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Troyer, Kelly L.; Lee, Dong Hoon

doi:10.1023/a:1009560330359

Cited by 101 publications

(23 citation statements)

References 64 publications

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“…For example, both HB-EGF and Betacellulin bind ErbB-1, but mice defective for each factor display distinct phenotypes (41). Another example relates to mammary development, which seems to involve nonoverlapping activities of several ligands of ErbB-1 (42). In this respect, EPG displays unique features, including specificity to ErbB-1 (Figs.…”

Section: Discussionmentioning

confidence: 99%

Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

Kochupurakkal

Harari

Di-Segni

et al. 2005

Journal of Biological Chemistry

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Four ErbB receptors and multiple growth factors sharing an epidermal growth factor (EGF) motif underlie transmembrane signaling by the ErbB family in development and cancer. Unlike other ErbB proteins, ErbB-2 binds no known EGF-like ligand. To address the existence of a direct ligand for ErbB-2, we applied algorithms based on genomic and cDNA structures to search sequence data bases. These searches reidentified all known EGF-like growth factors including Epigen (EPG), the least characterized ligand, but failed to identify novel factors. The precursor of EPG is a widely expressed transmembrane glycoprotein that undergoes cleavage at two sites to release a soluble EGF-like domain. A recombinant EPG cannot stimulate cells singly expressing ErbB-2, but it acts as a mitogen for cells expressing ErbB-1 and co-expressing ErbB-2 in combination with the other ErbBs. Interestingly, soluble EPG is more mitogenic than EGF, although its binding affinity is 100-fold lower. Our results attribute the anomalous mitogenic power of EPG to evasion of receptor-mediated depletion of ligand molecules, as well as to inefficient receptor ubiquitylation and down-regulation. In conclusion, EPG might represent the last EGF-like growth factor and define a category of low affinity ligands, whose bioactivity differs from the more extensively studied high affinity ligands.

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Section: Discussionmentioning

confidence: 99%

Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

Kochupurakkal

Harari

Di-Segni

et al. 2005

Journal of Biological Chemistry

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“…We have recently shown that estrogens induce ductal elongation during puberty acting through the ER␣ in the mammary epithelium by a paracrine mechanism. EGFR signaling has been implicated downstream of estrogen signaling in the mammary gland (6), and several EGF family members, such as EGF, TGF␣, and amphiregulin, are induced by estrogens in different breast cancer cell lines (20)(21)(22). To test whether EGF family members are regulated by estrogen in vivo in the puberal mammary gland at a time of exponential cell expansion, we mimicked the beginning of puberty in a controlled fashion.…”

Section: Transcriptional Regulation Of Egf Family Members By Estrogenmentioning

confidence: 99%

“…The epidermal growth factor receptor (EGFR) signaling pathway has long been implicated in mammary gland development and human breast cancer (6). EGFR, a member of the ErbB receptor tyrosine kinase family (7), is activated by members of the EGF-like family of ligands, including EGF, transforming growth factor ␣ (TGF-␣), amphiregulin, heparin binding-EGF (HB-EGF), betacellulin (BTC), and epiregulin (EPR).…”

mentioning

confidence: 99%

Amphiregulin is an essential mediator of estrogen receptor α function in mammary gland development

Ciarloni¹,

Mallepell²,

Brisken

2007

Proc. Natl. Acad. Sci. U.S.A.

281

236

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Most mammary gland development occurs after birth under the control of systemic hormones. Estrogens induce mammary epithelial cell proliferation during puberty via epithelial estrogen receptor ␣ (ER␣) by a paracrine mechanism. Epidermal growth factor receptor (EGFR) signaling has long been implicated downstream of ER␣ signaling, and several EGFR ligands have been described as estrogen-target genes in tumor cell lines. Here, we show that amphiregulin is the unique EGF family member to be transcriptionally induced by estrogen in the mammary glands of puberal mice at a time of exponential expansion of the ductal system. In fact, we find that estrogens induce amphiregulin through the ER␣ and require amphiregulin to induce proliferation of the mammary epithelium. Like ER␣, amphiregulin is required in the epithelium of puberal mice for epithelial proliferation, terminal end buds formation, and ductal elongation. Subsequent stages, such as sidebranching and alveologenesis, are not affected. When amphiregulin ؊/؊ mammary epithelial cells are in close vicinity to wild-type cells, they proliferate and contribute to all cell compartments of the ductal outgrowth. Thus, amphiregulin is an important paracrine mediator of estrogen function specifically required for pubertyinduced ductal elongation, but not for any earlier or later developmental stages.ductal morphogenesis ͉ epithelial-stromal cross-talk ͉ paracrine

