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)

Transmembrane receptor tyrosine kinases that bind to peptide factors transmit essential growth and differentiation signals. A growing list of orphan receptors, of which some are oncogenic, holds the promise that many unknown ligands may be discovered by tracking the corresponding surface molecules. The neu gene (also called erbB-2 and HER-2) encodes such a receptor tyrosine kinase whose oncogenic potential is released in the developing rodent nervous system through a point mutation. Amplification and overexpression of neu are thought to contribute to malignancy of certain human adenocarcinomas. The search for soluble factors that interact with the Neu receptor led to the discovery of a 44 kDa glycoprotein that induces phenotypic differentiation of cultured mammary tumor cells to growth-arrested and milk-producing cells. The Neu differentiation factor (NDF or heregulin), however, also acts as a mitogen for epithelial, Schwann and glial cells. Multiple forms of the factor are produced by alternative splicing and their expression is confined predominantly to the central and to the peripheral nervous systems. One identified neuronal function of this family of polypeptides is to control the formation of neuromuscular junctions, but their physiological role in secretory epithelia is still unknown. Other open questions relate to the transmembrane topology of various precursors, the identity of a putative coreceptor, the possible existence of additional ligands of Neu and the functional significance of the interaction between Neu and at least three highly related receptor tyrosine kinases.
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PMID:Neu and its ligands: from an oncogene to neural factors. 790 91

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

Hepatocyte growth factor (HGF), identical to scatter factor, (SF) is a secretory glycoprotein from fibroblasts which dissociates and increases the motility of various types of epithelial cells. After treatment of three gastric carcinoma cell lines (MKN-28, MKN-45 and TMK-1) with HGF (10 ng/ml), TMK-1 cells lost their tight cell to cell contact and showed marked scattering, while the two other cell lines remained unaffected. To learn about the underlying mechanism of the HGF induced scattering, we examined the expression of adhesion molecules and growth factor/receptor systems at the mRNA and protein level. The observed scattering of treated TMK-1 cells was associated with a reduction in the expression of E- and P-cadherin protein. The respective mRNA levels remained unchanged after HGF/SF treatment. In the two other cell lines, which showed no scattering, there were no changes in the expression of E- and P-cadherin. All other growth factors and their receptors examined (TGF-alpha, EGFR, c-met and c-erbB2) remained constant and were not affected by HGF treatment. The results suggest that HGF/SF may regulate cell adhesion in gastric carcinomas via E- and P-cadherin expression at the protein level.
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PMID:Effect of hepatocyte growth factor on the expression of E- and P-cadherin in gastric carcinoma cell lines. 795 99

Recent data indicate that epidermal growth factor (EGF) is a potent mitogen to normal pituitary cells. Its receptor (EGFR or c-erbB-1), a cellular homologue of a viral oncoprotein erbB, is knonw to be overexpressed in many tumors, but little is known about the expression of EGF and EGFR in pituitary tumors. Immunocytochemical analyses of EGF, EGFR, and c-erbB-2 (an EGFR-related oncoprotein) were carried out on paraffin-embedded sections of 54 pituitary tumors. In sections from normal pituitary, EGF was localized mainly in the gonadotrophs and thyrotrophs. EGFR was detected in only 5-10% of the cells in all of the normal pituitary sections and was almost undetectable in all (34/34) of the hormone-secreting tumors (19 GH-, 9 ACTH-, 4 PRL- and 2 TSH-secreting tumors). However, in 16/20 of the samples from clinically nonfunctioning tumors, EGFR was markedly overexpressed. The EGFR found in these tumors and in the normal tissue was not the truncated form of the EGFR because all sections stained positively with monoclonal antisera to both the intra- and extracellular domains of the EGFR. EGF was coexpressed in the same NFT samples that stained positively for EGFR and was also found in 2/19 GH-, 2/4 PRL-, and 1/2 of TSH-secreting tumors. The expression of c-erbB-2 was detected in all normal tissue, all NFT, and about half of GH-secreting tumors. No correlation was found with clinical parameters other than tumor categories. Because the overexpression of structurally intact EGFR was confined to NFT, the response of the tumor cells to EGF in vitro was examined. The addition of 1 nM EGF to NFT-derived cells resulted in an increase in [3H]thymidine uptake to 237.5 +/- 19.8% (mean +/- SEM, n = 3) of the control value. EGF also stimulated EGFR messenger RNA levels, shown by Northern blot analysis. In contrast, the expression of glycoprotein hormone common alpha-subunit gene in the tumor cells was reduced by EGF, T3, and 17 beta-estradiol. The novel findings of overexpression of EGFR in most NFT combined with the in vitro response to EGF resulting in an increase in tumor cell growth, up-regulation of EGFR gene and suppression of hormone gene expression implicate a role for EGF and its receptor in the development and/or progression of NFT.
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PMID:Expression of epidermal growth factor (EGF), its receptor, and related oncoprotein (erbB-2) in human pituitary tumors and response to EGF in vitro. 795 24

