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)

Even though alterations in receptor and nonreceptor kinases are involved in the development of human cancer, many cancer cell lines still retain their responsiveness to growth factors. We have investigated the hypothesis that cellular signaling events regulate the sensitivity of cancer cells to chemotherapeutic agents. In 2008 human ovarian carcinoma cells, activation of a number of different transduction pathways resulted in a 2 to 4-fold increase in the sensitivity to cisplatin. These signaling events include pathways activated by the epidermal growth factor (EGF) receptor, tumor necrosis factor alpha (TNF alpha) receptor, bombesin receptor, protein kinase A (PKA), and protein kinase C (PKC). Enhanced sensitivity to chemotherapeutic agents is presumed to be mediated by phosphorylation of critical target protein(s). beta-tubulin has been identified as one such target for the protein kinase signaling cascade. For other signal transduction pathways the key substrates that regulate drug sensitivity have not yet been identified. Recent work has shown that DNA damaging agents activate signaling cascades one of which involves the Src, Ras, and Raf proteins as intermediates and results in induction of a number of genes, including c-fos, c-jun, and the growth arrest and DNA damage-inducible (gadd) genes. This signaling cascade has been shown to involve activation of protein kinase C and to have a protective function. With the growing understanding of how signaling events relate to damage response and drug sensitivity, new and potentially useful strategies for modulating drug sensitivity are evolving.
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PMID:Signaling and drug sensitivity. 792 49

We have isolated from KB cells stimulated with interleukin-1 (IL-1) a protein kinase that phosphorylates a peptide (T669) based on the sequence around T669 of the epidermal growth factor (EGF) receptor. The enzyme, which had an apparent molecular mass of 45 kDa on gel-filtration chromatography, was purified 170,000-fold from cytosolic extracts by sequential chromatography on Mono Q, Mono S, phenyl-Sepharose, Superose 12, ATP-Sepharose and Mono Q. The enzyme activity co-chromatographed at the last step with a 45 kDa protein band that stained for phosphotyrosine. This peak fraction also contained some actin and a 60 kDa protein that stained weakly for phosphotyrosine. The T669 peptide is a substrate for mitogen-activated protein (MAP) kinase. Amounts of IL-1-induced T669 kinase and activated recombinant p42 MAP kinase having equal activity on T669 peptide were compared on commonly used MAP kinase substrates. T669 kinase was two or three orders of magnitude less active on myelin basic protein or microtubule-associated protein-2 than was MAP kinase. The IL-1-induced T669 kinase did not react with antiserum to p42/p44 MAP kinase. It was inactivated by treatment with protein phosphatase 2A or protein phosphotyrosine phosphatase 1B, so it may be regulated by dual phosphorylation in similar fashion to MAP kinase. The dephosphorylated enzyme was not re-activated by MAP kinase kinase. This novel enzyme could lie on a kinase cascade induced by IL-1. It may be responsible for phosphorylating T669 of the EGF receptor.
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PMID:Interleukin-1 activates a novel protein kinase that phosphorylates the epidermal-growth-factor receptor peptide T669. 794 18

We have studied the effect of activation of the c-erbB-2 receptor tyrosine kinase on protein kinase C (PKC) in cultured SKBR-3 human breast cancer cells. Treatment with the agonistic anti-receptor monoclonal antibody TAb 250 induces receptor autophosphorylation and stimulates phospholipase C-gamma 1 (L. K. Shawver et al. Cancer Res., 54: 1367-1373, 1994). TAb 250 induced a rapid and marked translocation of PKC histone phosphorylation activity to the particulate fraction of SKBR-3 cells. By immunoblot, however, this translocation was limited to specific PKC isozymes. beta PKC and zeta PKC translocated to the particulate fraction, whereas epsilon PKC underwent "partial reversed translocation" to the cell soluble fraction after receptor stimulation. Furthermore, beta PKC was rapidly degraded following TAb 250 treatment. By immunocytochemistry, beta IPKC translocated from the perinuclear area to the cytosol and into the nucleus, whereas zeta PKC translocated to the perinuclear region and into the nucleus. Consistent with the Western blot results, epsilon PKC translocated from the nucleus to the perinuclear area and the cytosol. These changes in the localization of PKC isozymes were not observed after addition of normal IgG1 or a nonagonistic anti-c-erbB-2 monoclonal antibody to SKBR-3 cells. alpha, beta II, or delta PKC present in these cells did not translocate following receptor stimulation. These data indicate that c-erbB-2 signal transduction may involve the activation of specific PKC isozymes. The biological role of these enzymes in the phenotype and cellular responses of c-erbB-2-overexpressing carcinoma cells remains to be studied.
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PMID:Distinct responses of protein kinase C isozymes to c-erbB-2 activation in SKBR-3 human breast carcinoma cells. 798 52

