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)

Multiple endocrine neoplasia type 2A (MEN2A) is a dominantly inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. The gene responsible for MEN2A was localized by linkage analysis to chromosome 10q11.2 in 1987, and recently mutations in RET, a proto-oncogene in the candidate region, were discovered in patients with MEN. The majority of mutations found so far in MEN2A patients have been located in nucleotide sequences encoding cysteine residues in the extracellular domain of RET. To characterize MEN2A germline alterations in the Japanese population, we screened DNA from eight unrelated patients for mutations in exons 10 and 11 of the RET proto-oncogene and found mutations in all eight patients, at codons 618, 620, or 634; each of these sites encodes a cysteine residue in the extracellular domain of RET. The mutations were confirmed in other affected individuals in the respective families by digestion of polymerase chain reaction (PCR) products containing the mutated codons with restriction enzymes (Rs alpha I, CfoI, or AluI) for which cleavage sites had been generated by the specific genetic alteration. These PCR-restriction enzyme systems will be useful for genetic diagnosis in members of families carrying these mutations.
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PMID:Germline mutations of the RET proto-oncogene in eight Japanese patients with multiple endocrine neoplasia type 2A (MEN2A). 786 65

Induction of the human c-fos proto-oncogene by mitogens depends on the formation of a ternary complex by p62TCF with the serum response factor (SRF) and the serum response element (SRE). We demonstrate that Elk-1, a protein closely related to p62TCF in function, is a nuclear target of two members of the MAP kinase family, ERK1 and ERK2. Phosphorylation of Elk-1 increases the yield of ternary complex in vitro. At least five residues in the C-terminal domain of Elk-1 are phosphorylated upon growth factor stimulation of NIH3T3 cells. These residues are also phosphorylated by purified ERK1 in vitro, as determined by a combination of phosphopeptide sequencing and 2-D peptide mapping. Conversion of two of these phospho-acceptor sites to alanine impairs the formation of ternary complexes by the resulting Elk-1 proteins. Removal of these serine residues also drastically diminishes activation of the c-fos promoter in epidermal growth factor-treated cells. Analogous mutations at other sites impair activation to a lesser extent without affecting ternary complex formation in vitro. Our results indicate that phosphorylation regulates ternary complex formation by Elk-1, which is a prerequisite for the manifestation of its transactivation potential at the c-fos SRE.
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PMID:ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. 788 42

The HER4/ERBB4 gene encodes a 180K transmembrane protein (HER4/p180erbB4) that is structurally related to the 185K product (HER2/p185erbB2) of the HER2/ERBB2 proto-oncogene. A 45K heparin-binding glycoprotein (p45) has been characterized that specifically activates the intrinsic tyrosine kinase activity of HER4 (ref. 2). This HER4 ligand shares several features with the heregulin family of proteins, including molecular mass, ability to induce differentiation of breast cancer cells, activation of tyrosine phosphorylation in MDA-MB453 cells, and amino-terminal protein sequence. Heregulin exists as multiple isoforms and all are presumed to interact directly with HER2 (refs 3-6). We have used binding and phosphorylation studies with recombinant ligand on cell lines expressing recombinant receptors, and report here that heregulin, like p45, is a specific ligand for HER4. Furthermore, heregulin fails to induce phosphorylation of HER2 in the absence of HER4. These findings suggest that activation of the HER4 receptor is involved in signal transduction by heregulin.
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PMID:Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. 790 37

Amplification and overexpression of the neu (c-erbB2) proto-oncogene has been implicated in the pathogenesis of 20 to 30% of human breast cancers. Although the activation of Neu receptor tyrosine kinase appears to be a pivotal step during mammary tumorigenesis, the mechanism by which Neu signals cell proliferation is unclear. Molecules bearing a domain shared by the c-Src proto-oncogene (Src homology 2) are thought to be involved in signal transduction from activated receptor tyrosine kinases such as Neu. To test whether c-Src was implicated in Neu-mediated signal transduction, we measured the activity of the c-Src tyrosine kinase in tissue extracts from either mammary tumors or adjacent mammary epithelium derived from transgenic mice expressing a mouse mammary tumor virus promoter/enhancer/unactivated neu fusion gene. The Neu-induced mammary tumors possessed six- to eightfold-higher c-Src kinase activity than the adjacent epithelium. The increase in c-Src tyrosine kinase activity was not due to an increase in the levels of c-Src but rather was a result of the elevation of its specific activity. Moreover, activation of c-Src was correlated with its ability to complex tyrosine-phosphorylated Neu both in vitro and in vivo. Together, these observations suggest that activation of the c-Src tyrosine kinase during mammary tumorigenesis may occur through a direct interaction with activated Neu.
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PMID:Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity. 790 21

