta, tumor-necrosis factor (TNF)-alpha, G-colony-stimulating factor (CSF) and GM-CSF were expressed at lower levels. Melanocytes showed greatly reduced cytokine RNA transcripts, and only gro alpha was consistently detected. No expression of IL-2, IL-3, IL-4, IL-9, the p40 chain of IL-12, IFN-alpha or IFN-gamma RNA transcripts was detected in melanomas or melanocytes. The growth factors expressed by melanomas and, after further signal amplification, by melanocytes were transforming growth factor (TGF)-alpha, epidermal growth factor (EGF), TGF-beta, endothelial-cell growth factor (ECGF), basic-fibroblast growth factor (bFGF), nerve growth factor (NGF) and steel. The receptors EGFR, FGFR, NGFRp70 and c-kit were also expressed by melanomas and melanocytes. These results point to new possible autocrine and paracrine pathways in melanoma biology.
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PMID:Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes. 750 78

About one in three people in modern industrialised countries die of the consequences of malignant tumours or are found to carry an unsuspected one at the time of autopsy. Early resection of such lesions and appropriate adjuvant therapy is very effective in curing the disease. There is therefore a strong clinical incentive to find effective methods of early diagnosis, assessment of prognosis and treatment of neoplastic lesions and research on this topic is directed at a numerically significant medical problem. Recently it has been found that many human tumours show severe abnormalities in the expression of the CD44 gene which increase with progression to metastatic malignancy. By alternative splicing mechanisms this gene codes for a family of heavily glycosylated cell surface proteins involved in many important cellular activities. In neoplasia there is gross overexpression of various products of the gene associated with disorderly splicing, which can be detected in clinical samples with the sensitive technique of reverse transcription-polymerase chain reaction (RT-PCR). These disturbances begin early in the neoplastic process and can be detected in very small biopsy samples. It has also been shown that it is possible to achieve non-invasive diagnosis of malignancy by analysis of CD44 expression in exfoliated cells in body fluids and waste products. The potential significance of these observations for early diagnosis of symptomatic cancer and for screening of the population for asymptomatic lesions are readily seen and await further investigation. Separate work in our laboratory has succeeded in DNA-mediated transfer of metastatic capability through two rounds of transfection into non-metastatic tumour cells and a metastasis-associated human DNA fragment has been recovered from the transfectants and sequenced. Using primers designed to anneal to a coding region identified by computer analysis within the novel sequence, it has been shown with RT-PCR that it is heavily expressed in metastatic cancer tissues, but not in corresponding normal ones. This could be of value in assessing the prognosis of patients using small biopsy samples from their primary tumours and the potential of this sequence for such purposes and for possible therapeutic intervention is currently being explored. Recent work in several laboratories has shown that elevated expression of certain other specific growth factor genes, including c-met and EGFR, correlates with metastatic capability. Combined evaluation of such markers in further studies will in time give useful information on the prognosis of individual patients to guide therapeutic decisions and the implications of these recent advances for clinical practice and future research are discussed below.
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PMID:Deranged activity of the CD44 gene and other loci as biomarkers for progression to metastatic malignancy. 751 58

We analyzed the binding site(s) for Grb2 on the epidermal growth factor (EGF) receptor (EGFR), using cell lines overexpressing EGFRs containing various point and deletion mutations in the carboxy-terminal tail. Results of co-immunoprecipitation experiments suggest that phosphotyrosines Y-1068 and Y-1173 mediate the binding of Grb2 to the EGFR. Competition experiments with synthetic phosphopeptides corresponding to known autophosphorylation sites on the EGFR demonstrated that phosphopeptides containing Y-1068, and to a lesser extent Y-1086, were able to inhibit the binding of Grb2 to the EGFR, while a Y-1173 peptide did not. These findings were confirmed by using a dephosphorylation protection assay and by measuring the dissociation constants of Grb2's SH2 domain to tyrosine-phosphorylated peptides, using real-time biospecific interaction analysis (BIAcore). From these studies, we concluded that Grb2 binds directly to the EGFR at Y-1068, to a lesser extent at Y-1086, and indirectly at Y-1173. Since Grb2 also binds Shc after EGF stimulation, we investigated whether Y-1173 is a binding site for the SH2 domain of Shc on the EGFR. Both competition experiments with synthetic phosphopeptides and dephosphorylation protection analysis demonstrated that Y-1173 and Y-992 are major and minor binding sites, respectively, for Shc on the EGFR. However, other phosphorylation sites in the carboxy-terminal tail of the EGFR are able to compensate for the loss of the main binding sites for Shc. These analyses reveal a hierarchy of interactions between Grb2 and Shc with the EGFR and indicate that Grb2 can bind the tyrosine-phosphorylated EGFR directly, as well as indirectly via Shc.
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PMID:Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. 751 60

