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)

In summary, evidence is beginning to accumulate in support of a major role for tyrosine kinase receptors (and their activating growth factors) and steroid hormones and their receptors in normal development and differentiation of the mammary gland. A point of intersection of their mechanisms of action in growth control appears to be the induction of nuclear protooncogenes such as c-myc. When c-myc is amplified, as it is in many breast cancers, EGF and FGF receptor tyrosine kinase action becomes transforming, not simply mitogenic. A source of the transforming factors could be either stromal or epithelial. This mechanism could function early in the progression of breast cancer. c-erbB-2 and EGF receptor overexpression and amplification, when they occur, appear to render tumors even more malignant and of especially poor prognosis. These mechanisms could function late in the progression of breast cancer. Transgenic mouse studies have begun to echo these themes. They have established that a growth factor (TGF-alpha) and its receptor (EGF receptor), which appear to be important in normal mouse and human proliferation and gland development, and a protooncogene (c-myc), commonly amplified and overexpressed in human and mouse breast cancer, can each contribute to mammary carcinogenesis. The mechanisms of the two are likely to be distinct. myc is likely to be acting as a tumor initiator in combination with normal proliferative factors, whereas TGF-alpha is likely to be acting as a hyperproliferative (promotional) factor in combination with a normal background of mutational events. The role of unmutated but amplified erbB-2 in the transgenic mouse is not yet known.
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PMID:Tyrosine kinase receptor--nuclear protooncogene interactions in breast cancer. 136 Feb 36

K-SAM gene was originally isolated as an amplified gene in a stomach cancer cell line by in-gel DNA renaturation method. K-SAM encodes a membrane receptor with tyrosine kinase and is often amplified in poorly differentiated type of stomach cancer, while c-ERBB-2 is often amplified in well differentiated type of stomach cancer. There are several forms of K-SAM mRNAs which are generated by alternative splicing, and two types of K-SAM protein without transmembrane region. The ligand of K-SAM is considered to be growth factor(s) belonging to fibroblast growth factor (FGF) or heparin binding growth factor (HBFG) family. We have also frequently found amplification of HST-1 or HSTF1 gene in esophageal cancer. HST-1 gene, originally found as a transforming gene, is located on human chromosome 11q13, and it locates 35 kbp apart from its related gene, INT-2. Neither of the genes was expressed even in cancer cells with the co-amplification. By cosmid walking, we have identified at least two genes, designated tentatively as EXP1 and EXP2, on the same amplicon as HST-1 and INT-2, and the mRNAs for EXP1 and EXP2 genes were increased in amounts proportional to the degree of amplification.
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PMID:Biological significance of gene amplification in carcinogenesis. 184 51

We report the use of structure-based drug design to create a selective erbB-1 (a.k.a. epidermal growth factor receptor) and erbB-2 (a.k.a. neu/her2 growth factor receptor) tyrosine kinase inhibitor. Using the X-ray crystal structure of the ternary complex of the cAMP-dependent Ser/Thr kinase together with a sequence alignment of the catalytic domains of a representative set of Ser/Thr and Tyr protein kinases, we have examined the nucleotide binding site for potential positions to attach an irreversible inhibitor. This information, combined with homology modeling of the erbB-1 and erbB-2 tyrosine kinase catalytic domains, has led to the identification of Cys797 of erbB1 and Cys805 of erbB2, which are structurally equivalent to Glu127 in the cAMP dependant Ser/Thr kinase as potential target residues. The X-ray structure of the cAMP Ser/Thr kinase shows Glu127 to be involved in a hydrogen-bonding interaction with the 2'-OH of the ribose portion of ATP. Using molecular modeling, it was predicted that the Cys side chains in erbB-1 and erbB-2 performed an analogous role, and it was postulated that the replacement of the 2'-OH of adenosine with a thiol might allow for a covalent bond to form. Since only erbB-1 and erbB-2 have a Cys at this position, the inhibitor should be selective. This model was subsequently tested experimentally by chemical synthesis of 2'-thioadenosine and assayed against the full length erbB-1 receptor and the catalytic domains of erbB-2, insulin receptor, beta-PDGF receptor, and the FGF receptor. Our results show that thioadenosine covalently inactivates erbB-1 with a second-order rate constant of k(max)/K(S) = 2000 +/- 500 M(-1) s(-1). Inactivation is fully reversed by 1 mM dithiothreitol, suggesting that inactivation involves the modification of a cysteine residue at the active site, presumably Cys797. The rate of inactivation saturates with increasing thioadenosine concentrations, suggesting that inactivation occurs through initial formation of a noncovalent complex with K(D) = 1.0 +/- 0.3 microM, followed by the slow formation of a disulfide bond with a rate constant of k(max) = (2.3 +/- 0.2) x 10(-3) s(-1). This approach may have application in the design of selective irreversible inhibitors against other members of the kinase family.
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PMID:Structure-based design of a potent, selective, and irreversible inhibitor of the catalytic domain of the erbB receptor subfamily of protein tyrosine kinases. 908 34

