Cross-Talk between Peptide Growth Factor and Estrogen Receptor: ER PHOSPHORYLATION(2)

For example, a point mutant (serine118 —» alanine118) form of human ER is more active in COS-1 than in HeLa cells and is a more effective activator of the pS2-CAT synthetic target gene than the chicken ovalbumin gene-derived reporter construct, pDH30V/CAT, in both cell lines. One possible explanation for these cell- and promoter-dependent differences in ER mutant transcriptional activity is that receptor-mediated gene expression is influenced by cell- and/or promoter-specific accessory proteins, such as coactivators and corepressors.

Estrogens do not induce phosphorylation of tyrosine537, and this amino acid is therefore referred to as a basal phosphorylation site. This residue is conserved in the ER sequence of every species examined to date and is located immediately amino-terminal to the AF-2 activation helix. This amphipathic, a-helical structure is critical for AF-2 function, and mutagenesis studies suggest that coactivator interactions with the ER may depend on the integrity of this activation region. buy diabetes drugs
The importance of this tyrosine (tyrosine537 in human ER, tyrosine541 in mouse ER) for ER function is highlighted by site-directed mutagenesis studies in which amino acid substitutions (serine or alanine for tyrosine537 in human ER; aspartic acid, glutamic acid, or alanine for tyrosine541 in mouse ER) create constitutively active ER mutants. In contrast to wild-type ER, these receptor mutants interact with coactivator proteins such as SRC-1, RIP 140, TIF1, and to a lesser extent ERAP140 in the absence of hormone. Taken together, these data suggest that tyrosine537 and the adjacent amphipathic helix form a conformation-dependent interaction surface for coactivators, and that this region is important for ER transcriptional activity.
Fig1Cross-talk between
FIG. 1. Full-length human ER is composed of 595 amino acids. The location of the DNA (domain C) and ligand binding (domain E) regions are indicated. The position of the amino-terminal (Activation Function-1) and carboxyl-terminal (Activation Function-2) activation domains also are shown. The position of the five known phosphorylation sites in human ER are represented by “P.” (Ser, serine; Tyr, tyrosine).

Fig2Cross-talk between
FIG. 2. Schematic representation of an МАРК signaling pathway. Binding of growth factors to their cognate receptors results in the intracellular activation of а МАРК signal transduction cascade that ultimately influences the transcriptional activity of the ER.

This entry was posted in Growth Factor and tagged Estrogen, Peptide Growth Factor, Receptor, Signaling.