Stretch-induced Fetal Type II Cell Differentiation Is Mediated via ErbB1-ErbB4 Interactions

• Published in: The Journal of biological chemistry Vol. 287; no. 22; pp. 18091 - 18102
• Main Authors: Huang, Zheping, Wang, Yulian, Nayak, Pritha S., Dammann, Christiane E., Sanchez-Esteban, Juan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25-05-2012; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Base Sequence; Cell Differentiation; Cell Differentiation - physiology; Cell Surface Receptor; Development; DNA Primers; Epidermal Growth Factor Receptor (EGFR); ErbB Receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; ErbB Receptors - physiology; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Fetus - cytology; Lung; Mechanotransduction; Mechanotransduction, Cellular - physiology; Mice; Mice, Knockout; Pregnancy; Protein Binding; Real-Time Polymerase Chain Reaction; Receptor, ErbB-4; Signal Transduction; Epidermal Growth Factor Receptor (EGFR); Lung; Development; Cell Differentiation; Mechanotransduction; Cell Surface Receptor; ErbB Receptors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.313163

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.
Mechanical forces and ErbB receptors are critical for fetal lung development.
Deletion of ErbB1 or down-regulation or ErbB4 prevented stretch-induced type II cell differentiation via ERK.
Interactions between ErbB1 and ErbB4 are critical for stretch-induced type II cell differentiation.
Learning how mechanical signal regulate fetal lung development is critical to develop strategies to accelerate lung maturation.