In addition to EGF and TGFa, several other growth factors are capable of activating ER-dependent gene expression. In primary rat uterine cell cultures treated with IGF-I, target gene expression is stimulated to an extent similar to estradiol, and both responses were blocked by ICI 164 384 as well as the cyclic nucleotide-dependent protein kinase inhibitor, H8. IGF-I also activates the ER in GH3 pituitary cells and the neuroblastoma cell line, SK-ER3, where, like estradiol, it inhibits cell growth and promotes differentiation. Insulin also will stimulate ER activity in neuroblastoma cells in a ligand-independent manner. In addition, the EGF-like growth factor, heregulin, acting through erb B2/erb B3 heterodimeric receptors in MCF-7 cells, appears to stimulate proliferation and PR gene expression in an ER-dependent manner. Thus, in diverse cell types, a variety of growth factors can initiate signaling pathways that cross-talk with the ER, and it therefore appears likely that ligand-independent activation of the ER is not a cell-restricted event. flovent inhaler
The structural features of the ER required for its activation by growth factor signal transduction pathways are incompletely understood. Human or mouse ER mutants lacking the amino-terminal, AF-1 domain are activated by estradiol, but not by EGF or IGF-I signaling pathways. Conversely, ER mutants lacking the ligand binding domain are activated by EGF and IGF-I, but not by estradiol, and this indicates that the AF-1 domain is necessary to respond to growth factor signaling pathways. In contrast, insulin activation of the ER does not require the A/В domain, and receptor deletion mutants consisting of the DNA and ligand binding domains are active in insulin-treated cells to nearly the same extent as they would be in estrogen-treated cells.