title: Stretch-induced fetal type II cell differentiation is mediated via ErbB1-ErbB4 interactions.
abstract: Stretch-induced differentiation of lung fetal type II epithelial cells is mediated through EGFR (ErbB1) via release of HB-EGF and TGF-α ligands. Employing an EGFR knock-out mice model, we further investigated the role of the ErbB family of receptors in mechanotranduction during lung development. Deletion of EGFR prevented endogenous and mechanical stretch-induced type II cell differentiation via the ERK pathway, which was rescued by overexpression of a constitutively active MEK. Interestingly, the expression of ErbB4, the only ErbB receptor that EGFR co-precipitates in wild-type cells, was decreased in EGFR-deficient type II cells. Similar to EGFR, ErbB4 was activated by stretch and participated in ERK phosphorylation and type II cell differentiation. However, neuregulin (NRG) or stretch-induced ErbB4 activation were blunted in EGFR-deficient cells and not rescued after ErbB4 overexpression, suggesting that induction of ErbB4 phosphorylation is EGFR-dependent. Finally, we addressed how shedding of ligands is regulated by EGFR. In knock-out cells, TGF-α, a ligand for EGFR, was not released by stretch, while HB-EGF, a ligand for EGFR and ErbB4, was shed by stretch although to a lower magnitude than in normal cells. Release of these ligands was inhibited by blocking EGFR and ERK pathway. In conclusion, our studies show that EGFR and ErbB4 regulate stretch-induced type II cell differentiation via ERK pathway. Interactions between these two receptors are important for mechanical signals in lung fetal type II cells. These studies provide novel insights into the cell signaling mechanisms regulating ErbB family receptors in lung cell differentiation.
authors.affiliation: Department of Pediatrics, Women & Infants Hospital of Rhode Island and the Warren Alpert Medical School of Brown University, Providence, Rhode Island 02905, USA.
authors.forename: Zheping
authors.initials: Z
authors.lastname: Huang
authors.forename: Yulian
authors.initials: Y
authors.lastname: Wang
authors.forename: Pritha S
authors.initials: PS
authors.lastname: Nayak
authors.forename: Christiane E
authors.initials: CE
authors.lastname: Dammann
authors.forename: Juan
authors.initials: J
authors.lastname: Sanchez-Esteban
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000166:cytology*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D066247:Receptor, ErbB-4
chemical_list: D017931:DNA Primers; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D048049:Extracellular Signal-Regulated MAP Kinases