Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of tyrosine kinase inhibitor, erbstatin, on cell growth and mRNA expression of growth-factor/receptor system was examined in 6 human gastric-carcinoma cell lines. Erbstatin inhibited both EGF-induced and serum-stimulated cell growth of all 6 cell lines (TMK-1, MKN-1, -7, -28, -45, -74) in a dose-dependent manner. 3H-thymidine incorporation by TMK-1 cells was also suppressed by erbstatin. Erbstatin inhibited protein kinase activity of EGF receptor, p185ERBB2 and pp60c-src in TMK-1 cells. The expression of mRNA of EGF receptor gene and ERBB-2 by TMK-1 cells was not changed by erbstatin treatment, whereas that of c-src was slightly decreased. Interestingly, erbstatin decreased membrane-bound TGF-alpha precursor as measured by anti-TGF-alpha antibody-binding assay, although mRNA expression for TGF-alpha was not altered by erbstatin. Our findings suggest that erbstatin may act as a growth inhibitor for human gastric-carcinoma cells and may not only inhibit tyrosine kinase activities but also negatively modulate the post-transcriptional step of TGF-alpha expression.
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PMID:Effects of tyrosine kinase inhibitor, erbstatin, on cell growth and growth-factor/receptor gene expression in human gastric carcinoma cells. 184 25

Various derivatives of thiazolidine-diones have been identified as tyrosine protein kinase inhibitors. The epidermal growth factor (EGF) receptor kinase and c-src kinase were inhibited in vitro with IC50 values in the range of 1-7 microM. The v-abl tyrosine protein kinase was not inhibited by thiazolidine-diones. Inhibition was found to be specific for tyrosine protein kinases. Inhibition of serine/threonine protein kinases was not observed. The active derivatives were shown to inhibit EGF-induced receptor autophosphorylation, either in vitro or in intact cells, and were also found to inhibit growth of the EGF-dependent BALB/MK and A431 cell lines (IC50 1-3 microM). Growth of the interleukin-3-dependent myeloid cell line FDC-P1 was inhibited with equal efficiency. Thus, in these cell lines, members of the c-src kinase family are also potential targets for inhibition by the compounds.
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PMID:Thiazolidine-diones. Biochemical and biological activity of a novel class of tyrosine protein kinase inhibitors. 217 10

Protooncogenes expressed in murine embryonal carcinoma (EC) cells or their differentiated daughter cells include more or less ubiquitously expressed protooncogenes such as c-myc, c-K-ras, and c-abl, as well as c-onc genes with a very restricted expression pattern. Examples of the latter are N-myc, c-mos, and int-2. These c-onc genes are transcriptionally active in EC cells, as well as in germ cells and/or early embryonic cells. When EC cells are induced to differentiate some protooncogenes or oncogene-related products undergo changes in expression. Thus, EC cell differentiation has been associated with increased expression of c-src, c-fos, int-1, int-2, and the epidermal growth factor (EGF) receptor, whereas decreased expression has been observed for c-mos, c-K-ras, c-myc, N-myc, and platelet-derived growth factor. The relationships between these changes in expression and EC cell differentiation are not understood. They may be important for the differentiation process or for expression of a differentiated phenotype. They may, however, also be secondary events with no functional significance to EC cell differentiation.
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PMID:Changes in c-onc expression during embryonal carcinoma cell differentiation. 264 82

Previous reports have indicated that the C termini of the membrane-associated tyrosine kinases encoded by c-src and c-fms proto-oncogenes have a negative effect on their biological activity and that this effect is mediated by their C-terminal tyrosine residue. To determine whether this was true for the human epidermal growth factor (EGF) receptor, which is also a membrane-associated tyrosine kinase proto-oncogene, we have constructed two premature termination mutants, dc19 and dc63, that delete the C-terminal 19 and 63 amino acids, respectively, from the human full-length receptor (hEGFR). The smaller deletion removes the C-terminal tyrosine residue, while the larger deletion removes the two most C-terminal tyrosines; similar deletions are found in v-erbB. As previously shown for the gene encoding the full-length EGF receptor, the two C-terminal mutants induced EGF-dependent focal transformation and anchorage-independent growth of NIH 3T3 cells. However, both dc19 and dc63 were quantitatively less efficient than the gene encoding the full-length receptor, with dc63 being less active than dc19. Although the C-terminal mutants displayed lower biological activity than the gene encoding the full-length receptor, the mutant receptors were found to be similar in several respects to the full-length receptor. These parameters included receptor localization, stability in the absence of EGF, receptor half-life in the presence of EGF, EGF binding, extent of EGF-dependent autophosphorylation in vitro, and EGF-dependent phosphorylation of an exogenous substrate in vitro. Therefore, the C-terminal 63 amino acids of the human receptor have no detectable influence on EGF-dependent early events. We conclude that in contrast
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PMID:Functional heterogeneity of proto-oncogene tyrosine kinases: the C terminus of the human epidermal growth factor receptor facilitates cell proliferation. 278 42

