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

This review considers the biology of the type 1 growth factor receptor family which is increasingly recognised as important in the control of normal cell proliferation and in the pathogenesis of human cancer. The family currently comprises three closely related members: the epidermal growth factor (EGF) receptor, c-erbB-2 and c-erbB-3, all of which show abnormalities of expression in various human tumours. The family of factors related to EGF has also expanded recently and now includes transforming growth factor alpha, heparin-binding EGF, amphiregulin, cripto and heregulin, as well as several other potential ligands for the c-erbB2-2 receptor. The involvement of these receptors and growth factors in human cancer has implications for the design of novel forms of therapy for cancer, and we review recent advances and future avenues for investigation.
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PMID:The type 1 (EGFR-related) family of growth factor receptors and their ligands. 135 72

We have used the reverse transcription-polymerase chain reaction (RT-PCR) to determine whether transcripts for the epidermal growth factor (EGF) receptor and its four known ligands--EGF, transforming growth factor alpha (TGF alpha), amphiregulin (Ar), and heparin-binding EGF (HB-EGF)--are expressed in porcine oviduct and endometrium. We were able to detect mRNA for the EGF receptor, EGF, TGF alpha, and Ar in both the oviduct and endometrium, whereas HB-EGF mRNA was not detectable in either tissue. Through use of an antiserum raised against recombinant pig EGF, expression of EGF was found to be localized to the columnar epithelial cells of the oviduct and to the glandular epithelial cells of the endometrium. The possible physiological roles of the EGF family in the reproductive tract are discussed.
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PMID:Expression of the genes for the epidermal growth factor receptor and its ligands in porcine oviduct and endometrium. 751 85

The expression of amphiregulin (AR), heregulin (HRG), and cripto-1 (CR-1) mRNA transcripts was assessed in 60 human primary breast carcinoma. AR and HRG transcripts were expressed respectively in 58% and 25% of the carcinomas as measured by Northern blot analysis. CR-1 mRNA was found in 77% of the carcinomas using Reverse Transcriptase-PCR analysis. Coexpression of two or three of these peptides was observed in several specimens. There was no significant association between AR, HRG, and CR-1 expression and nodal status, EGF receptor, or c-erbB-2 protooncogene expression in these tumors. However, a significant association between AR expression and estrogen receptor positivity was observed.
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PMID:Expression of messenger RNA for amphiregulin, heregulin, and cripto-1, three new members of the epidermal growth factor family, in human breast carcinomas. 757

Limited information is available concerning the involvement of growth factor receptors and their ligands in the pathogenesis of human pancreatic cancer. We analyzed 12 human pancreatic cancer cell lines by Northern blot analysis for the expression of 9 receptor tyrosine kinase (RTKs) and 6 growth factors. The effect of a monoclonal antibody (MAb) against transforming growth factor-alpha (TGF-alpha) on in vitro pancreatic cancer cell growth was also assessed, mRNA for EGF-R, c-erbB-2 and c-erbB-3 was expressed in 12 (100%), 12 (100%), and 7 (58%), respectively, of the cell lines examined. In addition, 8 (67%) cell lines expressed the c-met/receptor for hepatocyte growth factor. As for ligands, TGF-alpha mRNA was detected in 10 (83%) cell lines; MAb against TGF-alpha inhibited growth of the 2 cell lines examined. Furthermore, mRNA for amphiregulin (AR) was expressed in 10 (83%) cell lines. Coexpression of TGF-alpha, AR, and EGF-R was observed in 9 (75%) cell lines. These results support the concept that several specified types of RTKs and their ligands are closely involved in regulation of the growth of human pancreatic cancer cells.
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PMID:Frequent expression of genes for receptor tyrosine kinases and their ligands in human pancreatic cancer cells. 759 66

