UNIPROT:P04626 - FACTA Search

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Query: UNIPROT:P04626 (erbB-2)
5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A link between inflammation of the colon in inflammatory bowel disease (IBD) and the increased risk of colon cancer in ulcerative colitis (UC) may be provided by growth factor receptor genes. Their expression may be altered in response to growth factors present in the mucosa, and this, in turn, may induce further genetic changes, linked to carcinogenesis, in the cells of the colonic epithelium. To test this hypothesis, we assayed steady-state levels of eight growth factor receptor mRNAs in colonic epithelial cells of IBD patients and controls. Four of these genes (EGF-R, IGFI-R, CSF1-R, and PDGF-R-beta) were expressed in epithelial cells, whereas four (erbB-2, erbB-3, NGF-R, and met) were not. The level of the former in involved or uninvolved IBD was considerably lower than in normal epithelial cells from either sporadic colon cancer or diverticulitis patients. In contrast, expression was much higher in IBD patients with colon tumors than in active chronic IBD. The level of PDGF-R-beta mRNA was two- to fourfold higher in involved than in uninvolved areas of the colons of two UC patients, but not in one Crohn's disease patient. Message abundance of its ligand, PDGF-beta, however, was the same in paired UC samples. The pattern of expression of PDGF-beta and cripto was identical to that of EGF-R, whereas the level of mRNA of amphiregulin was the same in active chronic IBD and IBD patients with tumors. A fourth growth factor, Kfgf, was not expressed. Increased levels of PDGF-R-beta mRNA in involved UC relative to uninvolved UC may be related to the disease process in UC. Decreased expression of growth factor- and growth factor receptor-encoded mRNA in active chronic IBD may be related to the disease process, or it may be an effect of steroid therapy undergone by these patients. Enhanced expression of these genes in IBD patients with tumors compared to those without tumors suggests that this may be a marker for development of colon cancer in IBD.
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PMID:Expression of growth factor receptor-encoded mRNA by colonic epithelial cells is altered in inflammatory bowel disease. 789 32

Proto-oncogenes encoding growth factor receptors constitute several distinct families with close overall structural homology. The highest degree of homology can be observed in their catalytic domains, which are essential for intrinsic tyrosine kinase activity. Growth factor receptors in several of these families play critical roles in the regulation of normal cell growth and development. Some of these molecules have been implicated in the neoplastic process as well. A related DNA fragment distinct from epidermal growth factor receptor and erbB-2 genes was detected by reduced stringency hybridization of v-erbB to normal genomic human DNA. The expression of erbB-3 was studied by southern and northern blot technique in a subset of nine head and neck tumor cell lines, as well as in three immortalized cultures established from normal human salivary glands. No gene amplification of erb-B-3 was noted in any of the head and neck cell lines. The 6.2 kb transcript of erbB-3 was elevated significantly in an epidermoid carcinoma of the larynx (A388) and an esophageal carcinoma (HA 114).
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PMID:erbB-3, a third member of the erbB/epidermal growth factor receptor gene family: its expression in head and neck cancer cell lines. 828 3

The predicted human erbB-3 gene product is closely related to epidermal growth factor receptor (EGFR) and erbB-2, which have been implicated as oncogenes in model systems and human neoplasia. We expressed the erbB-3 coding sequence in NIH 3T3 fibroblasts and identified its product as a 180-kDa glycoprotein, gp180erbB-3. Tunicamycin and pulse-chase experiments revealed that the mature protein was processed by N-linked glycosylation of a 145-kDa erbB-3 core polypeptide. The intrinsic catalytic function of gp180erbB-3 was shown by its ability to autophosphorylate in vitro. Ligand-dependent signaling of its cytoplasmic domain was established employing transfectants that express a chimeric EGFR/erbB-3 protein, gp180EGFR/erbB-3. EGF induced tyrosine phosphorylation of the chimera and promoted soft agar colony formation of such transfectants. These findings combined with the detection of constitutive tyrosine phosphorylation of gp180erbB-3 in 4 of 12 human mammary tumor cell lines implicate the activated erbB-3 product in the pathogenesis of some human malignancies.
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PMID:Demonstration of ligand-dependent signaling by the erbB-3 tyrosine kinase and its constitutive activation in human breast tumor cells. 846 5

