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PubMed1995

Prognostic significance of ERBB3 overexpression in oral squamous cell carcinoma.

Immunohistochemical analysis of erbB3, as the third member of epidermal growth factor receptor gene family, was performed on 41 cases of oral squamous cell carcinoma, correlating the staining pattern with clinical outcome. High expression of erbB3 protein (ERBB3) was significantly associated with lymph node metastasis (P < 0.05), survival rate (P < 0.05) and mode of invasion (P < 0.01) in this series. These results demonstrated that ERBB3 expression may be helpful in identifying those oral squamous cell carcinomas with higher malignant potential.

Adult↗
PubMed1992

The type 1 (EGFR-related) family of growth factor receptors and their ligands.

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.

Amino Acid Sequence↗
PubMed1992

Expression of the ERBB3 gene product in breast cancer.

Abnormalities of the EGF receptor and/or the related ERBB2 receptor occur in a significant proportion of cases of human breast cancer and are important influences in the behaviour of this tumour type. In this report we demonstrate by nucleic acid analysis and immunohistochemistry that the recently recognised third member of this gene family, ERBB3, shows a wide range of expression in breast cancer, and shows stronger immunoreactivity than that observed in normal tissue in 43 out of 195 cases (22%) of primary breast cancer. Overexpression of ERBB3 appears to result from increased levels of gene transcription since in none of the cell lines or primary cancers analysed did we find evidence of gene amplification. High expression of ERBB3 is positively associated with the presence of lymph node metastases, but there was no demonstrable relationship with patient survival in this series.

Blotting, Southern↗
PubMed1995

c-erbB-3 protein expression in ovarian tumours.

In this study the expression of c-erbB-3 protein was investigated in a range of human ovarian tumours using a monoclonal antibody (RTJ1) raised to a synthetic peptide from the cytoplasmic domain of the human c-erbB-3 protein. A total of 73 samples from 71 patients were graded as negative, weak, moderate or strong according to the intensity of immunohistochemical staining observed, and this was related to tumour characteristics and other clinical parameters. In terms of positivity vs negativity, of the 73 samples examined, 62 (85%) showed positive immunohistochemical staining for c-erbB-3. The majority of all ovarian tumours studied were positive for c-erbB-3 regardless of whether they were malignant (89%), borderline (100%) or benign (61%), however the incidence of positivity was significantly less in the benign group than in overtly malignant tumours (P = 0.03). c-erbB-3 positivity was not significantly associated with either age at diagnosis, tumour stage, differentiation, ploidy, percentage in S-phase or post-operative tumour bulk in malignant tumours. In terms of intensity of staining no significant difference was observed either within the common epithelial group or between this group and tumours of a benign nature. A significantly more intense pattern of c-erbB-3 staining was observed in tumours of borderline malignancy when compared with their overtly malignant counterparts (P = 0.002). Patients presenting with early-stage malignant tumours (I/II) were more likely to display intense tumour staining than those with late-stage disease (III/IV) (P = 0.04). These investigations suggest that c-erbB-3 protein is frequently expressed in both benign and malignant ovarian tumours, and that overexpression is more common in borderline and early invasive lesions.

Age Factors↗
PubMed1989

Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors.

A related DNA fragment distinct from the epidermal growth factor receptor and ERBB2 genes was detected by reduced stringency hybridization of v-erbB to normal genomic human DNA. Characterization of the cloned DNA fragment mapped the region of v-erbB homology to three exons with closest identity of 64% and 67% to a contiguous region within the tyrosine kinase domains of the epidermal growth factor receptor and ERBB2 proteins, respectively. cDNA cloning revealed a predicted 148-kDa transmembrane polypeptide with structural features identifying it as a member of the ERBB gene family, prompting us to designate the gene as ERBB3. It was mapped to human chromosome 12q13 and was shown to be expressed as a 6.2-kilobase transcript in a variety of normal tissues of epithelial origin. Markedly elevated ERBB3 mRNA levels were demonstrated in certain human mammary tumor cell lines. These findings suggest that increased ERBB3 expression, as in the case of epidermal growth factor receptor and ERBB2, may play a role in some human malignancies.