The COOH-terminal half of the amphiregulin (AR) molecule has sequence homology to epidermal growth factor (EGF). The ability of AR to elicit in vivo phosphorylation of the EGF receptor (EGFR) and p185erbB2 was studied in four human epithelial cell lines which expressed either or both of the receptor tyrosine kinases. AR induced the phosphorylation of the EGFR and p185erbB2, and phosphoamino acid analysis revealed enhanced phosphorylation of tyrosine residues in both receptor proteins. A monoclonal antibody (mAb) which binds to the extracellular domain of the EGFR blocked the phosphorylation of the EGFR and p185erbB2 as well as AR-induced mitogenesis indicating that the EGFR mediated these responses. In MDA-MB-453 cells which lack EGFRs, AR did not induce phosphorylation of p185erbB2, did not affect proliferation, and had no detectable effect on the phosphorylation of cellular proteins isolated using an anti-phosphotyrosine mAb. Qualitatively, in vivo phosphorylations induced by AR and EGF were found to be indistinguishable as demonstrated by analysis of cellular 32P-labeled proteins isolated with the anti-phosphotyrosine mAb. Moreover, in the presence of the anti-EGFR mAb, AR had no effect on the proliferation of cells. These results provide strong evidence that the EGFR is the sole cell surface mediator of the action of AR in human epithelial cells.
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PMID:Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor and p185erbB2. Evidence that amphiregulin acts exclusively through the epidermal growth factor receptor at the surface of human epithelial cells. 767 4

Autocrine activation of the epidermal growth factor (EGF) receptor on keratinocytes has been recognized as an important growth regulatory mechanism involved in epithelial homeostasis, and, possibly, hyperproliferative diseases. Insulin-like growth factor (IGF)-1 and insulin have been shown to be paracrine keratinocyte mitogens that bind to the type I IGF receptor which is expressed on actively proliferating keratinocytes in situ. In this report, we demonstrate that IGF-1/insulin induced production of keratinocyte-derived autocrine growth factors that bind to the EGF receptor. Increased steady-state mRNA levels for transforming growth factor alpha (TGF-alpha) and for amphiregulin (AR) were observed upon incubation of keratinocytes with mitogenic concentrations of IGF-1. IGF-1 also induced production and secretion of TGF-alpha and AR proteins as detected by immunoassays. An EGF receptor antagonistic monoclonal antibody abolished the mitogenic effect of IGF-1 on cultured keratinocytes. These results suggest that stimulation of keratinocyte growth of IGF-1 requires activation of an EGF receptor-mediated autocrine loop.
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PMID:Induction of autocrine epidermal growth factor receptor ligands in human keratinocytes by insulin/insulin-like growth factor-1. 770 70

Infection with multiple sexually transmitted agents has been associated with inflammation of the cervix and an increased risk of cervical cancer in women infected with human papillomaviruses (HPVs). Two proinflammatory cytokines, interleukin 1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF-alpha), inhibited proliferation of normal epithelial cells cultured from human cervix. In contrast, both cytokines significantly stimulated proliferation of cervical cell lines (5 of 7) immortalized by transfection with HPV-16 or -18 DNAs or lines derived from cervical carcinomas (7 of 11). Stimulation was dose dependent from 0.01 to 1.0 nM and was blocked by specific inhibitors, such as the IL-1 receptor antagonist or the TNF type 1 or 2 soluble receptors. Growth stimulation by IL-1 alpha or TNF-alpha was accompanied by a 6- to 10-fold increase in RNA encoding amphiregulin, an epidermal growth factor (EGF) receptor ligand. Recombinant human amphiregulin (0.1 nM) was as effective as IL-1 alpha or TNF-alpha in promoting proliferation. Monoclonal antibodies that blocked signal transduction by the EGF receptor or that neutralized amphiregulin activity prevented mitogenic stimulation by IL-1 alpha or TNF-alpha. These studies indicate that IL-1 alpha and TNF-alpha stimulate proliferation of immortal and malignant cervical epithelial cells by an EGF receptor-dependent pathway requiring autocrine stimulation by amphiregulin. Furthermore, they suggest that chronic inflammation and release of proinflammatory cytokines might provide a selective growth advantage for abnormal cervical cells in vivo.
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PMID:Interleukin 1 alpha and tumor necrosis factor alpha stimulate autocrine amphiregulin expression and proliferation of human papillomavirus-immortalized and carcinoma-derived cervical epithelial cells. 770 34