Betacellulin is a member of the epidermal growth factor (EGF) family. These soluble proteins are ligands for one or more of the four receptor tyrosine kinases encoded by the erbB gene family (erbB-1/epidermal growth factor receptor (EGFR), neu/erbB-2/HER2, erbB-3/HER3 and erbB-4/HER4). While evidence suggests that betacellulin is a ligand for the EGFR, the ability of betacellulin to regulate other erbB family receptors has not been analysed. Previously we engineered derivatives of the mouse Ba/F3 hematopoietic cell line to ectopically express erbB family receptors, singly and in pairwise combinations. We have stimulated this panel of cell lines with betacellulin and two other EGF family members, EGF itself and neuregulin-beta (NRG-beta). In the cell lines expressing a single erbB family receptor, betacellulin not only stimulated EGFR tyrosine phosphorylation, but it activated erbB-4 as well. Furthermore, in the double recombinant Ba/F3 derivatives, betacellulin stimulated a complex pattern of receptor phosphorylation distinct from the patterns activated by NRG-beta and EGF. Moreover, betacellulin stimulated a complex pattern of interleukin-3 independence in the Ba/F3 derivatives distinct from those activated by NRG-beta and EGF. These data identify a novel receptor for betacellulin and establish that different EGF family ligands activate distinct patterns of receptor phosphorylation and coupling to cellular signaling pathways.
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PMID:Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta. 857 Feb 11

Growth factor-independent proliferation is an essential aspect of the transformation process. To study the influence of c-erbB-2 overexpression on the autonomous growth of human mammary cancer cells, we used a series of non-neoplastic and neoplastic human mammary epithelial cell lines isolated from a patient with intraductal and invasive ductal carcinoma of the breast. The non-neoplastic cell line, H16N-2, which expresses a normal level (single gene copy) of c-erbB-2, was used for comparison with the neoplastic cell lines. Both the metastatic tumor cell lines, 21MT-1 and 21 MT-2, showed equivalent amplification of the c-erbB-2 gene; however, 21MT-1 cells showed a higher level of c-erbB-2 overexpression. Therefore, the H16N-2, 21MT-2, and 21MT-1 cell series forms a distinct gradient of progressively increasing c-erbB-2 gene expression. Furthermore, the overexpression of c-erbB-2 in the 21MT cell lines was concordant with increases in the constitutive tyrosine kinase activity of p185erb-2 measured in the absence of exogenous growth factors in culture. Normal mammary epithelial cells require both insulin-like growth factor (IGF)-l (or supraphysiological concentrations of insulin) and epidermal growth factor (EGF) to proliferate under serum-free conditions in culture. By contrast, 21MT-2 cells showed a reduced requirement for IGF but still required EGF to proliferate. 21MT-1 cells did not require either insulin or EGF to proliferate. Therefore, the progressive increases in constitutive p185erbB-2, tyrosine kinase activity in the 21MT-2 and 21MT-1 cell lines was directly correlated with IGF independence and combined IGF and EGF independence under defined conditions in culture. Experiments using conditioned media and anti-IGF-1 receptor and anti-EGF receptor neutralizing antibodies showed that the growth-factor independence of the tumor cells did not involve detectable IGF- or EGF-like autocrine activity expressed by the 21MT cells. Furthermore, neu differentiation factor/heregulin, a ligand that indirectly activates p185erbB-2 by direct binding to erbB-3 receptors, potently stimulated the proliferation of the growth factor-dependent H16N-2 cells (which expressed c-erbB-2 and c-erbB-3 but not c-erbB-4) in the absence of both IGF and EGF. Thus, HRG-induced mitogenesis mimicked the autonomous growth seen in the 21MT cells that have the highest level of constitutive p185erbB-2 activation. These data support the hypothesis that the constitutive activation of p185erbB-2 in human mammary carcinoma cells causes growth-factor independence by directly activating multiple signal-transduction pathways that substitute for both IGF and EGF during proliferation.
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PMID:Insulin-like growth factor and epidermal growth factor independence in human mammary carcinoma cells with c-erbB-2 gene amplification and progressively elevated levels of tyrosine-phosphorylated p185erbB-2. 859 35