We have identified the 170 kDa epidermal growth factor (EGF) receptor in crude membrane fractions isolated from Ehrlich ascites tumor cells by its EGF-dependent phosphorylation with [gamma-32P]ATP. An apparent affinity constant for the ligand of 40-50 nM, based on the extent of its EGF-dependent phosphorylation, was calculated. [125I]EGF binds to the 170 kDa receptor and Scatchard plot analysis shows high affinity and low affinity Kds of 1.7 nM and 24 nM, respectively, in whole cells, and 0.2-0.8 nM and 39-116 nM, respectively, in isolated non-phosphorylated membrane fractions. We have estimated the presence of 48 x 10(3) high affinity and 275 x 10(3) low affinity EGF binding sites per tumor cell. Phosphoamino acid analysis shows EGF-dependent phosphorylation of tyrosine and serine residues. A polyclonal antibody to a human EGF receptor/c-erbB-2 product common cytoplasmic domain epitope immunoprecipitates a 45 kDa phosphopolypeptide from the tumor membrane fractions and from whole cell lysates. Phosphoamino acid analysis of the immunoprecipitated 45 kDa phosphopolypeptide shows the presence of phosphoserine. The immunoprecipitated 45 kDa polypeptide is able to undergo EGF-independent phosphorylation, although no significant protein kinase activity towards exogenous substrates is detected.
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PMID:Characterization of the epidermal growth factor receptor from Ehrlich ascites tumor cells. 806 May 39

MCF-10A is a spontaneously immortalized, non-transformed human mammary epithelial cell line. We have recently obtained MCF-10A clones (MCF-10A HE cells) that are transformed following over-expression of both a human point-mutated c-Ha-ras and the c-erbB-2 proto-oncogenes. Two isoforms of the cAMP-dependent protein kinase (cAK) have been described in mammalian cells. Enhanced levels of type-I cAK (cAKI) are generally found in tumor cells. To determine whether inhibition of cAKI expression may interfere with ras and erbB-2 oncogene-induced transformation of human mammary epithelial cells, we have tested the effects of 2 agents that specifically down-regulate cAKI, such as 8-chloro-cAMP and an anti-sense oligodeoxynucleotide targeted against the RI alpha regulatory subunit of cAKI on MCF-10A HE cells. Treatment of MCF-10A HE cells with 8-chloro-cAMP induces a dose-dependent growth inhibition under both monolayer and soft-agar growth conditions, that is correlated with an accumulation of MCF-10A HE cells in G0/G1 phases of the cell cycle and a reduction of the number of cells in S phase. In contrast, 8-chloro-cAMP has no effect on MCF-10A cell growth. Furthermore, 8-chloro-cAMP treatment of MCF-10A HE cells induces a 4- to 6-fold reduction in p185erbB-2 expression and brings p21ras expression to levels comparable to those found in MCF-10A cells. Treatment of MCF-10A HE cells with an RI alpha anti-sense oligodeoxynucleotide determines a comparable inhibition of both anchorage-dependent and anchorage-independent cell growth. Our results suggest that cAKI may act as a mediator of ras and erbB-2 oncogene action in human breast cells and that interference with cAKI action provides a potential tool for inhibiting the growth-promoting effects of these oncogenes.
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PMID:Down-regulation of RI alpha subunit of cAMP-dependent protein kinase induces growth inhibition of human mammary epithelial cells transformed by c-Ha-ras and c-erbB-2 proto-oncogenes. 809 73

The fungal metabolite BE-23372M is a structurally novel protein kinase inhibitor. Its IC50 for epidermal growth factor (EGF) receptor kinase was 0.03 microM. IC50 values of BE-23372M for other protein tyrosine kinases, erbB-2, p43v-abl, insulin receptor kinase, and p60c-src were 0.42, 1.0, 3.3, and 4.5 microM, respectively, and the IC50 for protein kinase C, a serine/threonine kinase, was 4.1 microM. Cdc2 kinase, casein kinases I and II and cAMP-dependent protein kinase were not inhibited by 20 microM BE-23372M. A kinetic study showed that BE-23372M was competitive with respect to the substrate peptide and to ATP. Autophosphorylation of solubilized EGF receptor kinase was clearly inhibited by 0.1 microM BE-23372M. Autophosphorylation of EGF receptor in A431 cells was also inhibited. These results show that BE-23372M is a potent and specific EGF receptor kinase inhibitor. It should be a valuable tool for EGF receptor kinase research.
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PMID:BE-23372M, a novel and specific inhibitor for epidermal growth factor receptor kinase. 818 23