The epidermal growth factor (EGF) receptor is well known as a mediator of mitogenic signaling and its tyrosine kinase activity has been suggested as a viable target in cancer chemotherapy. To explore the consequences of abolishing the kinase activity of this receptor, we have utilized a potent and specific inhibitor of the enzyme, PD 153035, to sustain a long-term suppression of its activity. This compound inhibits EGF receptor autophosphorylation in cells with an IC50 in the low nanomolar range and does not block PDGF or FGF receptor kinase until concentrations are greater than 10 microM. [1] Human epidermoid carcinoma A431 cells were grown in the presence of PD 153035 and were passed weekly until cells grew in the presence of 1 microM inhibitor. These cells, referred to as A431R, showed a remarkable change in morphology, becoming flattened and spread out. A comparison of the sensitivity of EGF receptor autophosphorylation to PD 153035 between A431 and A431R showed a similar dose response, indicating that the cells had not developed any defect in the kinase which might make it resistant to the inhibitor. Likewise, EGF receptor autophosphorylation in response to exogenously added EGF, as well as receptor internalization, was similar between the two cell lines. Furthermore, analysis of A431R cells by flow cytometry showed no significant change in DNA content or percentage of cells in any one phase of the cell cycle compared to the parent line. 125I-labeled EGF/receptor binding studies showed that receptor number in the A431R cells was equivalent to that of the parent line; however, the Scatchard plot was linear, in contrast to the typical biphasic plot obtained with the parent cells, implying a loss of high-affinity receptors. Cytoskeletal preparations from both cell lines indicated that the A431R had fourfold less EGF receptor associated with the cytoskeleton than A431. This was accompanied by a remarkable increase in polymerized actin stress fibers throughout the A431R cells, which most likely accounts for their flattened morphology. The A431R cells also exhibited a twofold increase in the expression of focal adhesion kinase, which is consistent with a greater contact area for their cell surface and increase in focal adhesions. Finally, although the A431R cells have a doubling time of 24 h, similar to that of the parent line, these cells stop growing as the monolayer approaches confluence, reminiscent of the contact inhibition seen in nontransformed cells. These data indicate that long-term suppression of the EGF receptor tyrosine kinase activity in A431 human epidermoid carcinoma results in certain cellular properties which are more consistent with a differentiated and nontransformed phenotype.
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PMID:Cytoskeletal and morphological changes associated with the specific suppression of the epidermal growth factor receptor tyrosine kinase activity in A431 human epidermoid carcinoma. 919

