Stretch-induced fetal type II cell differentiation is mediated via ErbB1-ErbB4 interactions

Zheping Huang, Yulian Wang, Pritha S. Nayak, Christiane E. Dammann, Juan Sanchez-Esteban

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 thatEGFR 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.

Original languageEnglish (US)
Pages (from-to)18091-18102
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number22
DOIs
StatePublished - May 25 2012

Fingerprint

Cell Differentiation
Ligands
MAP Kinase Signaling System
Phosphorylation
Lung
Neuregulins
Cell signaling
Mitogen-Activated Protein Kinase Kinases
Precipitates
Chemical activation
Knockout Mice
Epithelial Cells
ErbB Receptors
Heparin-binding EGF-like Growth Factor

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Stretch-induced fetal type II cell differentiation is mediated via ErbB1-ErbB4 interactions. / Huang, Zheping; Wang, Yulian; Nayak, Pritha S.; Dammann, Christiane E.; Sanchez-Esteban, Juan.

In: Journal of Biological Chemistry, Vol. 287, No. 22, 25.05.2012, p. 18091-18102.

Research output: Contribution to journalArticle

Huang, Zheping ; Wang, Yulian ; Nayak, Pritha S. ; Dammann, Christiane E. ; Sanchez-Esteban, Juan. / Stretch-induced fetal type II cell differentiation is mediated via ErbB1-ErbB4 interactions. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 22. pp. 18091-18102.
@article{3891572b4e3c4958898348de73389768,
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 thatEGFR 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.",
author = "Zheping Huang and Yulian Wang and Nayak, {Pritha S.} and Dammann, {Christiane E.} and Juan Sanchez-Esteban",
year = "2012",
month = "5",
day = "25",
doi = "10.1074/jbc.M111.313163",
language = "English (US)",
volume = "287",
pages = "18091--18102",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "22",

}

TY - JOUR

T1 - Stretch-induced fetal type II cell differentiation is mediated via ErbB1-ErbB4 interactions

AU - Huang, Zheping

AU - Wang, Yulian

AU - Nayak, Pritha S.

AU - Dammann, Christiane E.

AU - Sanchez-Esteban, Juan

PY - 2012/5/25

Y1 - 2012/5/25

N2 - 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 thatEGFR 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.

AB - 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 thatEGFR 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.

UR - http://www.scopus.com/inward/record.url?scp=84861563021&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861563021&partnerID=8YFLogxK

U2 - 10.1074/jbc.M111.313163

DO - 10.1074/jbc.M111.313163

M3 - Article

C2 - 22493501

AN - SCOPUS:84861563021

VL - 287

SP - 18091

EP - 18102

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 22

ER -