title: Epidermal growth factor receptor activity is necessary for mouse basal cell proliferation.
abstract: 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 EGFR-dominant 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 ∼66%. 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 ∼34 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.
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Brechbuhl
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado.
authors.forename: Bilan
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado.
authors.forename: Russell W
authors.initials: RW
authors.lastname: Smith
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado reynoldss@njhealth.org.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009281:Naphthalenes / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D014132:Trachea / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D020032:Tyrphostins / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; D019061:src-Family Kinases; C098214:tyrphostin AG825; C101044:RTKI cpd; C007229:decalin; C524056:Erbb2 protein, mouse; C053102:proto-oncogene proteins c-fgr
keywords: EGFR; ERB receptors; basal cells; epidermal growth factor; proliferation