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.
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
(RAR
)
gene as an early marker of NHBE differentiation. In contrast to
immortalized cell lines, in NHBEs strong retinoid-induced RAR
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 RAR
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 RAR
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.
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