The glycoprotein gene of the rabies virus vaccine strain Vnukovo-32 was sequenced and the deduced protein sequence was analyzed and compared with that of various laboratory and street strains. The amino acid sequence homologies of strain Vnukovo-32 were compared with fixed strains ERA, SAD B19, PV, HEP-Flury, CVS and two street strains, canine and CXX89-1, were 98.9% (6 replacements), 98.3% (9), 96.2% (20), 91.4% (45), 87.0% (68), 93.5% (34) and 91.4% (45), respectively. Sequence alignments of the proteins revealed that the most conserved region is the ectodomain, whereas the transmembrane and cytoplasmic domains showed significant divergence.
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PMID:Nucleotide and deduced amino acid sequences of the glycoprotein gene of rabies virus vaccine strain Vnukovo-32. 797 81

We have isolated mouse cDNA clones encoding Tyro 3, a receptor protein-tyrosine kinase (PTK) of the mammalin central nervous system (CNS). Expression of the Tyro 3 gene is strongly up-regulated in neurons of the mouse neocortex, cerebellum, and hippocampus after the day of birth, during periods of active synaptogenesis, and high expression is maintained in the adult CNS. The sequence of Tyro 3 cDNAs predicts a glycoprotein receptor with similarity to neural cell recognition and adhesion molecules--the extracellular (ligand binding) region of this receptor is composed of two immunoglobulin-related domains followed by two fibronectin type III repeats. Immunoblot and immunoprecipitation analyses with anti-Tyro 3 antibodies indicate that the 125 kD Tyro 3 protein is abundantly expressed in CNS synaptosomes, and immunohistochemical analysis of cultured hippocampal cells demonstrates that Tyro 3 is a product of neurons. Rat-2 fibroblasts stably transfected with a Tyro 3 expression construct acquire the ability to grow in soft agar, suggesting that Tyro 3 is potentially oncogenic.
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PMID:Structure, expression, and activity of Tyro 3, a neural adhesion-related receptor tyrosine kinase. 805 20

Neu differentiation factor (NDF/heregulin) is a 44-kDa glycoprotein that interacts with the Neu/ErbB-2 receptor tyrosine kinase to increase its phosphorylation on tyrosine residues. In vitro NDF promotes differentiation of certain mammary tumor cell lines to milk-producing cells. As a first step toward understanding the physiological role of NDF, we performed in situ hybridization analyses to determine mRNA distribution in the mouse embryo and to map the gene to human karyotypes. In 14.5-day-postcoitum mouse embryos, NDF expression is confined predominantly to the central and peripheral nervous system, including the neuroepithelium that lines the lateral ventricles of the brain, the ventral horn of the spinal cord, and the intestinal as well as dorsal root ganglia. Other tissues that contain NDF transcripts are the adrenal gland, liver, and distinct cell layers of the dermis and germinal ridge. In situ hybridization of a 3H-labeled probe to human metaphase spreads localized the NDF gene to the short arm of chromosome 8 at bands p12-p21.
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PMID:Neural expression and chromosomal mapping of Neu differentiation factor to 8p12-p21. 809 34