Grb2, composed entirely of SH2 and SH3 domains, serves as an adaptor protein in signaling from growth factor-activated tyrosine kinase receptors. It interacts via its SH2 domain with the autophosphorylated carboxyl-terminal tail of activated epidermal growth factor (EGF) receptor and via its SH3 domains with proline-rich sequences in the Ras guanine nucleotide releasing factor, Son of sevenless (Sos). Recruitment of the Grb2-Sos complex to the receptor upon its stimulation leads to Ras activation. A major question remains as to whether SH2-mediated binding of Grb2 to the activated receptor results in conformational changes that influence its SH3-mediated association with Sos, thereby affecting Sos activity. This question is addressed through studies of the binding to intact Grb2 of an EGF receptor-derived phosphotyrosine-containing peptide and a Sos-derived proline-rich peptide using isothermal titration calorimetry and surface plasmon resonance measurements. The phosphopeptide binds to Grb2 in a 1:1 complex, with a KD of 0.4 microns. The Sos proline-rich peptide binds to Grb2 in a 2:1 complex, with a KD of 22 microns. Saturation of the SH2 domain of Grb2 with the EGFR phosphopeptide was found not to affect its subsequent binding to the Sos peptide. Thus we detected no influence of SH2 binding upon SH3-mediated interactions, suggesting that the domains do not communicate, and that recruitment itself of Sos to the cell surface is sufficient for Ras signaling.
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PMID:Independent binding of peptide ligands to the SH2 and SH3 domains of Grb2. 752 91

The prostatic growth factors require a membrane specific receptor to which they must bind in order to carry out their biological activities correctly. The aim of this study was to isolate and quantify the epidermal growth factor receptor in prostatic tissue and indirectly determine the growth factors acting on it (EGF, TGF alpha, PDGF, NGF, IGF). From September, 1992 to June, 1993, we studied 55 patients. These were divided into two groups: the first group comprised 49 patients with benign prostatic hyperplasia (BPH) and 6 patients with prostatic carcinoma comprised the second group. Samples of the prostate were obtained following suprapubic (12 cases), TUR (38 cases), radical prostatectomy (1 case) and transrectal biopsy (4 cases). The EGFR was determined by radioimmunoassay (EGFR-RIA, Vienna Lab, Labordiagnostica GmbH). For the overall group of patients, we obtained mean EGFR values of 6.36 +/- 0.59 fmol/mg of protein and a positivity of 96.36% and 100% for BPH and malignant proliferative processes, respectively. The foregoing data show that EGFR was isolated from the tissue we analyzed and has an evident role in the regulation of prostate growth.
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PMID:[Involvement of epidermal growth factor receptor (EGFR) in the etiopathogenesis of prostatic proliferative processes]. 752 95

Esophageal cancer is an important problem in the United States. It results in more deaths (over 10,000 annually) than rectal cancer. Furthermore, the incidence of esophageal adenocarcinoma is increasing at a rate faster than that of nearly any other cancer and the reasons for the increase are not well understood. A variety of tumor-suppressor genes (including p53, APC, DCC and Rb) and proto-oncogenes (including prad1, EGFR, c-erb-2 and TGF alpha) may be involved in the development and progression of esophageal cancer. Clinical prognostic factors include stage, Karnofsky performance status, sex, age, anatomic location of the tumor, and degree of weight loss. A new staging system based on depth of wall penetration and lymph node involvement correlates well with prognosis for patients undergoing esophagectomy. Newer staging procedures including endoscopic ultrasound as well as the use of minimally invasive surgery, such as thoracoscopy and laparoscopy, may allow accurate staging without esophagectomy. Surgical resection provides excellent palliation; however, the chance for cure with esophagectomy alone is only 10% to 20%. Adjuvant treatment with pre- or postesophagectomy radiation may improve local-regional control but does not improve survival. Nor has preoperative chemotherapy been shown to improve survival; however, it remains an active area of investigation. Multimodality therapy, namely, chemotherapy and radiation (chemoradiation), given concurrently prior to surgical resection shows promise, with one study indicating a 5-year survival of 34%. A complete pathologic response to chemoradiation correlates with improved survival. Chemoradiation has been shown to be superior to radiation as primary management of esophageal cancer. There has been no successfully completed randomized trial of surgery versus definitive radiation or chemoradiation. However, chemoradiation represents a reasonable alternative to esophagectomy in the primary management of squamous cell carcinoma of the esophagus and chemoradiation also appears to be effective in the treatment of patients with adenocarcinoma of the esophagus, offering significant palliation and a chance for long-term survival as well. Randomized studies of preoperative chemoradiation versus surgery or versus chemoradiation alone are needed. The treatment of advanced esophageal cancer must be directed toward palliation of symptoms. Newer endoscopic techniques, including the use of expansile metal stents, laser ablation, intraluminal high-dose rate brachytherapy, BICAP tumor probe, or photodynamic therapy, offer selected patients short-term palliation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Esophageal cancer. 753 69


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