The Neu proto-oncogene (also called ErbB-2 and HER-2) encodes a tyrosine kinase transmembrane receptor homologous to the epidermal growth factor receptor (EGF-R). Overexpression, a point-mutation, and co-expression with EGF-R activate the oncogenic potential of the Neu protein by permanent coupling to signal transducing pathways. The search for ligands that elevate tyrosine phosphorylation of Neu led to the discovery of a 44-kDa glycoprotein that acts either as a differentiation factor or as a mitogen for mammary tumor cells. This protein, termed Neu differentiation factor (NDF), is derived from a transmembrane precursor that contains an EGF-like motif and an immunoglobulin-like domain. Alternative splicing generates a dozen NDF-related proteins that are expressed in a variety of mesenchymal and neuronal tissues. This unprecedented multiplicity raises the possibility that different isoforms fulfill distinct biological roles.
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PMID:Neu differentiation factors: a family of alternatively spliced neuronal and mesenchymal factors. 791 39

Abnormalities in the expression, structure, or activity of proto-oncogene products have been implicated in the development and maintenance of the malignant cells. Proto-oncogene c-erbB2/HER2 gene product P185HER2 is one such regulatory cellular protein, elevated expression of which can result in transformed phenotypes of mouse fibroblast NIH3T3 cells, and has been also shown to be overexpressed in a number of human tumors including breast carcinoma. In the studies presented here, we have investigated the effects of antiproliferative cytokines such as interferons (INFs) and tumor necrosis factor-alpha (TNF-alpha) on the modulation of expression of P185HER2 and growth-rate of human mammary carcinoma SK-BR-3 cells which overexpress P185HER2. It was observed that the antiproliferative effects of IFN-gamma and TNF-alpha on the cultures of SK-BR-3 cells were associated with reduction in the steady-state levels of P185HER2 with no change in the steady state levels of expression of c-erbB2 mRNA. Treatment of SK-BR-3 cells with either IFN-gamma or TNF-alpha was accompanied by inhibition of rate of synthesis of the protein, enhanced turnover of newly synthesized P185HER2, and reduced expression of P185HER2 on the cell surface. These observed effects on the expression of P185HER2 were more pronounced by more growth inhibitory TNF-alpha than IFN-gamma. These observations suggest that the growth regulation of SK-BR-3 cells by IFN-gamma and TNF-alpha may be associated with reduced expression P185HER2.
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PMID:Reduced expression of c-erbB2 gene product in human mammary carcinoma SK-BR-3 cells treated with interferon-gamma and tumor necrosis factor-alpha. 791 5

Amplification of the Neu/c-erbB-2 receptor tyrosine kinase has been implicated as an important event in the genesis of human breast cancer. Indeed, transgenic mice bearing either an activated form of neu or the wild-type proto-oncogene under the transcriptional control of the mouse mammary tumor virus promoter-enhancer frequently develop mammary carcinomas (L. Bouchard, L. Lamarre, P. J. Tremblay, and P. Jolicoeur, Cell 57:931-936, 1989; C. T. Guy, M. A. Webster, M. Schaller, T. J. Parson, R. D. Cardiff, and W. J. Muller, Proc. Natl. Acad. Sci. USA 89:10578-10582, 1992; W. J. Muller, E. Sinn, R. Wallace, P. K. Pattengale, and P. Leder, Cell 54:105-115, 1988). Induction of mammary tumors in transgenic mice expressing the wild-type Neu receptor is associated with activation of the receptor's intrinsic tyrosine kinase activity (Guy et al., Proc. Natl. Acad. Sci. USA 89:10578-10582, 1992). Here, we demonstrate that activation of Neu in these transgenic mice occurs through somatic mutations located within the transgene itself. Sequence analyses of these mutations revealed that they contain in-frame deletions of 7 to 12 amino acids in the extracellular region proximal to the transmembrane domain. Introduction of these mutations into a wild-type neu cDNA results in an increased transforming ability of the altered Neu tyrosine kinase. These observations suggest that oncogenic activation of Neu in mammary tumorigenesis frequently occurs by somatic mutation.
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PMID:Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. 793 22

