FIG. 9.

Model for integration of growth factor-, retinoid-, and ECM-derived signaling pathways during normal mucosecretory cell differentiation. Randomly growing NHBEs express and secrete TGF-α and amphiregulin, one or both of which participate in an autocrine loop, signaling via the endogenous EGFR. In addition, NHBEs respond to exogenous EGF present in growth media or produced by neighboring cells in vivo. Differentiation-promoting ECMs (e.g., collagen) suppress autocrine and paracrine activation of the MAPK pathway by the EGFR, acting downstream of the EGFR and upstream of Raf. This is correlated with an inability to achieve high levels of tyrosyl-phosphorylated p66^SHC and its association with GRB2. However, it remains possible that as yet unidentified differences in EGFR-dependent signaling may actually account for the ECM-dependent inhibition of Raf, MEK, and MAPK activation. Ultimately, reduction in MAPK activity inactivates an inhibitor of retinoid receptor activity and results in the strong induction of RARβ expression in the presence of retinoids.