Activation of the ER by estrogenic ligands is associated with increases in overall receptor phosphorylation. Using a combination of direct (amino acid and radiolabel sequencing) and indirect (deletion and site-directed mutagenesis) approaches, five phosphorylation sites have been mapped within the human ER (Fig. 1). Four of these sites (serine104, serine106, serine118, and serine167) are located in the A/В domain while the fifth site (tyrosine537) is located within the ligand binding domain. buy asthma inhalers
The phosphorylation of the amino-terminal serine sites is hor-mone-inducible, and it has been proposed by several laboratory groups that serine118 is the major estrogen-inducible phosphorylation site in ER isolated from COS-1 cells, while another group has reported that serine167 fulfills this role in MCF-7 cells. Mutation of three of the amino-terminal phosphorylation sites (serine104, serine106, and serine118) to alanine residues significantly reduces ER transcriptional activity and highlights the importance of these amino acids for full receptor function. An explanation for the presence of two distinct, major hor-mone-inducible phosphorylation sites has not been established, but it is possible that phosphoacceptor site usage may be related to the different cell types used in these studies. In support of this, it has been demonstrated that the extent to which phosphorylation mutants affect ER transcriptional activity varies with both cell type and promoter context.