Tyrosine phosphorylation of beta-catenin, an intracytoplasmic E-cadherin-binding protein, has been shown to disrupt the cadherin-mediated cell adhesion system in vitro. In order to investigate the relationships of expression and tyrosine phosphorylation of cadherin-catenin molecules and expression of growth factor receptor-tyrosine kinase with loose cell-to-cell adhesion, immunohistochemical staining for E-cadherin, alpha- and beta-catenin, phosphorylated tyrosine residues and tyrosine kinase receptors, including c-erbB-2, epidermal growth factor-receptor (EGF-R), c-met and K-sam, in 17 undifferentiated- and 10 differentiated-type human gastric cancers was performed. Loss or reduced expressions of E-cadherin and alpha- and beta-catenin (11, 11, 10 cancers, respectively) were observed in the former, but not the latter. Diffuse cytoplasmic staining of E-cadherin, alpha- and beta-catenin and phosphotyrosine residues was observed frequently in the undifferentiated-type cancers. The cytoplasmic localization of phosphotyrosine residues in undifferentiated-type cancers was correlated significantly with K-sam expression (P < 0.01) and diffuse cytoplasmic staining of E-cadherin (P < 0.05) and beta-catenin (P < 0.05). Expression of K-sam protein was detected significantly more frequently in undifferentiated- (6/17; P < 0.05) than differentiated-type adenocarcinomas whereas the converse applied to c-erbB-2 expression (8/10 of the latter, P < 0.05). Tyrosine phosphorylation of beta-catenin was directly confirmed in the protein extracts of one undifferentiated-type gastric cancer. These data indicate that alteration of tyrosine phosphorylation status associated with K-sam expression may cause the cytoplasmic distribution of cadherin-catenin molecules and loose cell-cell adhesion in undifferentiated-type gastric cancers.
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PMID:Expression of cadherin-catenin cell adhesion molecules, phosphorylated tyrosine residues and growth factor receptor-tyrosine kinases in gastric cancers. 976 19

Immunohistochemical analysis of the expression of keratinocyte growth factor receptor (KGFR) was performed in human endometrial carcinomas from 18 patients and in normal proliferative and secretory endometrium. The level of immunostaining was correlated with the clinico-pathological characteristics of the endometrial carcinoma patients and with the parallel expression of the epidermal growth factor receptor (EGFR) and erbB-2. The results showed that KGFR expression increased with the stage of the tumor and that the simultaneous overexpression of the three growth factor receptors appeared to be related to the depth of myometrial invasion. Taken together, these observations suggest that KGFR may represent an additional prognostic indicator in endometrial cancer.
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PMID:Expression of keratinocyte growth factor receptor compared with that of epidermal growth factor receptor and erbB-2 in endometrial adenocarcinoma. 1042 21

The four members of the EGF receptor family are capable of homomeric as well as heteromeric interactions. HER-2/neu (erbB-2) dominates as the preferred coreceptor that amplifies mitogenic signaling. An alternative HER-2/neu product, herstatin, consists of a segment of the ectodomain of p185HER-2 and an intron-encoded C-terminus. Recombinant herstatin was found to bind with nM affinity and inhibit p185HER-2. To further examine the impact on receptor activity, herstatin was expressed with various receptor tyrosine kinases. In CHO cells that overexpressed HER-2, herstatin caused a sevenfold inhibition of colony formation that corresponded to a reduction in the tyrosine phosphorylation of p185HER-2. Herstatin also prevented HER-2 mediated transactivation of the kinase impaired HER-3 as reflected in transphosphorylation of HER-3 and heteromers between HER-2 and HER-3. In EGF receptor-overexpressing cells, EGF induction of receptor dimerization and tyrosine phosphorylation were reduced more than 90%, and receptor down-regulation as well as colony formation were also suppressed by coexpression with herstatin. Inhibition was selective for the EGF receptor family since herstatin expression did not reduce tyrosine phosphorylation mediated by the FGF receptor-2 or by insulin-like growth factor -1. Herstatin bound to the EGF receptor as well as to p185HER-2 in pull-down assays suggesting that complex formation may be involved in receptor inhibition. Our findings indicate that herstatin has the capability to negatively regulate combinations of interactions between group I receptor tyrosine kinases that confer synergistic growth signals.
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PMID:Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor. 1152 9

