Differentiation of human airway epithelia is dependent on erbB2

Vermeer, Paola D.; Panko, Lacey; Karp, Philip H.; Lee, John H.; Zabner, Joseph

doi:10.1152/ajplung.00547.2005

Cited by 46 publications

(52 citation statements)

References 31 publications

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“…Similarly, Fischer and colleagues (10) demonstrated that ERB-B2 was necessary for human basal cell proliferation following neutrophil elastase-mediated damage in vitro. Finally, a recent report by Vermeer et al (50) indicated that ERB-B2 inhibitor treatment of a breast cancer patient led to a lung epithelial repair defect. Collectively, these data suggest that ERB-B2 activation via EGFR contributes to the EGFR-dependent proliferation signal in basal cells.…”

Section: Complementation Of the Egfr Proliferation Signalmentioning

confidence: 98%

Epidermal growth factor receptor activity is necessary for mouse basal cell proliferation

Brechbuhl

Smith

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Brechbuhl HM, Li B, Smith RW, Reynolds SD. Epidermal growth factor receptor activity is necessary for mouse basal cell proliferation. Am J Physiol Lung Cell Mol Physiol 307: L800-L810, 2014. First published September 12, 2014 doi:10.1152/ajplung.00201.2014.-ERB family receptors (EGFR, ERB-B2, ERB-B3, and ERB-B4) regulate epithelial cell function in many tissue types. In the human airway epithelium, changes in ERB receptor expression are associated with epithelial repair defects. However, the specific role(s) played by ERB receptors in repair have not been determined. We aimed to determine whether ERB receptors regulate proliferation of the tracheobronchial progenitor, the basal cell. Receptor tyrosine kinase arrays were used to evaluate ERB activity in normal and naphthalene (NA)-injured mouse trachea and in air-liquid interface cultures. Roles for epidermal growth factor (EGF), EGFR, and ERB-B2 in basal cell proliferation were evaluated in vitro. NA injury and transgenic expression of an EGFRdominant negative (DN) receptor were used to evaluate roles for EGFR signaling in vivo. EGFR and ERB-B2 were active in normal and NA-injured trachea and were the only active ERB receptors detected in proliferating basal cells in vitro. EGF was necessary for basal cell proliferation in vitro. The EGFR inhibitor, AG1478, decreased proliferation by 99, and the Erb-B2 inhibitor, AG825, decreased proliferation by ϳ66%. In vivo, EGFR-DN expression in basal cells significantly decreased basal cell proliferation after NA injury. EGF and EGFR are necessary for basal cell proliferation. The EGFR/EGFR homo-and the EGFR/ERB-B2 heterodimer account for ϳ34 and 66%, respectively, of basal cell proliferation in vitro. Active EGFR is necessary for basal cell proliferation after NA injury. We conclude that EGFR activation is necessary for mouse basal cell proliferation and normal epithelial repair.

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Section: Complementation Of the Egfr Proliferation Signalmentioning

confidence: 98%

Epidermal growth factor receptor activity is necessary for mouse basal cell proliferation

Brechbuhl

Smith

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…368 Similarly differentiation was induced in primary human lung epithelial cells when NRG was added to the basolateral medium. 369 Coculturing of airway epithelial cells with primary lung fibroblasts, which expressed all ERBB ligands except betacellulin, also resulted in epithelial differentiation. Blocking ERBB2 activation with trastuzumab caused dedifferentiation of well-differentiated human airway epithelial cells.…”

Section: Respiratory Tissuesmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…The EGF family of peptides, and corresponding receptor activation, plays important roles in epithelial growth and differentiation in numerous tissues (16)(17)(18). In the lung, the epithelium of both healthy individuals and those with chronic lung diseases produce EGFR-binding ligands, such as EGF, transforming growth factor-a (TGF-a), heparin-binding EGF-like growth factor, and AREG (19)(20)(21)(22)(23)(24)(25)(26)(27).…”

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confidence: 99%

Amphiregulin-Dependent Mucous Cell Metaplasia in a Model of Nonallergic Lung Injury

Manzo

Foster²,

Stripp³

2012

Am J Respir Cell Mol Biol

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Proliferation and differentiation of the pulmonary epithelium after injury is a critical process in the defense against the external environment. Defects in this response can result in airway remodeling, such as mucus cell metaplasia (MCM), commonly seen in patients with chronic lung disease. We have previously shown that amphiregulin (AREG), a ligand to the epidermal growth factor receptor (EGFR), is induced during the repair/differentiation process elicited by naphthaleneinduced lung injury. Thus, we hypothesized that AREG signaling plays an important role in epithelial proliferation and differentiation of the repairing airway. Mice deficient in AREG and lung epithelial EGFR were used to define roles for AREG-dependent EGFR signaling in airway repair and remodeling. We show that AREG and epithelial EGFR expression is dispensable to pulmonary epithelial repair after naphthalene-induced lung injury, but regulates secretory cell differentiation to a mucusproducing phenotype. We show that the pulmonary epithelium is the source of AREG, suggesting that naphthalene-induced MCM is mediated through an autocrine signaling mechanism. However, induction of MCM resulting from allergen exposure was independent of AREG. Our data demonstrate that AREG-dependent EGFR signaling in airway epithelial cells contributes to MCM in naphthaleneinduced lung injury. We conclude that AREG may represent a determinant of nonallergic chronic lung diseases complicated by MCM.Keywords: Clara cells; epidermal growth factor receptor; amphiregulin; mucus cell metaplasiaThe epithelium lining the lungs plays a critical role in defense against inhaled particles, viruses, and xenobiotics. In health, the pulmonary epithelium can adapt to these insults by the induction of defensive mechanisms, which include increased secretory cells and the secretions they produce, such as mucins (1). Even though these changes typically resolve after acute airway injury, in humans with chronic lung diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, these mechanisms may be compromised, resulting in pathologic remodeling of airways, including mucus cell metaplasia (MCM) and mucus hypersecretion (2-4). Much attention has been placed on understanding roles for T helper cell type 2 cytokines and inflammatory mediators in regulating epithelial remodeling and mucus production. Growth factors, such as epidermal growth factor (EGF) and related ligands for the EGF receptor (EGFR), have been shown to contribute to cellular proliferation and MCM that accompanies exposure to allergens and pneumotropic viruses (5). However, it is not clear what mechanisms drive epithelial remodeling and MCM in nonallergic lung diseases.We previously demonstrated that amphiregulin (AREG), a ligand that binds to EGFR, was significantly up-regulated during repair from naphthalene-induced lung injury (6). Parenterally delivered naphthalene is bioactivated to a toxic naphthalene dihydrodiol by cytochrome P450 mono-oxygenases, which results in depletion of airwa...

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Differentiation of human airway epithelia is dependent on erbB2

Cited by 46 publications

References 31 publications

Epidermal growth factor receptor activity is necessary for mouse basal cell proliferation

Epidermal growth factor receptor activity is necessary for mouse basal cell proliferation

The ERBB3 receptor in cancer and cancer gene therapy

Amphiregulin-Dependent Mucous Cell Metaplasia in a Model of Nonallergic Lung Injury

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