Receptor-bound growth factors elicit intracellular signals that lead to the phosphorylation and activation of numerous intracellular kinases and transcription factors with consequent changes in patterns of gene expression. Several oncogene products are able to mimic these signals, resulting in cell transformation and proliferation. For example, the introduction of oncogenic forms of Raf-1 kinase into fibroblasts induces transformation and leads to the constitutive expression of, among others, the c-fos proto-oncogene. Here it is shown that the elevation of c-fos promoter activity brought about by v-raf is mediated by TCF/Elk-1, which forms a ternary complex with SRF at the serum response element and is a substrate for mitogen-activating protein kinases in vitro. In NIH 3T3 fibroblasts, v-raf activates Erk2, and overexpression of an interfering mutant of Erk2 both blocks the ability of v-raf to activate the c-fos promoter and suppresses transformation. Mutation of individual mitogen-activating protein kinase phosphoacceptor sites in TCF/Elk-1 also compromises v-raf-activated expression of a Gal-Elk/Gal-chloramphenicol acetyltransferase reporter system. However, in at least one instance the introduction of glutamate, but not aspartate, at a phosphoacceptor site is compatible with activation. These results provide compelling evidence that phosphorylation of TCF/Elk-1 by Erk2 is a major link in the Raf-1 kinase-dependent signal transduction pathway that activates c-fos expression.
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PMID:Inhibition of v-raf-dependent c-fos expression and transformation by a kinase-defective mutant of the mitogen-activated protein kinase Erk2. 800 80

The HER2 (neu/erb-B2) proto-oncogene codes for a transmembrane receptor with tyrosine kinase activity and with high homology to the EGF receptor (HER1). The high incidence of HER2 overexpression in breast and ovary carcinomas prompted us to synthesize protein tyrosine kinase inhibitors (tyrphostins) which selectively inhibit the HER2 kinase activity. Two groups of tyrphostins were developed: one highly selective in inhibiting HER1 as opposed to HER2, the other highly selective in inhibiting HER2. Both the HER1 and the HER2 selective blockers were competitive with ATP binding. This suggests that even though the kinase domains of the respective receptors show an 80% degree of homology it is possible to design small molecules capable of discriminating between them. These results also show that the two kinases differ in their ATP binding sites. Mitogenic signaling induced by EGF in NIH3T3 cells overexpressing either HER1 or HER1-2 (possessing the HER2 kinase domain) was blocked identically by the agents that discriminate between the two in vitro. This paradox was further explored and elucidated. We propose that high intracellular ATP levels prevent inhibitor binding to the receptor. The antiproliferative action of the two distinct selective tyrphostins observed may result from the inhibition of a downstream element, presumably a tyrosine kinase, which mediates mitogenic signaling.
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PMID:Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins. 809 9

Bispecific monoclonal antibodies (BsmAb) with specificity for tumor Ag and effector cell trigger molecules have been shown to redirect the cytotoxicity of several peripheral blood mononuclear cell populations against relevant tumor. The BsmAb, 2B1, binds to the extracellular domain of the c-erbB-2 gene product of the HER2/neu proto-oncogene and to CD16. In this report, the binding and cytotoxic characteristics of 2B1 are presented. Maximal saturation binding of 2B1 to PBL and c-erbB-2 expressing SK-OV-3 cells occurred in the 1 microgram/ml concentration range. However, substantial lysis potentiation was observed at 1000-fold lower BsmAb concentrations. Optimal tumor lysis was obtained when the BsmAb, PBL, and target cells were continuously coincubated. When PBL were franked with 2B1, washed, and added to labeled targets, substantially less lysis was observed. These results suggest that the best way to therapeutically exploit the cytotoxic attributes of 2B1 may be to obtain continuous BsmAb exposure to tumor. Approaches based on franking of this BsmAb to PBL may not be warranted.
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PMID:Binding and cytotoxicity characteristics of the bispecific murine monoclonal antibody 2B1. 810 70


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