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“…Normal epithelial cells as well as cancer cells usually express more than one ErbB receptor (15,56). During proliferative phases in the cyclic development of some organs, e.g.…”

Section: Fig 6 Egf-induced Activation Of P38 Mapk Pathway In Skbr3/mentioning

confidence: 99%

Ligand-induced, p38-dependent Apoptosis in Cells Expressing High Levels of Epidermal Growth Factor Receptor and ErbB-2

Tikhomirov

Carpenter

2004

Journal of Biological Chemistry

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Increased expression of the epidermal growth factor (EGF) receptor (EGFR) and ErbB-2 is implicated into the development and progression of breast cancer. Constant ligand-induced activation of EGFR and ErbB-2 receptortyrosine kinases is thought to be involved in the transformation of fibroblasts and mammary epithelial cells. Data herein show that ligand stimulation of cells that express both the EGFR and the ErbB-2 may result either in cell proliferation or apoptosis depending on the expression levels of EGFR and ErbB-2. Mammary tumor cells that express low levels of both receptors or high levels of ErbB-2 and low levels of EGFR survive and proliferate in the presence of EGF. In contrast, fibroblastic cells or mammary tumor cells, which co-express high levels of EGFR and ErbB-2 invariably undergo apoptosis in response to EGF. In these cells persistent activation of p38 MAPK is an essential element of the apoptotic mechanism. Also, the data implicate a p38-dependent change in mitochondrial membrane permeability as a downstream effector of apoptosis. Ligand-dependent apoptosis in cells co-expressing high levels of EGFR and ErbB-2 could be a natural mechanism that protects tissues from unrestricted proliferation in response to the sustained activation of receptor-tyrosine kinases. EGFR1 /ErbB-1 and ErbB-2 are type I receptor-tyrosine kinases characterized by the presence of an extracellular ligand binding domain, a single transmembrane domain, and a cytoplasmic region that includes a tyrosine kinase domain. The extracellular domain of the EGFR is recognized by seven distinct ligands that are related in primary sequence, which results in tyrosine kinase activation (1). In response to ligand stimulation, the EGFR forms homo-or heterodimers as part of the activation and signaling mechanism (2, 3). ErbB-2 has no known direct ligand but can be activated through heterodimerization with EGFR or other members of the ErbB family. Studies of the interactions between ErbB receptors have shown that ErbB-2 is the preferred partner for heterodimerization and thereby potentiates transformation and pro-survival signaling pathways (2-6).Ligand binding induces the rapid internalization of the EGFR and its subsequent lysosomal degradation (7). In contrast, ErbB-2 transactivation by the activated EGFR does not stimulate rapid internalization of ErbB-2 (8 -11). Removal of transactivated ErbB-2 from the cell surface proceeds slowly through a combination of intracellular degradation mechanisms, including lysosomes, the proteasome, and other intracellular proteases (10, 12-13). Heterodimerization of ErbB-2 and the EGFR actually impedes the rapid ligand-dependent internalization of the EGFR and, thereby, results in increased activation of signaling pathways (4, 9, 14).Increased EGFR or ErbB-2 expression or structural alterations in either receptor are frequent in human malignancies (2, 15-17). Overexpression of the EGFR is observed in a significant proportion of brain tumors (18 -20). Also, glioblastomas and other tumors often express a del...

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Cited by 101 publications

References 64 publications

Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

Amphiregulin is an essential mediator of estrogen receptor α function in mammary gland development

Ligand-induced, p38-dependent Apoptosis in Cells Expressing High Levels of Epidermal Growth Factor Receptor and ErbB-2

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