Terminal airways are affected in many lung diseases and toxic inhalations. To elucidate the changes in terminal airways in these diverse situations it will be helpful to profile and quantify gene expression in terminal bronchiolar epithelium. We used laser capture microdissection (LCM) to collect terminal bronchiolar epithelial cells from frozen sections of lungs of mice subjected to intratracheal bleomycin. The RNA from these cells was used for analysis of select messenger RNAs (mRNAs) by quantitative real-time polymerase chain reaction (PCR). In parallel, we used real-time PCR to analyze mRNAs in whole-lung homogenates prepared from other mice given intratracheal bleomycin. We found reductions of Clara cell-specific protein and keratinocyte growth factor receptor mRNAs in both terminal bronchiolar epithelium and whole-lung homogenates 7 d after bleomycin. In contrast, terminal bronchiolar epithelial transforming growth factor (TGF)-alpha mRNA was reduced but whole-lung TGF-alpha mRNA was not changed, whereas terminal bronchiolar epithelial epidermal growth factor (EGF) receptor mRNA was not changed but whole-lung EGF receptor was reduced. We conclude that LCM can isolate terminal bronchiolar epithelial cells for studies of cell-specific gene expression by quantitative real-time PCR, and that cell-specific gene expression in terminal bronchiolar epithelium is not necessarily reflected in analysis of whole-lung gene expression.
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PMID:Laser capture microdissection and real-time reverse transcriptase/ polymerase chain reaction of bronchiolar epithelium after bleomycin. 1158 4

Fibroblast growth factor (FGF)-2 and transforming growth factor alpha (TGFalpha) promote astroglial proliferation during brain development and reactive processes. The mitogenic potential of both growth factors is attenuated by increasing intracellular cAMP levels, an effect currently assumed to depend on the inhibition of the mitogen-activated protein kinase cascade. In the present study, we sought to determine whether cAMP interferes with the mitogenic potential of FGF-2 and TGFalpha on astroglia by affecting the expression of respective growth factor receptors. Treatment of highly enriched cultures of cortical astrocytes with dibutyryl cAMP accelerated the TGFalpha-induced internalization and subsequent functional inactivation of epidermal growth factor (EGF) receptor by transiently inhibiting EGF receptor mRNA synthesis. In apparent contrast, both short- and long-term activation of cAMP-dependent signaling pathways robustly promoted the expression of FGF receptors 1 and 2, whereas expression levels of FGF receptor 3 remained unaffected. Moreover, elevation of intracellular cAMP levels did not prevent translocation of FGF receptor 1 to the cell nucleus, a mechanism thought to be essential for FGF-2-induced cell proliferation. We propose that cAMP controls the mitogenic effects of TGFalpha and FGF-2 on astroglial cells by distinctly different mechanisms. Whereas cAMP seems to interfere with the mitogenic effects of TGFalpha on astroglial cells by affecting both the expression level and signaling of the EGF receptor, the modulatory effects of cAMP on FGF-2-induced astroglial proliferation seem to solely result from an inhibition of FGF receptor-activated signaling pathways.
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PMID:Cyclic AMP differentially regulates the expression of fibroblast growth factor and epidermal growth factor receptors in cultured cortical astroglia. 1220 56

Responses to G protein-coupled receptor stimulation may be mediated by paracrine factors. We have developed a coculture system to study paracrine regulation of migration of gastric epithelial (AGS) cells after stimulation of gastrin-CCK(B) receptors. In cells expressing this receptor, G-17 stimulated migration by activation of protein kinase C. However, G-17 also stimulated the migration of cells expressing green fluorescent protein, but not the receptor, when they were cocultured with receptor-expressing cells consistent with activation of paracrine signals. The use of various pharmacological inhibitors indicated that gastrin stimulated migration via activation of the EGF receptor (EGR-R), the erbB-2 receptor tyrosine kinase, and the MAP kinase pathway. However, gastrin also released fibroblast growth factor (FGF)-1, and migration was inhibited by the FGF receptor tyrosine kinase inhibitor SU-5402. Flow cytometry indicated that in both cell types, gastrin increased MAP kinase via activation of EGF-R but not FGF-R1 or erbB-2. We conclude that gastrin-CCK(B) receptors stimulate epithelial cell migration partly via paracrine mechanisms; transactivation of EGF-R is only one component of the paracrine pathway.
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PMID:Stimulation of gastrin-CCKB receptor promotes migration of gastric AGS cells via multiple paracrine pathways. 1248 36


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