Amino Acid Sequence↗
PubMed1995

Heregulin stimulates mitogenesis and phosphatidylinositol 3-kinase in mouse fibroblasts transfected with erbB2/neu and erbB3.

Heregulin (HRG) is a pluripotent growth factor that can stimulate the growth of some human mammary tumor cells and the differentiation of others. Two members of the epidermal growth factor receptor family of receptor/tyrosine kinases, p180erbB3 and p180erbB4, serve as receptors for the HRG ligand. While HRG appears to be capable of stimulating the autophosphorylation activity of p180erbB4, the co-expression of p185erbB2/neu with p180erbB3 is necessary for the HRG-stimulated tyrosine phosphorylation of both of these receptors. On the basis of the sequences surrounding their putative tyrosine phosphorylation sites, we predict that the different HRG-responsive receptors couple to different intracellular SH2 domain-containing proteins. Hence, the different receptors may mediate different cellular responses to the HRG ligand. In the present study we show that HRG beta 1 is mitogenic for erbB3-transfected DHFR/G8 cells, an NIH3T3 mouse fibroblast derivative that over-expresses p185erbB2/neu. HRG stimulated the incorporation of [3H]thymidine into the DNA of these cells with an EC50 of 70 +/- 7 pM. HRG was not mitogenic for parental DHFR/G8 cells that do not express the ErbB3 protein. Phosphatidylinositol (PI) 3-kinase, an enzyme believed to be important in cellular growth regulation by growth factors and oncogenes, is predicted to couple to tyrosine-phosphorylated ErbB3. We observed that HRG stimulated the association of PI 3-kinase with both p185erbB2/neu and ErbB3 in transfected DHFR/G8 cells, but not in the parental cell line. We conclude that the ErbB3 protein is capable of mediating a proliferative response of fibroblasts to HRG, and that the activation of PI 3-kinase is an integral part of the growth signaling mechanism.

3T3 Cells↗
PubMed1995

The structural basis for the specificity of epidermal growth factor and heregulin binding.

Heregulin is a ligand for the erbB3 and erbB4 receptors, with a region of high homology to epidermal growth factor (EGF). Despite this homology, these ligands bind to their corresponding receptors with great specificity. We report here the synthesis of heregulin beta 177-241 and show that a region consisting of amino acids 177-226 is sufficient both for binding and stimulation of receptor phosphorylation. Studies of chimeric EGF/heregulin peptides revealed that amino acids 177-181 of heregulin provide the specificity for binding to the heregulin receptor. The substitution of amino acids 177-181 of heregulin for the N terminus of EGF produced a unique bifunctional agonist that binds with high affinity to both the EGF receptor and the heregulin receptor.

Amino Acid Sequence↗
PubMed1995

Heregulin-stimulated signaling in rat pheochromocytoma cells. Evidence for ErbB3 interactions with Neu/ErbB2 and p85.

We have reported that overexpression of Neu leads to heregulin-stimulated neurite outgrowth and the tyrosine-phosphorylation of Neu and other cellular proteins in PC12 cells. Considering that Neu/ErbB2 alone is not able to functionally couple to heregulin, we looked for the possible involvement of ErbB3 in these neurite outgrowth and tyrosine phosphorylation responses. We found that heregulin stimulates the tyrosine phosphorylation of endogenous ErbB3 protein in PC12 cells and that this phosphorylation, like that of Neu, is greatly enhanced in cells that overexpress Neu. Furthermore, overexpression of ErbB3 in PC12 cells led to heregulin-stimulated neurite extension. In addition to becoming tyrosine-phosphorylated, Neu/ErbB2 and ErbB3 associate with each other, and each associates with the 85-kDa regulatory subunit (p85) of phosphatidylinositol 3-kinase in a heregulin-dependent manner. Thus, Neu/ErbB2 and ErbB3 appear to cooperate to mediate the heregulin signal in PC12 cells. Like heregulin, epidermal growth factor (EGF) also stimulate the tyrosine phosphorylation of both Neu and ErbB3. However, there are clear differences between the EGF- and heregulin-stimulated phosphorylations of ErbB3. In the heregulin response, two tyrosine-phosphorylated forms of ErbB3 are detected. Of these, only the more quickly migrating form (on SDS-polyacrylamide gel electrophoresis) is found to be associated with Neu, whereas the other, more slowly migrating form is uniquely capable of forming stable complexes with p85. In the EGF response, at least two tyrosine-phosphorylated forms of ErbB3 are detected, but these phosphoproteins have distinctly lower apparent molecular weights compared with the heregulin-stimulated ErbB3 phosphoproteins and do not complex with p85. Thus the formation of a stable ErbB3-p85 complex in PC12 cells is a unique outcome of heregulin signaling that correlates with the differences in cell morphology induced by the activated EGF receptor and the Neu tyrosine kinase.