A new human breast cancer cell line (SUM-52PE), originating from a malignant pleural effusion specimen, that can be cultured under serum-free conditions has been isolated. Experiments were conducted to examine the relationship between expression of the erbB family of growth factor receptors and growth regulation in these cells. SUM-52PE cells are epidermal growth factor receptor negative but express single copy levels of erbB-2 protein. Southern blot analysis indicates that the erbB-2 gene is not amplified in these cells. The cells also express mRNA for both erbB-3 and erbB-4. Phosphotyrosine Western blot analysis of membrane protein obtained from SUM-52PE cells indicates the presence of a constitutively tyrosine phosphorylated M(r) 185,000 protein. Immunoprecipitation, using antibodies to erbB-2 or erbB-3, coupled to phosphotyrosine Western blot analysis indicates that both erbB-2 and erbB-3 are constitutively tyrosine phosphorylated in proliferating SUM-52PE cells. Conditioned medium obtained from SUM-52PE cells does not induce tyrosine phosphorylation of p185erbB-2 in a sensitive indicator cell line, suggesting that an erbB-2 activating factor is not secreted by these cells. However, neu differentiation factor/heregulin (NDF/HRG) mRNA is expressed by the cells, and Western blot analysis of SUM-52PE membrane protein revealed the presence of a M(r) 90,000 immunoreactive NDF/HRG protein. Thus, SUM-52PE cells synthesize a membrane bound form of NDF/HRG that may activate erbB-2 and erbB-3 via a juxtacrine mechanism. The addition of exogenous beta-2-NDF/HRG to the culture medium of SUM-52PE cells yields enhanced tyrosine phosphorylation of p185erbB-2/erbB-3 but has only a small stimulatory effect on the proliferation of these cells. By contrast, an erbB-2 monoclonal antibody that binds to the extracellular domain of erbB-2 is potently mitogenic for these cells. SUM-52PE cells were also found, by phosphotyrosine Western blot analysis, to express an inordinately large number of tyrosine phosphoproteins. Direct measurement of phosphotyrosine phosphatase (PTPase) activity in SUM-52PE cell membrane protein revealed 2-3-fold lower levels of PTPase activity compared to other normal and neoplastic breast epithelial cell lines. Thus, SUM-52PE cells exhibit altered growth phenotypes not identified previously in human breast cancer cells. The constitutive activation of erbB-2 and erbB-3 in these cells, coupled with their low, membrane-associated, PTPase activity are likely to play direct roles in driving proliferation of these breast cancer cells.
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PMID:erbB family receptor expression and growth regulation in a newly isolated human breast cancer cell line. 863 Oct 31

The tyrosine kinase receptor family, including the epidermal growth factor receptor (EGF-R), c-erbB2 and, more recently, the c-erbB3, has been recognized as being of particular importance in many human malignancies. This study was undertaken to define the role of c-erb B2 and c-erbB3 in adenoid cystic carcinomas (A.C.C.) of the salivary glands. Sixteen cases of A.C.C. were studied immunohistochemically, using antibodies against each erbB gene family product. EGF-R was not detected in any of these samples but c-erbB2 and c-erbB3 gene products (ERBB2and ERBB3) were demonstrated in all A.C.C. sections with some degree of straining. Tubular and cribriform patterns overexpressed particularly large amounts of ERBB2 and ERBB3. Strong staining was mainly demonstrated in tumor cells of the invasive area. These results suggested that overexpression of ERBB2 and ERBB3 is related to tumor differentiation and invasion in adenoid cystic carcinomas.
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PMID:Expression of c-erbB family gene products in adenoid cystic carcinoma of salivary glands: an immunohistochemical study. 866 36

Previously we reported that neu differentiation factor (NDF)/heregulin (HRG) elevates tyrosine phosphorylation of its receptors erbB-3, erbB-4, and erbB-2 (through heterodimer formation). We also showed that both NDF/HRG and antibodies to erbB-2 can arrest growth and induce differentiation in breast cancer cells. In this study, we report on the mechanism of NDF/HRG-induced cellular effects. We show that NDF/HRG and antibodies to erbB-2 receptors up-regulate expression of p53 by stabilizing the protein. This is accompanied by up-regulation of the p53 inducible gene, p21CIP1/WAF1, in a variety of cell lines: MCF7 and their derivatives (MCF7/HER2, MN1 and MCF-7-puro), ZR75T and LnCap cells. The induction of p21 is further enhanced when cells are treated with both NDF/HRG and DNA-damaging chemotherapeutic agents (i.e. doxorubicin). The NDF/HRG mediated induction of p21 is dependent on wildtype p53, as it fails to occur in cells expressing dominant negative p53 (MDD2). Furthermore, p21 induction is capable of inactivating cdk2 complexes as measured by Histone H1 phosphorylation assays. Finally, we show that in primary cultures of breast and other cancers, p21 is significantly induced in response to NDF/HRG treatment. Collectively, these observations suggest that the mechanism of breast cancer cell growth inhibition and differentiation via erbB receptors activation is through a p53-mediated pathway.
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PMID:Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells. 870 May 12

