Figure 1

Estrogen receptor functional domains and signal transduction schemes. (a) Different domains of estrogen receptor (ER). Both ERα and ERβ isoforms consist of five functional domains: an N-terminal A/B domain, a DNA binding domain (DBD), a hinge domain, a ligand binding domain (LBD) and a C-terminal domain. The A/B domain contains a constitutively active, estrogen-independent, transcriptional activation domain (activation function 1 (AF1)) and is involved in co-activator binding and transcriptional activation of target genes. The DBD contains two zinc finger motives by which binding of the receptor to the estrogen response elements (ERE) of target genes is mediated. This domain contributes to dimerization and activation of the receptor. The LBD consists of 12 α-helices that form a hydrophobic pocket, responsible for ligand binding. In addition, the LBD contains an estrogen-responsive transcriptional activation domain (activation function 2 (AF2)). The region between the LBD and the DBD is called the hinge region. Finally, the C-terminal domain is probably involved in differentiating between agonists and antagonists. (b) ER signal pathway. In the classical genomic pathway, ER binds directly to the DNA. Estradiol (E2) binds to ER, which induces the release of heat shock protein (hsp) 90. ER dimerizes and translocates to the nucleus, where it can bind to EREs. The nonclassical genomic pathway differs from the classical genomic signaling pathway in that ER does not bind to the DNA directly, but the ER dimer interacts with other transcription factors that bind to the DNA. As such, other subsets of genes are regulated. In the nongenomic pathway, ER does not stimulate transcription by binding to the DNA but ER activates a subset of secondary signaling pathways: ER binds to the p85α regulator subunit leading to activation of phosphatidylinositol-3 kinase (PI3K)/Akt. Another mechanism in which ERa regulates the cell in a nongenomic signaling pathway is by activating Ras, which activates the mitogen-activated protein kinase (MAPK) and PI3K signaling pathway. MEKK, MAPK/Erk kinase; P, Phosphogroup; RAF, RAF proto-oncogene serine/threonine-protein kinase; RAS, Rat sarcoma; TF, transcription factor.