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 neu protooncogene (also called HER2 and c-erbB2) encodes a cell-surface tyrosine kinase structurally related to the receptor for the epidermal growth factor (EGF). We have previously reported that a candidate ligand for the neu receptor is secreted by ras-transformed fibroblasts. Biochemical analyses of the neu stimulatory activity indicate that the ligand is a 35-kDa glycoprotein that is heat stable but sensitive to reduction. The factor is precipitable by either high salt concentrations or acidic alcohol. Partial purification of the molecule by selective precipitation, heparin-agarose chromatography, and gel filtration in dilute acid resulted in an active ligand, which is capable of stimulating the protooncogenic receptor but is ineffective on the oncogenic neu protein, which is constitutively active. The purified fraction, however, retained the ability to stimulate also the related receptor for EGF, suggesting that these two receptors are functionally coupled through a bidirectional mechanism. Alternatively, the presumed ligand interacts simultaneously with both receptors. The presented biochemical characteristics of the factor are expected to enable a completely purified factor with which to explore these possibilities.
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PMID:Biochemical analysis of the ligand for the neu oncogenic receptor. 167 25

Ten astrocytomas were tested for gene amplification or rearrangement utilizing distinct probes to nine different oncogenes by Southern hybridization. The probes spanned the four major protein-coding classes of oncogenes; growth factor proteins (csis); growth factor receptor/tyrosine kinase-related proteins [erbB1 (epidermal growth factor receptor, EGF-R), neu (HER2/neu, erbB2), mos, yes]; nuclear binding proteins (c-myc, c-fos); and guanosine 5'-triphosphate binding proteins (N-ras, H-ras). Three astrocytomas, all glioblastomas, showed amplification of EGF-R-related sequences, and two of these amplifications were rearranged. Both rearrangements appeared similar by two different restriction endonucleases. Our findings suggest that it is primarily the EGF-R protooncogene (erbB1) that is amplified or rearranged in astrocytic neoplasms. No other oncogenes were amplified or rearranged, although EGF-R and neu cross-hybridization produced a "pseudo-rearranged" pattern for neu in EGF-R-amplified cases. The similar EGF-R restriction endonuclease abnormalities seen in two patients warrant further study.
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PMID:Oncogene abnormalities in astrocytomas: EGF-R gene alone appears to be more frequently amplified and rearranged compared with other protooncogenes. 167 68

We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins. The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalononitrile moiety. In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides. Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2). These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.
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PMID:Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. 167 28

The neu/HER2 proto-oncogene encodes a transmembrane tyrosine kinase homologous to receptors for polypeptide growth factors. The oncogenic potential for the presumed receptor is released through multiple genetic mechanisms including a specific point mutation, truncation at the extracellular domain and overexpression of the protooncogene. Here we show that all these modes of oncogenic activation result in a constitutively phosphorylated neu protein and an increase in tyrosine phosphorylation of a phosphatidylinositol-specific phospholipase (PLC gamma). The examined transforming neu/HER2 proteins, unlike the normal gene product, also co-immunoprecipitated with PLC gamma molecules. A kinase-defective mutant of a transforming neu failed to mediate both tyrosine phosphorylation and association with PLC gamma, suggesting direct interaction of the neu kinase with PLC gamma. This possibility was examined by employing a chimeric protein composed of the extracellular ligand-binding domain of the epidermal growth factor receptor and the neu cytoplasmic portion. The chimeric receptor mediated rapid ligand-dependent modification of PLC gamma on tyrosine residues. It also physically associated, in a ligand-dependent manner, with the phosphoinositidase. Based on the presented results we suggest that the mechanism of cellular transformation by the neu/HER2 receptor involves tyrosine phosphorylation and activation of PLC gamma.
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PMID:Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma. 167 73