Malignant insulinoma is an rare form of cancer with poor prognosis and a reported 5-year survival of 35%. Relatively little is known about the etiology of this disease or of the oncogenes and tumor suppressor genes that participate in its genesis and progression. To address this issue, several protooncogenes, including K-ras, N-ras, erbB-2, erbB-3,c-myc, c-fos, c-jun were examined. Also analyzed was the expression of the growth factors TGF-alpha, EGF, and insulin as well as the EGF receptor (EGF-R), p53 and the putative anti-metastasis gene nm23-H1. These were examined in malignant insulinomas, benign insulinomas, pancreatic B cell hyperplasias and in normal endocrine pancreas. Normal endocrine pancreas showed moderate immunoreaction for c-myc and a strong reaction for insulin. All other parameters were negative. Benign pancreatic B cell hyperplasias were slightly or moderately positive for N-ras and TGF-alpha, and were weakly positive for EGF-R. They were strongly positive for c-myc and insulin. In malignant insulinomas there was strong immunoreaction for c-myc, TGF-alpha, N-ras, K-ras and p53. Insulin reaction was moderate or strong. Molecular genetic studies have been performed for the presence of activating point mutations in codon 12 of the c-K-ras oncogene. Mutations were detected using primer-mediated, mutant-enriched, polymerase chain reaction-restriction fragment length polymorphism analysis and were further characterized by allele-specific oligonucleotide hybridization. Four out of six patients with malignant insulinoma and two out of eight patients with benign insulinoma harbored K-ras point mutations at codon 12. All patients with mutated K-ras oncogene also had elevated levels of p53 protein as well as c-myc and TGF-alpha. In one extremely malignant case we found concomitant mutation at codon 12 of K-ras and codon 61 of the N-ras gene. Our data are consistent with the idea that malignant progression is accompanied by the progressive accumulation of multiple genetic lesions and suggest that activation of myc, TGF-alpha and ras genes may be early events in the development of insulinoma.
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PMID:Molecular genetics of malignant insulinoma. 871 89

Amplification and overexpression of the c-erbB-2 gene in 21MT-2 and 21MT-1 human breast carcinoma cells results in progressively elevated levels of constitutively tyrosine-phosphorylated p185erbB-2 and is associated with progressive insulin-like growth factor (IGF) and combined IGF/epidermal growth factor (EGF) independence in culture. In addition, the neu differentiation factor/heregulins (HRGs), a family of ligands that activate p185erbB-2 through direct binding to erbB-3 or erbB-4, are potent mitogens for various nonneoplastic mammary epithelial cells and carcinoma cell lines in the absence of both IGF and EGF in culture. We have investigated the ability of ligand induction with HRGs or the constitutive activation of p185erbB-2 in the 21MT breast carcinoma cells to induced the recruitment of phosphatidylinositol 3-kinase (PI3K) by p185erbB-2 and erbB-3. HRG was found to potently induce the recruitment of the M(r) 85,000 regulatory subunit of PI3K by phosphotyrosine proteins in both nonneoplastic H16N-2 mammary epithelial cells (which express normal c-erbB-2 levels) and in the 21MT-2 and 21MT-1 cell lines, which were all isolated from a single patient with intraductal and invasive ductal carcinoma of the breast and express c-erbB-3 but not c-erbB-4 in culture. The activation of PI3K in these cells was also associated with high-level mitogenic responsiveness to HRG, as well as the IGF/EGF-independent proliferation of the 21MT cell lines in culture. The recruitment of PI3K by phosphotyrosine protein during ligand-induced activation, or that seen constitutively in the 21MT tumor cells, did not involve detectable tyrosine phosphorylation of p85. The HRG-induced recruitment of p85 and the constitutive recruitment of p85 in the 21MT cell lines involved direct association with both p185erbB-2 and erbB-3, although greater levels were recruited directly by erbB-3. Wortmannin, a potent inhibitor of PI3K enzymatic activity, also blocked the autonomous proliferation of the 21MT cells, and this effect was reversible in long-term cultures. These data indicate that PI3K may be an especially important mediator of HRG-induced proliferation in mammary epithelial cells and is involved in the autonomous proliferation of growth factor-independent breast carcinoma cells with c-erbB-2 gene amplification.
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PMID:Phosphatidylinositol 3-kinase recruitment by p185erbB-2 and erbB-3 is potently induced by neu differentiation factor/heregulin during mitogenesis and is constitutively elevated in growth factor-independent breast carcinoma cells with c-erbB-2 gene amplification. 873 65

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