Estrogen receptor alpha (ERa, ER, ESR, ESRA, Era, NR3A1, estrogen receptor 1) is a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding and activation of transcription. Alternative splicing results in several ERa mRNA transcripts, which differ primarily in their 5' untranslated regions. ERa undergoes phosphorylation in response to estradiol binding. Human ERa is predominately phosphorylated on Ser 118 and to a lesser extent on Ser 104 and Ser 106. In response to activation of the mitogen-activated protein kinase pathway, phosphorylation occurs on Ser 118 and Ser 167. These serine residues are all located within the activation function 1 region of the N-terminal domain of ERa. In contrast, activation of protein kinase A increases the phosphorylation of Ser 236, which is located in the DNA-binding domain. Src kinase-dependent Tyr 537 phosphorylation may enhance estrogen binding to ERa. Mutation of Tyr 537 of the human ERa produces receptors having a range of constitutive activity.
