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Molecular and Cellular Biology, November 1998, p. 6666-6678, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Integration of Growth Factor, Extracellular Matrix, and Retinoid Signals during Bronchial Epithelial Cell Differentiation

Nadeem Moghal and Benjamin G. Neel*

Cancer Biology Program and Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215

Received 23 March 1998/Returned for modification 28 April 1998/Accepted 21 July 1998

Epithelial cell differentiation is regulated by specific combinations of growth factors, hormones, and extracellular matrix (ECM). How these divergent signals are integrated is largely unknown. We used primary cultures of normal human bronchial epithelial cells (NHBEs) to investigate mechanisms of signal integration. In defined, serum-free media, NHBEs undergo mucosecretory differentiation only when grown in the presence of retinoids and on the appropriate substratum (collagen gels). We identified the retinoic acid receptor beta  (RARbeta ) gene as an early marker of NHBE differentiation. In contrast to immortalized cell lines, in NHBEs strong retinoid-induced RARbeta transcription occurs only when cells are grown on collagen gels, and it requires new protein synthesis and a cis-acting element that maps outside the known RARbeta promoter elements. NHBEs grown on collagen gels exhibit reduced epidermal growth factor (EGF)-induced Raf, MEK, and mitogen-activated protein kinase (MAPK) activity. This correlates with a specific inability to achieve high levels of p66SHC tyrosyl phosphorylation and association of p66SHC with GRB2, despite high levels of EGF receptor (EGFR) autophosphorylation. Notably, inhibition of EGFR or MEK/MAPK activation replaces the ECM requirement for RARbeta induction. Our results strongly suggest that a key mechanism by which specific ECMs facilitate retinoid-induced mucosecretory differentiation of NHBEs is by restricting the level of EGFR-dependent MEK/MAPK activation evoked by autocrine and/or paracrine EGFR ligands.

* Corresponding author. Mailing address: Cancer Biology Program and Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-2823. Fax: (617) 667-0610. E-mail: bneel{at}bidmc.harvard.edu.

Molecular and Cellular Biology, November 1998, p. 6666-6678, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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