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At least 19 recordsLinked to original sources
PubMed1995

ErbB3 and ErbB2/neu mediate the effect of heregulin on acetylcholine receptor gene expression in muscle: differential expression at the endplate.

Motor neurons modulate acetylcholine receptor (AChR) gene expression in skeletal muscle by two signalling pathways: the transmitter-evoked depolarization of muscle membrane inhibits AChR gene transcription throughout the myofibre presumably via activation of a serine/threonine kinase, while the transcription rates of AChR genes in the synaptic region are increased by nerve-derived trophic factors including AChR-inducing activity (ARIA). To gain further insight into these interactions we characterized the receptor for heregulin (HRG)/ARIA in muscle. We showed that HRG increases AChR alpha-subunit mRNA levels via tyrosine phosphorylation of ErbB3 and ErbB2/neu in myotubes. The protein tyrosine phosphatase inhibitor, pervanadate, potentiated the responses to HRG that were in turn blocked by the tyrosine kinase inhibitor erstatin, indicating the relevance of tyrosine phosphorylation to these events. The effects of HRG were inhibited by enhanced cellular serine/threonine phosphorylation which has been implicated in the repression of AChR genes by electrical activity. Immunocytochemical analysis of adult rat muscle revealed that while ErbB2/neu is present throughout the entire surface of the myofibre membrane, ErbB3 expression is exclusively restricted to the endplate suggesting its involvement in synapse-specific transcription of AChR genes by HRG/ARIA.

Animals↗
PubMed2021

ERBB3 overexpression due to miR-205 inactivation confers sensitivity to FGF, metabolic activation, and liability to ERBB3 targeting in glioblastoma.

In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy.

Antibodies↗
PubMed1995

Multiple essential functions of neuregulin in development.

Neuregulin (also called NDF, heregulin, GGF and ARIA) is a member of the EGF family which induces growth and differentiation of epithelial, glial and muscle cells in culture. The biological effects of the factor are mediated by tyrosine kinase receptors. Neuregulin can bind directly to erbB3 and erbB4 and receptor heterodimerization allows neuregulin-dependent activation of erbB2 (refs 1, 2, 5). A targeted mutation in mice reveals multiple essential roles of neuregulin in development. Here we show that neuregulin -/- embryos die during embryogenesis and display heart malformations. In addition, Schwann cell precursors and cranial ganglia fail to develop normally. The phenotype demonstrates that in vivo neuregulin acts locally and frequently in a paracrine manner. All cell types affected by the mutation express either erbB3 or erbB4, indicating that either of these tyrosine kinase receptors can be a component in recognition and transmission of essential neuregulin signals.

Animals↗
PubMed1992

The erbB-3 gene in human pancreatic cancer.

Abnormalities of the type 1 growth factor receptor family have been implicated in the pathogenesis of pancreatic cancer. There is evidence for a potential autocrine loop involving overexpression of the epidermal growth factor (EGF) receptor and its ligands, as well as overexpression of the erbB-2 receptor. A third member of this receptor family, erbB-3, has recently been recognized and found to be abnormally expressed in some types of human cancer. In this study we show that overexpression of the erbB-3 protein occurs very frequently in carcinoma of the exocrine pancreas and also in chronic pancreatitis. We found no evidence of amplification or rearrangement of the erbB-3 gene by Southern blot analysis of DNA from pancreatic cancer cells lines.

Amino Acid Sequence↗
PubMed1990

Growth factor-regulated pathways in epithelial cell proliferation.

Investigations of the pathways regulating normal growth of epithelial cells have revealed the existence of two major growth-factor signaling cascades required for proliferation. One pathway is activated by IGF-1 or high insulin concentration. The other is triggered by EGF, TGF alpha, or members of the FGF family, including the recently discovered epithelial-cell-specific growth factor, designated keratinocyte growth factor (KGF). Its expression pattern in vivo suggests that KGF plays an important normal physiologic role as a stromal effector of epithelial cell proliferation. Oncogenes, which represent constitutively activated forms of genes critically involved in growth-factor signaling pathways, specifically abrogate the requirement for mitogens of the EGF pathway. Examples of such genes include the erbB/EGF receptor and erbB-2, which encode structurally related receptor proteins and are often amplified and/or overexpressed in epithelial malignancies. Employing reduced stringency hybridization with v-erbB as a probe, we recently identified a third member of this receptor family, designated erbB-3. cDNA cloning revealed a predicted 148-kD transmembrane polypeptide with structural features similar to those of the EGF receptor. Normal erbB-3 expression in keratinocytes and glandular epithelium suggests its physiologic role in these cell types. Moreover, markedly elevated erbB-3 mRNA levels in certain mammary tumor cell lines suggest that increased erbB-3 expression may also play a role in some human epithelial malignancies.

Animals↗
PubMed1992

Production and characterization of a polyclonal antibody to the c-erbB-3 protein: examination of c-erbB-3 protein expression in adenocarcinomas.

A polyclonal rabbit antibody was raised to the c-erbB-3 protein using a synthetic peptide corresponding to amino acids 1229-1241 of the predicted protein sequence of c-erbB-3. In Western blot analysis this antibody detects a single band at approximately 165 kD in a c-erbB-3 transfected (293/HER-3) human cell line. c-erbB-3 protein expression was then examined in a variety of adenocarcinomas. Expression of c-erbB-3 protein was indicated by membrane and/or cytoplasmic tumour cell immunoreactivity in formalin-fixed, paraffin-embedded tissue sections. c-erbB-3 protein was detected in a series of 13 out of 14 primary breast carcinomas, 3 of 5 gastric adenocarcinomas, 8 of 9 colonic adenocarcinomas, 2 of 9 prostatic adenocarcinomas, 0 of 6 renal cell carcinomas, 1 of 4 primary lung adenocarcinomas, and 5 of 7 endometrial adenocarcinomas. Immunohistochemical expression of the c-erbB-3 protein appears to be a relatively common event in adenocarcinomas, and further studies are now warranted to establish the role of the c-erbB-3 protein in neoplasia.

Adenocarcinoma↗
PubMed1995

Interaction between erbB-receptors and heregulin in breast cancer tumor progression and drug resistance.

The type I growth factor receptor family is increasingly recognized as important in the development and maintenance of breast cancer. The family currently consists of four closely related members: the epidermal growth factor receptor (EGF-R/erbB-1), erbB-2, erbB-3 and erbB-4. Putative ligands which bind directly to or indirectly activate erbB-2/3/4 have been characterized recently. This still growing family of EGF-related growth factors includes gp30, its homolog heregulin (HRG), the rat homolog neu differentiation factor (NDF), glial growth factors (GLIA), ARIA and a 50 kDa factor from COLO 16 cells. The understanding of the function, biology and interactions of these growth factor receptors and their ligands will have far-reaching implications for the prognosis and treatment of breast cancer. This review focuses on advances and future directions for further investigations intended to clarify the mechanism and significance of erbB/ligand interactions in breast cancer.

Animals↗
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↗
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↗
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↗
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↗