Animals↗
PubMed1995

Binding of Shc to the NPXY motif is mediated by its N-terminal domain.

Shc is an SH2-containing adapter protein that binds to and is phosphorylated by a large number of growth factor receptors. Phosphorylated Shc is able to interact with the Grb2-Sos complex which is responsible for mediating nucleotide exchange on Ras. We have shown previously that binding of Shc to the epidermal growth factor (EGF)-like receptor, c-ErbB-3, is through an NPXY motif (Prigent, S. A., and Gullick, W. J. (1994) EMBO J. 13, 2831-2841) shared by middle T antigen, TrkA, and EGF receptor. It has recently been reported that a region distinct from the SH2 domain is able to bind to tyrosine-phosphorylated proteins. In this paper we have used fusion proteins of various Shc domains to show that it is the N-terminal domain of Shc that is primarily responsible for binding EGF receptor and c-ErbB-3. Furthermore, by competition studies with synthetic phosphopeptides we have shown that this N-terminal domain binds to the previously identified NPXY motif.

3T3 Cells↗
PubMed1995

Binding of Neu differentiation factor with the extracellular domain of Her2 and Her3.

The interaction of neu differentiation factor (NDF) with the extracellular domains of Her2 (sHer2) and Her3 (sHer3) have been studied using native gels, light scattering, and sedimentation equilibrium. The full-length NDF beta 2 was shown to bind sHer3 with a dissociation constant of 26 +/- 9 nM, while it showed a 1000-fold weaker binding to sHer2. Taken together, these results demonstrate that NDF is a high affinity ligand for Her3, but not for Her2. No increase in affinity of the NDF beta 2 for sHer3 was observed upon addition of sHer2 to the NDF beta 2-sHer3 mixture. Binding of NDF beta 2 to sHer3 did not induce receptor dimerization or oligomerization, the stoichiometry being one sHer3 per one NDF molecule. This finding suggests that transmembrane and/or intracellular domains of receptor family members or perhaps additional unidentified components may be involved in NDF induced dimerization and autophosphorylation, or alternatively, that dimerization is not the mechanism for Her3 autophosphorylation and signal transduction.

Animals↗
PubMed2025

EGFR activation in cholangiocytes promotes extrahepatic bile duct regeneration after injury.

BACKGROUND: The EGF receptor family of 4 tyrosine kinases, EGFR and ERBB2-4, and their ligands regulate the development and homeostasis of digestive organs including the hepatobiliary system. It promotes intrahepatic cholangiocyte proliferation, bile duct development, and cholangiocarcinoma aggressiveness. The EGF signaling network's contribution to extrahepatic bile duct (EHBD), which is a distinct hepatobiliary entity, regeneration is poorly defined. This work aimed to determine the fundamental role of the EGF signaling network in the biliary proliferative response to EHBD obstruction. METHODS: We used mouse bile duct ligation to model obstructive EHBD injury, and human and mouse EHBD organoids for in vitro studies. We tested activating and inhibitory paradigms with recombinant EGF family ligands and receptor antagonists. Transcriptomic and immunohistochemistry analyses informed EGF signaling changes and cellular localization at homeostasis and after obstruction. RESULTS: At homeostasis, the EHBD expressed EGFR ligands Tgfa, Btc, Hbegf, and Nrg4 in cholangiocytes, and Egf and Nrg2 in stromal cells. Erbb2 and Erbb3 were predominant receptors expressed in cholangiocytes, and Egfr in stromal cells at baseline. Post-injury, biliary hyperproliferation was associated with increased abundance of Tgfa, Btc, Hbegf, and Areg ligands and Egfr receptor in cholangiocytes with resulting EGFR activation. EGFR ligands induced biliary organoid growth, and inhibition of EGFR, not ERBB2, dampened organoid proliferation. EGFR inhibition in mice led to a decrease in the biliary proliferative response after EHBD obstruction. CONCLUSIONS: The obstruction-induced biliary proliferation is EGFR-mediated, suggesting context-specific and receptor-specific EGF signaling network contribution to EHBD regeneration after injury.