The Neu/HER-2 receptor tyrosine kinase is overexpressed in some types of human adenocarcinomas, including tumors of the breast and the ovary. A 44 kDa glycoprotein that elevates tyrosine phosphorylation of Neu has been isolated and named Neu differentiation factor (NDF), or heregulin. Here we show that NDF affects tyrosine phosphorylation of Neu in human tumor cells of breast, colon and neuronal origin, but not in ovarian cells that overexpress the receptor. By using monoclonal antibodies (mAbs) to Neu, we found that the ovarian receptor is immunologically and biochemically similar to the mammary p185neu. Nevertheless, unlike breast-derived Neu, the ovarian protein did not display covalent cross-linking to radiolabeled NDF, and was devoid of ligand-induced association with phosphatidylinositol 3'-kinase. Direct binding analysis showed that NDF binds with high affinity (Kd approximately 10(-9) M) to mammary cells, but its weak association with ovarian cells is probably mediated by heparin-like molecules. Similar to the endogenous receptor, the ectopically overexpressed Neu of mammary cells, but not of ovarian and fibroblastic cells, exhibited elevated levels of NDF-induced phosphorylation and covalent cross-linking of the radiolabeled factor. Taken together, our results imply that NDF binding to cells requires both Neu and an additional cellular component, whose identity is still unknown, but its tissue distribution is more restricted than the expression of the neu gene.
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PMID:Cell-type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/HER-2 suggests complex ligand-receptor relationships. 809 77

Neu differentiation factor (NDF, also called heregulin) is a 44-kilodalton glycoprotein that stimulates tyrosine phosphorylation of the Neu/HER-2 receptor and induces phenotypic differentiation of certain mammary cancer cell lines to growth-arrested and milk-producing cells. To determine which molecules participate in the concomitant morphological alterations, we analyzed the expression of several cytoskeletal and surface molecules and found that NDF elevated the expression of the intercellular adhesion molecule 1 (ICAM-1) in cultured AU-565 human adenocarcinoma cells. The levels of both the protein and the mRNA of ICAM-1 were elevated after 3-5 days of treatment with NDF. Elevated expression of ICAM-1 was induced also by gamma-interferon and by the tumor-promoting phorbol ester (PMA), albeit with different kinetics. Down-regulation of protein kinase C or its inhibition by calphostin C partially inhibited the effect of NDF, implying that the induction of ICAM-1 may be mediated by protein kinase C. NDF transcripts were detectable in 3 of 9 human mammary tumors, suggesting that the in vitro effect of the factor may be relevant to breast cancer. By selecting Neu-positive human mammary tumors (n = 39), we found a significant correlation (P < 0.001) between the expression of ICAM-1 and histological features of invasive ductal carcinoma with a prominent carcinoma in situ component. When cultured in vitro the cells of these tumors grew in clusters and formed domelike structures reminiscent of comedo-type carcinoma in situ. In addition, the majority of patients with tumors that coexpressed ICAM-1 and Neu had no lymph node involvement, unlike most Neu-positive but ICAM-1-negative tumors, which metastasized to the lymphatic system. Taken together, our observations suggest that the induction of ICAM-1 by NDF may affect the morphology, differentiation state, and metastasis of Neu-expressing mammary tumor cells.
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PMID:Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors. 810 45

The human gene (AZGP1) encoding Zn-alpha 2-glycoprotein (Zn-alpha 2-gp), a protein present in several biological fluids and produced by a subtype of breast carcinomas, has been cloned and its complete nucleotide sequence determined. The gene spans over 9.7 kb, and its overall organization and nucleotide sequence are very similar to those of the first four exons of class I MHC genes. However, the Zn-alpha 2-gp gene differs from these genes in several significant ways. It lacks the coding information for the transmembrane and cytoplasmic domains typical of MHC genes, which is consistent with its presence as a soluble protein in different physiological and pathological fluids. In addition, it contains a high density of repetitive sequences, including Alu, MER, and MIR elements, which are not present at equivalent positions in class I MHC genes. Finally, its 5'-flanking region lacks the class I MHC regulatory complex and the interferon consensus sequence characteristic of class I MHC genes. These findings may explain the different expression pattern of Zn-alpha 2-gp and class I MHC genes in human tissues. Southern blot hybridization of DNA from several species with a cDNA probe indicated that Zn-alpha 2-gp genes are present in a wide variety of animal species, including monkey, rat, mouse, dog, cow, and rabbit. The human genome also contains a putative Zn-alpha 2-gp pseudogene that has been isolated and partially characterized. This pseudogene has an intron-exon organization identical to that of the functional gene, but it presents two deleterious mutations in the third exon that lead to the appearance of premature stop codons. Finally, considering the lack of polymorphism in the Zn-alpha 2-gp gene in comparison with MHC genes, putative roles for this human glycoprotein in the transport of nonpolymorphic substances or in intercellular recognition processes are proposed.
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PMID:Human Zn-alpha 2-glycoprotein: complete genomic sequence, identification of a related pseudogene and relationship to class I major histocompatibility complex genes. 830 68


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