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)

The neuregulin (NRG)/epidermal growth factor (EGF) family of growth factors consists of several ligands that specifically activate four erbB receptor-tyrosine kinases, namely erbB-1 (EGF-R), erbB-2 (neu), erbB-3, and erbB-4. We have previously shown that islet morphogenesis is impaired and beta-cell differentiation delayed in mice lacking functional EGF-R [EGF-R (-/-)]. The present study aims to clarify which erbB ligands are important for islet development. Pancreatic expression of EGF, TGF-alpha, heparin-binding EGF, betacellulin (BTC), and NRG-4 was detected as early as embryonic d 13 (E13). Effects of these ligands were studied in E12.5 pancreatic explant cultures grown for 5 d ex vivo. None of the growth factors affected the ratio of endocrine to exocrine cells. However, significant effects within the endocrine cell populations were induced by EGF, BTC, and NRG-4. beta-Cell development was augmented by BTC, whereas the development of somatostatin-expressing delta-cells was stimulated by NRG-4. Both ligands decreased the numbers of glucagon-containing alpha-cells. The effect of BTC was abolished in the EGF-R (-/-) mice. A soluble erbB-4 binding fusion protein totally inhibited the effects of NRG-4 but not of BTC. Neutralization of endogenous NRG-4 activity in the model system effectively inhibited delta-cell development, indicating that this erbB4-ligand is an essential factor for delineation of the somatostatin-producing delta-cells. Our results suggest that ligands of the EGF-R/erbB-1 and erbB-4 receptors regulate the lineage determination of islet cells during pancreatic development. BTC, acting through EGF-R/erbB-1, is important for the differentiation of beta-cells. This could be applied in the targeted differentiation of stem cells into insulin-producing cells.
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PMID:ErbB signaling regulates lineage determination of developing pancreatic islet cells in embryonic organ culture. 1239 41

The epidermal growth factor (EGF) receptor and its various ligands (EGF, TGF-alpha, amphiregulin, heparin-binding (HB)-EGF, heregulin, betacellulin) seem to be involved in the growth regulation of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors. However, few quantitative data investigating the impact of tumor-EGF receptor levels in gastrointestinal carcinomas on tumor stage and prognosis are available. Therefore, EGF receptors were quantitatively determined in colorectal carcinomas in comparison to adjacent normal mucosa by 125I[EGF]-binding studies. EGFR capacity was increased in advanced invasive colorectal carcinomas (T1/2 vs. T3/4 tumors, p<0.001) and advanced UICC stages (UICC I vs. UICC II/III, p<0.001). These findings were confirmed with quantitative 125[I]EGF autoradiography performed on frozen tissue slides and analyzed by laser densitometry (p=0.020). EGF receptor analysis with immunohistochemistry with EGFR antibodies directed against the extracellular domain of the receptor was not correlated with tumor invasion or prognosis. mRNA-expression of EGFR ligands was investigated using semiquantitative RT-PCR amplification using specific primers. RT-PCR transcripts of EGFR ligands (EGF, TGF-alpha, HB-EGF, and amphiregulin) were detected in both carcinomas and normal mucosa, indicating that autocrine growth stimulation of colorectal carcinomas is mediated by coexpression of EGF receptor ligands and upregulation of EGF receptors. Survival of colorectal cancer patients with increased tumor EGF receptor levels was significantly reduced in comparison to patients with low/unchanged tumor EGF receptor levels (mean survival+/-SD, 36.2+/-4.0 vs. 46.8+/-4.3 months; p=0.017). Further studies investigating EGF receptor levels in gastric cancer patients have shown that increased tumor EGF receptor levels were associated with poor prognosis in gastric cancer patients with tumors localized distal from the cardia. Several specific EGF receptor tyrosine kinase inhibitors have recently entered clinical phase I-III studies, with promising antitumor effects in several tumors, including gastrointestinal cancer. Therefore, patients with invasive gastric or colorectal carcinomas might benefit from therapies specifically blocking EGFR-mediated signal transduction.
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PMID:Clinical implications of the EGF receptor/ligand system for tumor progression and survival in gastrointestinal carcinomas: evidence for new therapeutic options. 1279 Mar 26