Animals↗
PubMed1994

ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor.

Conflicting results concerning the ability of the epidermal growth factor (EGF) receptor to associate with and/or activate phosphatidylinositol (PtdIns) 3-kinase have been published. Despite the ability of EGF to stimulate the production of PtdIns 3-kinase products and to cause the appearance of PtdIns 3-kinase activity in antiphosphotyrosine immunoprecipitates in several cell lines, we did not detect EGF-stimulated PtdIns 3-kinase activity in anti-EGF receptor immunoprecipitates. This result is consistent with the lack of a phosphorylated Tyr-X-X-Met motif, the p85 Src homology 2 (SH2) domain recognition sequence, in this receptor sequence. The EGF receptor homolog, ErbB2 protein, also lacks this motif. However, the ErbB3 protein has seven repeats of the Tyr-X-X-Met motif in the carboxy-terminal unique domain. Here we show that in A431 cells, which express both the EGF receptor and ErbB3, PtdIns 3-kinase coprecipitates with the ErbB3 protein (p180erbB3) in response to EGF. p180erbB3 is also shown to be tyrosine phosphorylated in response to EGF. In contrast, a different mechanism for the activation of PtdIns 3-kinase in response to EGF occurs in certain cells (PC12 and A549 cells). Thus, we show for the first time that ErbB3 can mediate EGF responses in cells expressing both ErbB3 and the EGF receptor.

Amino Acid Sequence↗
PubMed1995

Neu differentiation factor/heregulin modulates growth and differentiation of HC11 mammary epithelial cells.

The HC11 mouse mammary epithelial cell line has proven to be a valuable in vitro model to study the roles of peptide factors and hormones involved in the growth and differentiation of mammary cells. Treatment of HC11 cells with the lactogenic hormones, dexamethasone, insulin, and PRL (DIP), leads to cellular differentiation and production of the milk protein beta-casein. We have analyzed the effects of Neu differentiation factor (NDF)/heregulin, a newly described activating ligand for erbB-2 and other members of the epidermal growth factor (EGF) receptor family, on cell growth and the expression of milk proteins in HC11 cells. In these cells, NDF induces tyrosine phosphorylation of erbB-2 and erbB-3. Both NDF and EGF stimulate HC11 cell proliferation and promote the responsiveness of HC11 cells to lactogenic hormones. NDF induces the expression of a 22-kilodalton milk protein. This protein is up-regulated by other factors, including dexamethasone, EGF, and basic fibroblast growth factor, and is controlled in a manner distinct from that of beta-casein. Like EGF, NDF inhibits the DIP-induced expression of beta-casein at the level of transcription. The inhibition is due to the negative effect of NDF on the activation of mammary gland factor (MGF/Stat5), a member of the Stat family of transcription factors, which is essential for beta-casein gene expression.

Animals↗
PubMed1992

Expression of the c-erbB-3 protein in normal human adult and fetal tissues.

c-erbB-3 is a member of the type I family of growth factor receptors which includes the epidermal growth factor (EGF) receptor and c-erbB-2. Whereas for EGF receptor and c-erbB-2 the expression patterns in normal tissues are well documented, there is currently little information available about the sites of c-erbB-3 expression. In order to examine the normal tissue distribution of c-erbB-3, polyclonal antibodies were raised against eight synthetic peptides corresponding to distinct sites on the intracellular domain of c-erbB-3. Of these, three produced antibodies which reacted with a 160-kDa protein on immunoblots of human embryonal cells (293 cells) transfected with the cDNA encoding c-erbB-3, and two of the three antibodies immunoprecipitated a protein of similar size from the same cells. These antibodies were used for immunochemical staining of a wide variety of normal human adult and fetal tissues employing formalin-fixed, paraffin-embedded material. The c-erbB-3 protein was identified in cells of the gastrointestinal, reproductive, respiratory and urinary tracts as well as the skin, endocrine and nervous system in a distribution distinctly different from that observed for EGF receptor and c-erbB-2. The level of expression of the mRNA for c-erbB-3 was also examined in extracts of a selection of fetal tissues. In general the sites of mRNA and protein expression were concordant.