Amphiregulin (AR), a heparin-binding, epidermal growth factor (EGF) receptor ligand has homology with EGF but exhibits a lower affinity for the EGF receptor than EGF. As the mature form of AR is truncated at the C terminus and lacks a conserved leucine residue known to be essential for high affinity binding of EGF to the EGF receptor, wild-type AR (AR1-84), a C-terminally extended AR construct incorporating six residues from the predicted coding sequence of AR (AR1-90) and a similarly extended construct with a Met86 to Leu substitution (AR1-90(leu86)) were expressed as recombinant proteins in yeast, purified by heparin affinity and C18 reverse phase chromatography and their relative biological activities determined. The growth factors were tested in mitogenesis and EGF receptor autophosphorylation assays and their relative order of potencies was found to be leu86 > met86 > wt. The AR1-90(leu86) construct was found to be 50- to 100-fold more active than wild type AR1-84 consistent with previously reported studies of the role of the equivalent C-terminal leucine in EGF or TGF alpha. Significantly, the C-terminally extended form of AR, AR1-90, which utilized six residues from the predicted coding sequence, was 10-times more active than wild type AR1-84. This difference in activity of the C-terminally extended form of AR may be of biological significance since differential proteolytic processing of the AR precursor in vivo could result in production of multiple forms of the growth factor with differing affinities for the EGF receptor and hence differing biological potencies.
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PMID:Modulation of the receptor binding affinity of amphiregulin by modification of its carboxyl terminal tail. 771 25

Autocrine epidermal growth factor receptor activation by transforming growth factor alpha (TGF alpha) has been implicated in growth stimulation during epithelial neoplasia. Using keratinocytes isolated from mice with genetic defects in TGF alpha expression, we tested whether TGF alpha is required for transformation by the v-rasHa oncogene. Introduction of v-rasHa into primary epidermal cultures using a retroviral vector stimulated growth of both control (TGF alpha +/+, BALB/c) and TGF alpha-deficient (TGF alpha -/-, wa-1) keratinocytes. Moreover, v-rasHa elicited characteristic changes in marker expression (keratin 1 was suppressed; keratin 8 was induced), previously shown to be associated with epidermal growth factor (EGF) receptor activation, in both TGF alpha +/+ and TGF alpha -/- keratinocytes. v-rasHa markedly increased secreted (> 10-fold) and cell-associated (2-3-fold) TGF alpha levels in keratinocytes from TGF alpha +/+ and BALB/c mice, but not TGF alpha -/- or wa-1 mice. Based on Northern blot analysis, v-rasHa induced striking up-regulation of transcripts encoding the additional EGF family members amphiregulin, heparin-binding EGF-like growth factor, and betacellulin in cultured keratinocytes from all four mouse strains. Interestingly, in addition to the normal 4.5-kilobase TGF alpha transcript, wa-1 keratinocytes expressed two additional TGF alpha transcripts, 4.7 and 5.2 kilobases long. All three transcripts were up-regulated in response to v-rasHa, as well as exogenous TGF alpha or keratinocyte growth factor treatment, and were also detected in RNA isolated from wa-1 brain and skin. In vivo, v-rasHa keratinocytes from control as well as TGF alpha-deficient mice produced squamous tumors when grafted onto nude mice, and these lesions expressed high levels of amphiregulin, heparin-binding EGF-like growth factor, and betacellulin mRNA, regardless of their TGF alpha status. These findings indicate that TGF alpha is not essential for epidermal neoplasia induced by the v-rasHa oncogene and suggest that another EGF family member(s) may contribute to autocrine growth stimulation of ras-transformed keratinocytes.
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PMID:Autocrine transforming growth factor alpha is dispensible for v-rasHa-induced epidermal neoplasia: potential involvement of alternate epidermal growth factor receptor ligands. 772 56

Primary and metastatic ovarian cystadenocarcinomas, carcinomas of low malignant potential (borderline tumors), benign ovarian cystadenomas, and normal ovaries were compared for immunoperoxidase detection of the ligands epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), amphiregulin (AR), cripto, and the receptors, epidermal growth factor receptor (EGF-R), and c-erbB-2. This matrix analysis of these EGF family members indicated no specific pattern of ligand or receptor expression with a specific ovarian histologic category except in the case of AR and TGF-alpha. AR was detected almost exclusively in borderline tumors, suggesting that these tumors may not arise as a pathological continuum between benign cystadenomas and invasive cystadenocarcinomas. Second, the presence of TGF-alpha immunoreactivity in the absence of coexpression of cripto or EGF appeared to be associated only with adenocarcinomas of high grade and stage.
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PMID:Frequent immunohistochemical detection of EGF supergene family members in ovarian carcinogenesis. 781 96


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