There is increasing evidence that epidermal growth factor (EGF) receptor (EGFR) ligand and Kit ligand (KL) play critical roles in controlling follicular development in mammals. Because little is known about their expressions in the ovary of nonmammalian vertebrate, our study aimed to examine the expression, hormonal regulation, and interaction of HB-EGF and KL in the chicken ovary. Using semiquantitative RT-PCR, we demonstrated that ovarian HB-EGF expression increased dramatically with the posthatching ovarian growth. In line with this finding, HB-EGF was shown to be produced primarily by the growing oocytes and capable of stimulating the proliferation of granulosa cells in prehierarchal (3 mm) and preovulatory follicles (F5 and F1). Although HB-EGF expression is mainly restricted to the oocytes, its expression in cultured granulosa cells could be transiently yet strongly induced by HB-EGF and other EGFR ligands including EGF and TGF-alpha. And the inducing effect of HB-EGF was completely abolished by AG1478 (10 microM) or PD98059 (100 microM), indicating that the action of HB-EGF is mediated by EGFR and intracellular MAPK/ERK signaling pathway. Unlike mammals, only KL-1, not the other three isoforms identified (KL-2, -3, and -4), was detected to be predominantly expressed in the chicken ovary. Interestingly, KL expression in undifferentiated and differentiated granulosa cells could be transiently down-regulated by HB-EGF, implying an intrafollicular communication between growing oocyte and surrounding granulosa cells through the interplay of EGFR ligand and KL. Collectively, our data suggest that HB-EGF is likely a paracrine signal from the oocyte to regulate granulosa cell proliferation and HB-EGF and KL expression during ovarian follicular development.
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PMID:Epidermal growth factor (EGF) receptor ligands in the chicken ovary: I. Evidence for heparin-binding EGF-like growth factor (HB-EGF) as a potential oocyte-derived signal to control granulosa cell proliferation and HB-EGF and kit ligand expression. 1739 97

The human epidermal growth factor (EGF) receptor (HER) family members cooperate in malignancy. Of this family, HER2 does not bind growth factors and HER3 does not encode an active tyrosine kinase. This diversity creates difficulty in creating pan-specific therapeutic HER family inhibitors. We have identified single amino acid changes in epidermal growth factor receptor (EGFR) and HER3 which create high affinity sequestration of the cognate ligands, and may be used as receptor decoys to downregulate aberrant HER family activity. In silico modeling and high throughput mutagenesis were utilized to identify receptor mutants with very high ligand binding activity. A single mutation (T15S; EGFR subdomain I) enhanced affinity for EGF (two-fold), TGF-alpha (twenty-six-fold), and heparin-binding (HB)-EGF (six-fold). This indicates that T15 is an important, previously undescribed, negative regulatory amino acid for EGFR ligand binding. Another mutation (Y246A; HER 3 subdomain II) enhanced neuregulin (NRG)1-beta binding eight-fold, probably by interfering with subdomain II-IV interactions. Further work revealed that the HER3 subunit of an EGFR:HER3 heterodimer suppresses EGFR ligand binding. Optimization required reversing this suppression by mutation of the EGFR tether domain (G564A; subdomain IV). This mutation resulted in enhanced ligand binding (EGF, ten-fold; TGF-alpha, thirty-four-fold; HB-EGF, seventeen-fold; NRG1-beta, thirty-one-fold). This increased ligand binding was reflected in improved inhibition of in vitro tumor cell proliferation and tumor suppression in a human non-small cell lung cancer xenograft model. In conclusion, amino acid substitutions were identified in the EGFR and HER3 ECDs that enhance ligand affinity, potentially enabling a pan-specific therapeutic approach for downregulating the HER family in cancer.
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PMID:Rational optimization of a bispecific ligand trap targeting EGF receptor family ligands. 1904 33


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