A partially agonistic monoclonal antibody, 4D5, known to bind to the extracellular domain of p185HER2 and shown to inhibit long term growth of p185HER2-overexpressing breast cancer cells, was used to study signal transduction and phosphotyrosyl protein substrates associated with this receptor. Normal breast epithelial cells and breast carcinoma cells expressing low levels of p185HER2 were not affected by 4D5. HER2/neu-overexpressing breast cancer cells (BT-474 and SK-Br-3) exposed to 4D5 exhibited rapid phosphorylation of both p185HER2 and an associated 56-kDa phosphotyrosyl protein (ptyr56). Paralleling the 4D5- stimulated phosphorylation of p185HER2 and ptyr56 was a 5-10-fold induction of c-fos mRNA and phosphatidylinositol 4-kinase activity and a 2-fold induction of inositol 1,4,5-trisphosphate 3'-kinase activity. The increased phosphatidylinositol 4-kinase activity immunoprecipitated with p185HER2 and also co-eluted with ptyr56 from an antiphosphotyrosine immunoaffinity column. These results indicate that short term (less than 6 h) 4D5 activation of p185HER2 in overexpressing breast cancer cells produces agonistic-like signaling typical of homologous tyrosine kinase growth factor receptors such as epidermal growth factor receptor. The data also suggest that ptyr56 represents a novel phosphorylated substrate associated with 4D5-stimulated p185HER2.
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PMID:p185HER2 signal transduction in breast cancer cells. 167 43

The HER2 protooncogene encodes a 185-kDa transmembrane protein (p185HER2) with extensive homology to the epidermal growth factor (EGF) receptor. Clinical and experimental evidence supports a role for overexpression of the HER2 protooncogene in the progression of human breast, ovarian, and non-small cell lung carcinoma. These data also support the hypothesis that p185HER2 present on the surface of overexpressing tumor cells may be a good target for receptor-targeted therapeutics. The anti-p185HER2 murine monoclonal antibody (muMAb) 4D5 is one of over 100 monoclonals that was derived following immunization of mice with cells overexpressing p185HER2. The monoclonal antibody is directed at the extracellular (ligand binding) domain of this receptor tyrosine kinase and presumably has its effect as a result of modulating receptor function. In vitro assays have shown that muMAb 4D5 can specifically inhibit the growth of tumor cells only when they overexpress the HER2 protooncogene. MuMAb 4D5 has also been shown to enhance the TNF-alpha sensitivity of breast tumor cells that overexpress this protooncogene. Relevant to its clinical application, muMAb 4D5 may enhance the sensitivity of p185HER2-overexpressing tumor cells to cisplatin, a chemotherapeutic drug often used in the treatment of ovarian cancer. In vivo assays with a nude mouse model have shown that the monoclonal antibody can localize at the tumor site and can inhibit the growth of human tumor xenografts which overexpress p185HER2. Modulation of p185HER2 activity by muMAb 4D5 can therefore reverse many of the properties associated with tumor progression mediated by this putative growth factor receptor. Together with the demonstrated activity of muMAb 4D5 in nude mouse models, these results support the clinical application of muMAb 4D5 for therapy of human cancers characterized by the overexpression of p185HER2.
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PMID:Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. 167 63

The HER2 (c-erbB-2) gene encodes a protein, p185HER2, which possesses all of the structural characteristics and functional properties of a growth factor receptor, although its ligand has not yet been well characterized. HER2 is the human homolog of the rat proto-oncogene neu and is closely related to the gene encoding the epidermal growth factor receptor. Amplification of this gene and overexpression have been found to be a prognostic criterion for a 30% subpopulation of human breast cancer patients. In this study, we investigated the role of the transmembrane-spanning sequence in the biosynthesis and localization of p185HER2. A truncation mutant lacking the cytoplasmic and transmembrane domains was glycosylated and efficiently secreted. However, a mutant lacking only the transmembrane-spanning sequence was incompletely glycosylated and failed to reach the cell surface. Unexpectedly, although this deletion mutant was retained in the endoplasmic reticulum membrane, it was still able to transform NIH 3T3 cells when expressed at high levels.
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PMID:Cell transformation potential of a HER2 transmembrane domain deletion mutant retained in the endoplasmic reticulum. 168 81