The naphthodianthrone hypericin produces a potent and irreversible inhibition of the epidermal growth factor (EGF) receptor tyrosine kinase activity. The inhibition was time and temperature dependent but did not depend on EGF activation. The IC50 values obtained were 0.37-8.7 microM with membranes incubated for 30 min at 30 degrees or 10 min at 0 degree, respectively. Kinetic analyses with poly(Glu,Ala,Tyr) 6:3:1 [poly(GAT)] as an exogenous substrate were in agreement with the irreversible nature of the inhibition. Irradiation for 30 min with fluorescent light caused a dramatic photosensitizing effect and resulted in an IC50 value of 44 nM. This effect was due to a type I mechanism, since the exclusion of oxygen did not alter the inhibition curve. The inhibition was inversely proportional to the amounts of membranes used, which probably reflects the non-specific sequestration of hypericin into the lipid bilayer. Ser/Thr protein kinases such as protein kinase A, casein kinase 1 and 2 and the enzyme 5'-nucleotidase, were not inhibited by hypericin not even at high concentrations (> 100 microM).
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PMID:Inhibition of epidermal growth factor receptor tyrosine kinase activity by hypericin. 826 42

The relation between the concentration of epidermal growth factor (EGF) receptor and the effects of EGF on cell proliferation were studied using 16 newly established human esophageal cancer cell lines. According to 125I-EGF binding assay, the amount of EGF receptor was found to vary from 6 x 10(4) to 1.2 x 10(7) (sites/cell). Changes in EGF-stimulated tyrosine-specific protein kinase activity almost paralleled changes in the number of EGF receptors per cell. Amplification of EGF receptor gene was detected in only one cell line. Under monolayer culture conditions, we found three types of growth responses of esophageal cell lines to EGF; growth in 5 cell lines was inhibited and that in 4 cell lines was stimulated while that in the other 7 cell lines remained unaffected. Relation was observed between the number of EGF receptors per cell and the growth response to EGF. On the other hand, cell lines whose growth was inhibited by EGF in monolayer culture were stimulated by EGF in soft agar culture, though the opposite was not necessarily true.
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PMID:Relation of epidermal growth factor receptor concentration to growth of human esophageal cancer cell lines. 827 53

The relationship between the mos protooncogene protein and cAMP-dependent protein kinase (PKA) during the maturation of Xenopus oocytes was investigated. Microinjection of the PKA catalytic subunit (PKAc) into Xenopus oocytes inhibited oocyte maturation induced by the mos product but did not markedly affect the autophosphorylation activity of injected mos protein. By contrast, PKAc did not inhibit maturation promoting factor (MPF) activation or germinal vesicle breakdown (GVBD) that was initiated by injecting crude MPF preparations. In addition, inhibiting endogenous PKA activity by microinjecting the PKA regulatory subunit (PKAr) induced oocyte maturation that was dependent upon the presence of the endogenous mos product. Moreover, PKAr potentiated mos protein-induced MPF activation in the absence of progesterone and protein synthesis. These data are consistent with the hypothesis that progesterone-induced release from G2/M is regulated via PKAc and that PKAc negatively regulates a downstream target that is positively regulated by mos.
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PMID:Inhibition of mos-induced oocyte maturation by protein kinase A. 843 91

To understand the mechanism of Axl signaling, we have initiated studies to delineate downstream components in interleukin-3-dependent 32D cells by using a chimeric receptor containing the recombinant epidermal growth factor (EGF) receptor extracellular and transmembrane domains and the Axl kinase domain (EAK [for EGF receptor-Axl kinase]). We have previously shown that upon exogenous EGF stimulation, 32D-EAK cells are capable of proliferation in the absence of interleukin-3. With this system, we determined that EAK-induced cell survival and mitogenesis are dependent upon the Ras/extracellular-signal-regulated protein kinase (ERK) cascade. Although the phosphatidylinositol-3 kinase pathway is activated upon EAK signaling, it appears to be dispensable for the biological actions of the Axl kinase. Furthermore, we demonstrated that different threshold levels of Ras/ERK activation are needed to induce a block to apoptosis or proliferation in 32D cells. Recently, we have identified an Axl ligand, GAS6. Surprisingly, GAS6-stimulated 32D-Axl cells exhibited no blockage to apoptosis or mitogenic response which is correlated with the absence of Ras/ERK activation. Taken together, these data suggest that different extracellular domains dramatically alter the intracellular response of the Axl kinase. Furthermore, our data suggest that the GAS6-Axl interaction does not induce mitogenesis and that its exact role remains to be determined.
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PMID:Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase. 852 90


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