We have determined the total coding sequence of human c-yes, a non-receptor type protein-tyrosine kinase gene, and found that the c-yes gene closely resembles the c-src gene. Recently, two new genes, syn and lyn, were found to encode proteins closely related to the yes product. In addition, we also determined the partial sequence of fgr. These genes together with lck reported by two American groups have very closely related structures and are thought to compose a closely related group of non-receptor type protein-tyrosine kinases. Partial analysis of the structures of these genes indicated that they have identical splicing junctions at all sites so far examined. On the other hand, the erbB-1/EGF (epidermal growth factor) receptor gene and the erbB-2/neu gene have completely different splicing junctions from those of the above gene group even in the kinase domain, although these genes also have protein kinase activity specific for tyrosine residues and the erbB-1 and -2 genes share splicing sites. These results suggest that the genes of the group of six non-receptor type kinases and those of the erbB-1 and erbB-2 gene group are descendants evolved by duplication of two distinct ancestor genes and are members of two distinct multi-gene families. The genes coding for protein kinases may be members of a super-family including multiple distinct gene families.
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PMID:Nakahara memorial lecture. Non-receptor type protein-tyrosine kinases closely related to src and yes compose a multigene family. 333 5

The c-erbB-2 gene was first identified by virtue of its cross-hybridization with v-erbB. Nucleotide sequence analysis of complementary DNA clones suggested that the c-erbB-2 gene encodes a growth factor receptor similar to that for EGF. Antibodies against the carboxyl terminal sequence of the c-erbB-2 protein immunoprecipitated a 185-kDa glycoprotein which showed protein-tyrosine kinase activity in vitro. Despite the extensive similarity between the c-erbB-2 protein and EGF receptor, neither EGF nor TGF-alpha bound to the c-erbB-2 protein. Phosphorylation of the c-erbB-2 protein was stimulated by TPA via protein kinase C in vivo. EGF also induced phosphorylation of the c-erbB-2 protein. This phosphorylation occurred not only on serine and threonine residues but also on tyrosine residues. Preliminary data suggested that the latter was mediated by the kinase activity of the EGF receptor. Southern blot analysis of DNAs from primary tumors revealed that the c-erbB-2 gene tends to be amplified in adenocarcinomas, mostly of the stomach and the breast. By screening both human genomic and cDNA libraries using v-yes DNA as a probe, we obtained DNA clones of the c-yes gene, the pseudogene of c-yes, c-fgr gene and c-src gene and two novel yes-related genes, fyn and lyn. Complete nucleotide sequence analysis of the cDNA clones of c-yes, fyn and lyn revealed that these genes encode proteins similar to p60src both in size and sequence.
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PMID:[The erbB-related protooncogenes encoding growth factor receptors]. 349 52

The structural basis of the interactions between the activated epidermal growth factor (EGF) receptor and SH2 domain proteins was investigated. The c-src SH2 domain (second domain of src homology) was expressed as a recombinant fusion protein, and an in vitro assay was developed to monitor EGF receptor/SH2 domain interactions. EGF receptor tyrosine kinase domain (TKD) forms expressed in the baculovirus/insect cell system were shown to bind to the SH2 domain when phosphorylated. These TKD/SH2 domain interactions were characterized by dissociation constants of 60-320 nM. Deletion analysis indicated that the entire SH2 domain was required for recognition of the phosphorylated TKD. The binding of a highly truncated TKD protein to the SH2 domain suggested that the sites recognized by the SH2 domain included the EGF receptor autophosphorylation site, tyr992. A phosphorylated EGF receptor peptide containing tyr992 was also shown to interact with the SH2 domain. This residue may therefore mediate interactions between the EGF receptor and tyrosine kinases in the src family.
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PMID:Structural basis of interactions between epidermal growth factor receptor and SH2 domain proteins. 768 May 58

The 9E3/CEF4 gene codes for a chemokine that is highly homologous to human interleukin-8 and melanoma growth-stimulating activity/groalpha. These chemokines belong to a family of molecular mediators that are importantly involved in inflammation, wound healing, tumor development, and viral entry into cells. On the chorioallantoic membrane the 9E3 protein is chemotactic for monocyte/macrophages and lymphocytes and is angiogenic. In cultured chicken embryo fibroblasts, which have many of the properties of wound fibroblasts, the gene is stimulated by a variety of agents including oncogenes, growth factors, phorbol esters, and thrombin. The strong stimulation of 9E3 by thrombin in culture correlates well with the observation that in young chicks this gene is stimulated to very high levels in fibroblasts upon wounding and remains high throughout wound repair. Activation of 9E3 by thrombin: (i) occurs very rapidly, one minute exposure to thrombin is sufficient to initiate the signals necessary for gene activation; (ii) is independent of mitogenesis; (iii) operates through the proteolytically activated receptor for thrombin; (iv) is mediated by tyrosine kinases, including c-src and the epidermal growth factor (EGF) receptor, rather than Ser/Thr kinases such as protein kinase C and protein kinase A. Inhibition of either c-src or the EGF receptor tyrosine kinase inhibits the stimulation of 9E3 by thrombin. We show here for the first time that activation of the EGF receptor through a cell-surface receptor that does not have tyrosine kinase activity can lead to expression of an immediate early response gene which encodes for a secreted protein, a chemokine. This rapidly activated tyrosine kinase pathway may be a general stress response by which in vivo a localized cell population reacts to emergency situations such as viral infection, wounding, or tumor growth.
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PMID:Thrombin aivation of the 9E3/CEF4 chemokine involves tyrosine kinases including c-src and the epidermal growth factor receptor. 947 78