Incubation of Swiss 3T3 murine fibroblasts at low temperatures induces phosphorylation on tyrosine of a transmembrane protein of 175 kDa. This phenomenon is time and temperature dependent and reaches a maximum after 2 hr at 4 degrees C. The 175 kDa protein phosphorylated in vivo at low temperatures can be immunoprecipitated by phosphotyrosine antibodies and displays auto-kinase activity in vitro in the presence of radiolabelled ATP. This molecule was found to react with anti-peptide antibodies directed against the product of the HER2/neu proto-oncogene only when immunoprecipitated with phosphotyrosine antibodies from cold-stimulated cells. Activation of protein kinase-C by treatment of the cells with phorbol esters, bombesin or PDGF inhibits the effect of the exposure to low temperatures. Phosphorylation of p175 is not induced by treatment of the cells with the phosphatases inhibitor sodium orthovanadate. These results suggest that, at low temperatures, the tyrosine kinase associated with the putative receptor encoded by c-neu is activated by physico-chemical modifications of the plasma membrane.
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PMID:Ligand-independent tyrosine phosphorylation of the receptor encoded by the c-neu oncogene. 168 56

The HER2 protooncogene encodes a growth factor receptor-like transmembrane protein tyrosine kinase (p185HER2) whose ligand remains to be fully characterized. The overexpression of p185HER2 is implicated in aggressive forms of breast and ovarian cancers. The role of p185HER2 in aggressive malignancy, as well as its cell surface localization, makes it an attractive target for therapeutic monoclonal antibodies. In this report we have studied the modulation of p185HER2 function with 2 monoclonal antibodies, termed 4D5 and 6E9, which bind the extracellular domain of p185HER2. 4D5 inhibited proliferation of p185HER2 overexpressing SK-BR-3 human breast carcinoma cells (ED50 of approximately 1 nM) but did not inhibit proliferation of cultured human breast carcinoma MCF7 cells, low expressors of p185HER2. Monoclonal antibody 6E9 does not inhibit the growth of either cell line. Antibody binding studies revealed 2 populations of p185HER2 molecules on SK-BR-3 cells: one of high abundance (approximately 2 x 10(6) sites/cell) recognized by 4D5 (Kd approximately 6 nM) and the other of low abundance (2 x 10(4) sites/cell) recognized by 6E9 (Kd approximately 0.1 nM). 4D5, in an agonistic manner, downregulated SK-BR-3 cell surface p185HER2, was internalized, and stimulated p185HER2 phosphorylation in intact cells. Phosphoamino acid analysis of p185HER2 derived from SK-BR-3 cells incubated with the 4D5 monoclonal antibody demonstrated increased tyrosine, serine and threonine phosphorylation. 4D5, on short term (5 min) exposure to SK-BR-3 cells, stimulated inositol lipid hydrolysis as evidenced by increased intracellular levels of inositol polyphosphates (InsP) and sn-1,2-diacylglycerol (sn-1,2-DAG). On longer (24 h) exposure to the cells, the antibody appeared to downregulate this signalling pathway since the intracellular levels of InsP and sn-1,2-DAG decreased by 30 to 40%. 6E9 did not inhibit SK-BR-3 cell proliferation, downregulate surface p185HER2, stimulate receptor phosphorylation, or stimulate the second messenger pathway. Despite these agonistic properties, 4D5 was an inhibitor of SK-BR-3 cell proliferation at all concentrations tested (0.7 to 70 pM). The data suggest that 4D5 is a partial or weak agonist and thus may inhibit cell proliferation by mimicking ligand-like receptor downregulation.
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PMID:Characterization of an anti-p185HER2 monoclonal antibody that stimulates receptor function and inhibits tumor cell growth. 168 87

High levels of expression of either the epidermal growth factor receptor or the receptor-like HER2/neu gene product p185HER2 have been observed in a variety of human malignancies. Because of the association of this high level expression with certain human tumors, we have generated a panel of monoclonal antibodies specific for either the epidermal growth factor receptor or p185HER2 to study their structure, function, and antigenic domains in the normal and neoplastic states. We used the epidermoid carcinoma line A431 to generate five monoclonal antibodies which immunoprecipitate the epidermal growth factor receptor. These monoclonal antibodies bind to the extracellular domain of the epidermal growth factor receptor and demonstrate variable effects on epidermal growth factor binding. We used a stably transfected NIH 3T3 cell line expressing the HER2/neu gene to produce and characterize 10 monoclonal antibodies which immunoprecipitate p185HER2. These monoclonal antibodies bind to the extracellular domain of p185HER2 and do not cross-react with the epidermal growth factor receptor. The characteristics and potential applications of these monoclonal antibodies will be discussed.
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PMID:Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product. 168 12


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