Adult↗
PubMed1994

Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin.

The heregulin/neu differentiation factor gene products were purified and cloned based on their ability to stimulate the phosphorylation of a 185-kDa protein in human breast carcinoma cell lines known to express erbB2. However, not all cells that express erbB2 respond to heregulin, indicating that other components besides erbB2 may be required for heregulin binding. Cells that are transfected with the closely related receptor, erbB3, display a single class of lower affinity heregulin binding sites than has been previously observed on breast carcinoma cell lines. Little or no stimulation of tyrosine phosphorylation in response to heregulin occurs in cells that are transfected with erbB3 alone. Transfection of cells with erbB3 and erbB2 reconstitutes a higher affinity binding receptor, which is also capable of generating a tyrosine phosphorylation signal in response to heregulin. A monoclonal antibody to erbB2 will inhibit heregulin activation of tyrosine phosphorylation and binding in cells transfected with both receptors but not with erbB3 alone. In cells expressing erbB2 and erbB3, both proteins become tyrosine-phosphorylated upon interaction with heregulin. Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125I-heregulin followed by immunoprecipitation with antibodies specific for erbB2 or erbB3.

Animals↗
PubMed1995

Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas.

In the present study we demonstrate that erbB-3 and erbB-2 cooperate in neoplastic transformation. Under conditions in which neither gene alone induced transformation, they readily transformed NIH3T3 cells if co-expressed. Furthermore, at high expression levels of ErbB2 which cause transformation, ErbB3 enhanced focus formation by one order of magnitude. Synergy required an intact ErbB2 extracellular domain and tyrosine kinase activity. Cooperation between ErbB3 and ErbB2 involved heterodimerization and increased tyrosine phosphorylation of ErbB3. Signaling by the heterodimer resulted in increased PI 3-kinase recruitment as well as quantitative and qualitative differences in substrate phosphorylation. Evidence for signaling by an active ErbB3-ErbB2 heterodimer in four mammary tumor cell lines indicated relevance of this mechanism for human neoplasia. Our detection of the NDF/heregulin transcript in NIH3T3 cells implicates an autocrine loop involving this ligand in signaling by the ErbB3-ErbB2 heterodimer in the model system, whereas heregulin-independent mechanisms likely exist for cooperative signaling by ErbB3 and ErbB2 chronically activated in some human mammary carcinomas.

3T3 Cells↗
PubMed1995

Prognostic relevance of aberrations in the erbB oncogenes from breast, ovarian, oral and lung cancers: double-differential polymerase chain reaction (ddPCR) for clinical diagnosis.

We have determined the average gene copy numbers (AGCN) of the erbB-1 gene, encoding the epidermal growth factor receptor (EGF-R), the erbB-2 and the erbB-3 genes in breast, ovarian, oral, and lung cancer tissue by using double-differential PCR (ddPCR). The ddPCR method comprises the co-amplification of the single-copy gene HBB, the erbB-1, erbB-2 and erbB-3 oncogenes and the second single-copy reference gene SOD2 under equal reaction conditions. In a retrospective study the AGCN of the erbB genes and the time up to the appearance of metastases were subjected to life-table analysis in 128 women with primary breast cancer. Patients whose breast cancer tissue showed an AGCN for erbB-1 of less than 0.4 and greater then 1.6, as expected from the literature, for erbB-2 of greater than 2.0 and for erbB-3 of less than 1.75 had decreased disease-free survival (DFS). The quotient of erbB-1 and erbB-2 AGCN was the most significant in multivariate Cox analysis followed by nodal status and progesterone receptor status. In extensive studies a similar association between erbB AGCN and metastasis was seen in ovarian cancer and oral cancer, though erbB oncogene aberrations in those entities were not as frequent as in breast cancer. The AGCN of erbB oncogenes may not be of prognostic value in untreated lung cancer patients.

Base Sequence↗